PART 1 – APPLICANT DETAILS
Application FormGenomic testing for the diagnosis of neuromuscular disordersThis application form is to be completed for new and amended requests for public funding (including but not limited to the Medicare Benefits Schedule (MBS)). It describes the detailed information that the Australian Government Department of Health requires in order to determine whether a proposed medical service is suitable.Please use this template, along with the associated Application Form Guidelines to prepare your application. Please complete all questions that are applicable to the proposed service, providing relevant information only. Applications not completed in full will not be accepted.Should you require any further assistance, departmental staff are available through the Health Technology Assessment Team (HTA Team) on the contact numbers and email below to discuss the application form, or any other component of the Medical Services Advisory Committee process.Phone: +61 2 6289 7550Fax: +61 2 6289 5540Email: hta@.auWebsite: .au PART 1 – APPLICANT DETAILSApplicant details (primary and alternative contacts)Corporation / partnership details (where relevant): Corporation name: The Royal College of Pathologists of AustralasiaABN: 52 000 173 231Business trading name: The Royal College of Pathologists of AustralasiaPrimary contact name: REDACTEDPrimary contact numbersBusiness: REDACTEDMobile:REDACTEDEmail: REDACTEDAlternative contact name: REDACTEDAlternative contact numbersBusiness: REDACTEDMobile: REDACTEDEmail: REDACTEDAlternative contact name: REDACTEDAlternative contact numbersBusiness: Mobile: REDACTEDEmail: REDACTED (a) Are you a lobbyist acting on behalf of an Applicant? FORMCHECKBOX Yes FORMCHECKBOX No If yes, are you listed on the Register of Lobbyists? FORMCHECKBOX Yes FORMCHECKBOX No PART 2 – INFORMATION ABOUT THE PROPOSED MEDICAL SERVICEApplication title Genetic testing for the diagnosis of neuromuscular disorders.Provide a succinct description of the medical condition relevant to the proposed service (no more than 150 words – further information will be requested at Part F of the Application Form)Neuromuscular disorders (NMDs) are a broad range of disorders. NMDs can be roughly allocated into four categories: muscle disorders such as Duchenne muscular dystrophy (DMD); motor neuron disorders including spinal muscular atrophies (SMAs); neuropathies such as Charcot-Marie-Tooth disease (CMT); and neuromuscular junction disorders ADDIN EN.CITE <EndNote><Cite><Author>Arnold</Author><Year>2012</Year><RecNum>70</RecNum><IDText>22938877</IDText><DisplayText>(Arnold & Flanigan 2012)</DisplayText><record><rec-number>70</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1532399268">70</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Arnold, W. D.</author><author>Flanigan, K. M.</author></authors></contributors><auth-address>Division of Neuromuscular Disorders, Department of Neurology, Wexner Medical Center at the Ohio State University, The Ohio State University, 395 W. 12th Avenue, 7th Floor, Columbus, OH 43210, USA. William.Arnold@osumc.edu</auth-address><titles><title>A practical approach to molecular diagnostic testing in neuromuscular diseases</title><secondary-title>Phys Med Rehabil Clin N Am</secondary-title></titles><periodical><full-title>Phys Med Rehabil Clin N Am</full-title></periodical><pages>589-608</pages><volume>23</volume><number>3</number><keywords><keyword>Charcot-Marie-Tooth Disease/diagnosis/genetics</keyword><keyword>*Genetic Testing</keyword><keyword>Humans</keyword><keyword>*Molecular Diagnostic Techniques</keyword><keyword>Motor Neuron Disease/diagnosis/genetics</keyword><keyword>Muscular Dystrophies/diagnosis/genetics</keyword><keyword>Neuromuscular Diseases/*diagnosis/*genetics</keyword><keyword>Pedigree</keyword></keywords><dates><year>2012</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1558-1381 (Electronic)
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ADDIN EN.CITE.DATA (Fattahi et al 2017). Many NMDs present antenatally or in early infancy and are associated with significant disability or life-threatening complications. NMDs tend to be genetic in origin, can be inherited as autosomal dominant, autosomal recessive, X-linked, or mitochondrial traits, however, de novo pathogenic variants are also common ADDIN EN.CITE <EndNote><Cite><Author>Laing</Author><Year>2012</Year><RecNum>60</RecNum><IDText>22468856</IDText><DisplayText>(Laing 2012)</DisplayText><record><rec-number>60</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1531722525">60</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Laing, N. G.</author></authors></contributors><auth-address>Centre for Medical Research, University of Western Australia, Western Australian Institute for Medical Research, Nedlands, Western Australia, Australia. nlaing@cyllene.uwa.edu.au</auth-address><titles><title>Genetics of neuromuscular disorders</title><secondary-title>Crit Rev Clin Lab Sci</secondary-title></titles><periodical><full-title>Crit Rev Clin Lab Sci</full-title></periodical><pages>33-48</pages><volume>49</volume><number>2</number><edition>2012/04/04</edition><keywords><keyword>Humans</keyword><keyword>Mutation</keyword><keyword>Neuromuscular Diseases/ genetics</keyword></keywords><dates><year>2012</year><pub-dates><date>Mar-Apr</date></pub-dates></dates><isbn>1549-781X (Electronic)
1040-8363 (Linking)</isbn><accession-num>22468856</accession-num><urls><related-urls><url>;(Laing 2012). While historically treatment options for NMD were poor, new developments offer curative interventions or decrease morbidity and mortality ADDIN EN.CITE <EndNote><Cite><Author>Dowling</Author><Year>2018</Year><RecNum>124</RecNum><IDText>28889642</IDText><DisplayText>(Dowling et al 2018)</DisplayText><record><rec-number>124</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1537155677">124</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dowling, J. J.</author><author>D. Gonorazky H</author><author>Cohn, R. D.</author><author>Campbell, C.</author></authors></contributors><auth-address>Division of Neurology, Hospital for Sick Children, Toronto, Ontario, Canada.
Program for Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
Departments of Paediatrics and Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Department of Pediatrics, Clinical Neurological Sciences, Epidemiology, Western University, London, Ontario, Canada.</auth-address><titles><title>Treating pediatric neuromuscular disorders: The future is now</title><secondary-title>Am J Med Genet A</secondary-title></titles><periodical><full-title>Am J Med Genet A</full-title></periodical><pages>804-841</pages><volume>176</volume><number>4</number><edition>2017/09/11</edition><keywords><keyword>Charcot-Marie-Tooth disease</keyword><keyword>congenital myopathies</keyword><keyword>muscular dystrophies</keyword><keyword>neuromuscular disorders</keyword></keywords><dates><year>2018</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1552-4833 (Electronic)
1552-4825 (Linking)</isbn><accession-num>28889642</accession-num><urls><related-urls><url>;(Dowling et al 2018). Many of the new treatments for NMDs are guided by establishment of a definitive genetic diagnosis. Provide a succinct description of the proposed medical service (no more than 150 words – further information will be requested at Part 6 of the Application Form)Gene panel testing to identify pathogenic variants for genetic neuromuscular disorders in patients where clinical criteria or a family history indicate that genetic testing is warranted: As NMDs can be difficult to categorise, broad panels of genes sequenced by next generation sequencing (NGS) are considered the best option in order to capture as many potential causative variants as possible. Fewer genes on a panel would result in a reduced diagnostic rate. Based on clinical criteria, patients will be triaged to undergo testing with either a myopathy or neuropathy panel. Cascade testing of family members: Mutation-specific detection of a clinically actionable pathogenic variant previously identified in a biological relative. Prenatal genetic testing using mutation-specific detection of a clinically actionable pathogenic variant(s) previously identified in a relative.Prenatal genetic testing for NMD using gene panels: for a suspected NMD in the prenatal period with no previous genetic testing performed in the family, after appropriate counselling. (a) Is this a request for MBS funding? FORMCHECKBOX Yes FORMCHECKBOX No If yes, is the medical service(s) proposed to be covered under an existing MBS item number(s) or is a new MBS item(s) being sought altogether? FORMCHECKBOX Amendment to existing MBS item(s) FORMCHECKBOX New MBS item(s)If an amendment to an existing item(s) is being sought, please list the relevant MBS item number(s) that are to be amended to include the proposed medical service: N/AIf an amendment to an existing item(s) is being sought, what is the nature of the amendment(s)? FORMCHECKBOX An amendment to the way the service is clinically delivered under the existing item(s) FORMCHECKBOX An amendment to the patient population under the existing item(s) FORMCHECKBOX An amendment to the schedule fee of the existing item(s) FORMCHECKBOX An amendment to the time and complexity of an existing item(s) FORMCHECKBOX Access to an existing item(s) by a different health practitioner group FORMCHECKBOX Minor amendments to the item descriptor that does not affect how the service is delivered FORMCHECKBOX An amendment to an existing specific single consultation item FORMCHECKBOX An amendment to an existing global consultation item(s) FORMCHECKBOX Other (please describe below):If a new item(s) is being requested, what is the nature of the change to the MBS being sought? FORMCHECKBOX A new item which also seeks to allow access to the MBS for a specific health practitioner group FORMCHECKBOX A new item that is proposing a way of clinically delivering a service that is new to the MBS (in terms of new technology and / or population) FORMCHECKBOX A new item for a specific single consultation item FORMCHECKBOX A new item for a global consultation item(s)Is the proposed service seeking public funding other than the MBS? FORMCHECKBOX Yes FORMCHECKBOX NoIf yes, please advise:N/AWhat is the type of service: FORMCHECKBOX Therapeutic medical service FORMCHECKBOX Investigative medical service FORMCHECKBOX Single consultation medical service FORMCHECKBOX Global consultation medical service FORMCHECKBOX Allied health service FORMCHECKBOX Co-dependent technology FORMCHECKBOX Hybrid health technologyFor investigative services, advise the specific purpose of performing the service (which could be one or more of the following): FORMCHECKBOX To be used as a screening tool in asymptomatic populations FORMCHECKBOX Assists in establishing a diagnosis in symptomatic patients FORMCHECKBOX Provides information about prognosis FORMCHECKBOX Identifies a patient as suitable for therapy by predicting a variation in the effect of the therapy FORMCHECKBOX Monitors a patient over time to assess treatment response and guide subsequent treatment decisions FORMCHECKBOX A service that tests for heritable mutations in clinically affected individuals to make a genetic diagnosis and thus estimate their variation in (predisposition for) future risk of further disease and, when also appropriate, cascade testing of family members of those individuals who test positive for one or more relevant mutations, to make a genetic diagnosis and thus estimate each family member’s variation in (predisposition for) future risk of developing the clinical diseaseDoes your service rely on another medical product to achieve or to enhance its intended effect? FORMCHECKBOX Pharmaceutical / Biological FORMCHECKBOX Prosthesis or device FORMCHECKBOX No(a) If the proposed service has a pharmaceutical component to it, is it already covered under an existing Pharmaceutical Benefits Scheme (PBS) listing? FORMCHECKBOX Yes FORMCHECKBOX No If yes, please list the relevant PBS item code(s):N/AIf no, is an application (submission) in the process of being considered by the Pharmaceutical Benefits Advisory Committee (PBAC)? FORMCHECKBOX Yes (please provide PBAC submission item number below) FORMCHECKBOX NoN/AIf you are seeking both MBS and PBS listing, what is the trade name and generic name of the pharmaceutical?Trade name: Generic name: (a) If the proposed service is dependent on the use of a prosthesis, is it already included on the Prostheses List? FORMCHECKBOX Yes FORMCHECKBOX No N/AIf yes, please provide the following information (where relevant): Billing code(s): Trade name of prostheses: Clinical name of prostheses: Other device components delivered as part of the service: If no, is an application in the process of being considered by a Clinical Advisory Group or the Prostheses List Advisory Committee (PLAC)? FORMCHECKBOX Yes FORMCHECKBOX No Are there any other sponsor(s) and / or manufacturer(s) that have a similar prosthesis or device component in the Australian market place which this application is relevant to? FORMCHECKBOX Yes FORMCHECKBOX No If yes, please provide the name(s) of the sponsor(s) and / or manufacturer(s):N/APlease identify any single and / or multi-use consumables delivered as part of the service?Single use consumables: General single use laboratory consumables such as pipette tips, centrifuge tubes etcMulti-use consumables: NilPART 3 – INFORMATION ABOUT REGULATORY REQUIREMENTSThe National Association of Testing Authorities (NATA) and the Royal College of Pathologists Australasia (RCPA) oversee the regulation of massively parallel sequencing for clinical purposes. Laboratories require accreditation by a joint NATA/RCPA process to ISO 15189, and specifically accredited to provide genetic testing via massively parallel sequencing. This accreditation process covers the technical aspects of the laboratory sequencing, analysis pipelines, curation (or interpretation) of results and production of the report to a clinical standard. This allows any accredited laboratory to provide equivalent variant analysis services to a minimum standard. There are no requirements for use of specific manufacturer’s reagents, equipment or analysis pipelines.Note: A non-commercial IVD is required to be regulated but not to be listed on the ARTG: testing using an IVD would be delivered only by Approved Practising Pathologists in NATA Accredited Pathology Laboratories (as defined in MBS Pathology table) by referral only by registered Medical Practitioners (non-pathologists) in line with other tests in the MBS Pathology Table.(a) If the proposed medical service involves the use of a medical device, in-vitro diagnostic test, pharmaceutical product, radioactive tracer or any other type of therapeutic good, please provide the following details:Type of therapeutic good: In-vitro diagnostic testManufacturer’s name: N/ASponsor’s name: N/AIs the medical device classified by the TGA as either a Class III or Active Implantable Medical Device (AIMD) against the TGA regulatory scheme for devices? FORMCHECKBOX Class III FORMCHECKBOX AIMD FORMCHECKBOX N/A(a) Is the therapeutic good to be used in the service exempt from the regulatory requirements of the Therapeutic Goods Act 1989? FORMCHECKBOX Yes (If yes, please provide supporting documentation as an attachment to this application form) FORMCHECKBOX NoIf no, has it been listed or registered or included in the Australian Register of Therapeutic Goods (ARTG) by the Therapeutic Goods Administration (TGA)? FORMCHECKBOX Yes (if yes, please provide details below) FORMCHECKBOX NoARTG listing, registration or inclusion number: TGA approved indication(s), if applicable: TGA approved purpose(s), if applicable: If the therapeutic good has not been listed, registered or included in the ARTG, is the therapeutic good in the process of being considered for inclusion by the TGA? FORMCHECKBOX Yes (please provide details below) FORMCHECKBOX NoDate of submission to TGA: Estimated date by which TGA approval can be expected: TGA Application ID: TGA approved indication(s), if applicable: TGA approved purpose(s), if applicable: If the therapeutic good is not in the process of being considered for listing, registration or inclusion by the TGA, is an application to the TGA being prepared? FORMCHECKBOX Yes (please provide details below) FORMCHECKBOX NoEstimated date of submission to TGA: Proposed indication(s), if applicable: Proposed purpose(s), if applicable: PART 4 – SUMMARY OF EVIDENCEProvide an overview of all key journal articles or research published in the public domain related to the proposed service that is for your application (limiting these to the English language only). Please do not attach full text articles, this is just intended to be a summary.Type of study design*Title of journal article or research project (including any trial identifier or study lead if relevant)Short description of research (max 50 words)**Website link to journal article or research (if available)Date of publication***1.Cost-effectiveness analysisAustraliaCost-effectiveness of massively parallel sequencing for diagnosis of paediatric muscle diseasesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2hvZmllbGQ8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFy
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ADDIN EN.CITE.DATA (Schofield et al 2017)In 56 undiagnosed patients with childhood-onset muscle disorders, both NMD targeted gene panel and WES had increased diagnostic yields (from 46 to 75% for NMD panel, and 79% for WES), compared to muscle biopsy. The cost per diagnosis was reduced from US$16,495 to US$3,706 for the NMD panel and US$5,646 for WES. generation sequencing in a large cohort of patients presenting with neuromuscular disease before or at birth PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ub2RkPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Todd et al 2015)Contemporary multi-gene sequencing (NMD gene panel or WES) was used for 45 patients with fetal akinesia/hypokinesia, arthrogryposis or severe congenital myopathies from 38 unrelated Australian families A conclusive genetic diagnosis was achieved for 18 of the 38 families (47%). yieldUSAA Comprehensive Genomic Approach for Neuromuscular Diseases Gives a High Diagnostic Yield ADDIN EN.CITE <EndNote><Cite><Author>Ankala</Author><Year>2015</Year><RecNum>62</RecNum><IDText>25380242</IDText><DisplayText>(Ankala et al 2015)</DisplayText><record><rec-number>62</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1531722525">62</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ankala, A.</author><author>da Silva, C.</author><author>Gualandi, F.</author><author>Ferlini, A.</author><author>Bean, L. J.</author><author>Collins, C.</author><author>Tanner, A. K.</author><author>Hegde, M. R.</author></authors></contributors><auth-address>Department of Human Genetics, Emory University School of Medicine, Atlanta, GA.</auth-address><titles><title>A comprehensive genomic approach for neuromuscular diseases gives a high diagnostic yield</title><secondary-title>Ann Neurol</secondary-title></titles><periodical><full-title>Ann Neurol</full-title></periodical><pages>206-14</pages><volume>77</volume><number>2</number><edition>2014/11/08</edition><keywords><keyword>Computational Biology/methods</keyword><keyword>Genetic Testing/ methods</keyword><keyword>Genomics/ methods</keyword><keyword>Humans</keyword><keyword>Neuromuscular Diseases/ diagnosis/ genetics</keyword><keyword>Polymorphism, Single Nucleotide/genetics</keyword></keywords><dates><year>2015</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1531-8249 (Electronic)
0364-5134 (Linking)</isbn><accession-num>25380242</accession-num><urls><related-urls><url>;(Ankala et al 2015)Comparative studies for various genetic testing approaches indicated that NMD comprehensive panel testing has a 3-fold greater diagnostic yield (46%) than single gene testing (15–19%) and some variation may be missed by whole exome sequencing (about 18%). Targeted NMD panel is recommended as a first-tier test due to the highest clinical diagnostic yield for NMD. yieldIranImproved diagnostic yield of neuromuscular disorders applying clinical exome sequencing in patients arising from a consanguineous population PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GYXR0YWhpPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48
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ADDIN EN.CITE.DATA (Fattahi et al 2017)45 patients, mostly offspring of consanguineous marriages were examined using whole exome sequencing. Data analysis was performed to identify the most probable pathogenic rare variants in known NMD genes which led to the identification of causal variants for 33 out of 45 patients (73.3%). yieldUSADiagnostic utility of exome sequencing in the evaluation of neuromuscular disorders PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXNrZWxsPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48
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ADDIN EN.CITE.DATA (Kitamura et al 2016)42 Japanese patients referred with symptoms of muscle weakness and hypotonia neonatally and/or during childhood, and neuromuscular disorders. Muscle biopsy was performed in 16 of the 42 patients. For 34 patients, a definitive diagnosis was not yielded by conventional genetic tests. Causative genes were identified in 19/42 (45.2%) patients. yieldTaiwanExpanding genotype/phenotype of neuromuscular diseases by comprehensive target capture/NGS PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaWFuPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Tian et al 2015)Thirty-five unrelated NMD families (38 patients) with clinical and/or muscle pathologic diagnoses but without identified causative genetic defects were analysed. Deleterious mutations were found in 29 families (83%). Definitive causative mutations were identified in 21 families (60%) and likely diagnoses were established in 8 families (23%). yieldGermanyEarly-Onset Myopathies: Clinical Findings, Prevalence of Subgroups and Diagnostic Approach in a Single Neuromuscular Referral Center in Germany PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WaWxsPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Vill et al 2017)98 patients with clinical symptoms suggestive of NMD underwent genetic testing. The final diagnosis could be found in 63 out of 98 patients (64%) with molecular genetic analysis. In 55% targeted gene sequencing could establish the genetic diagnosis. yieldKoreaUtility of next generation sequencing in genetic diagnosis of early onset neuromuscular disorders PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFlPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Chae et al 2015)43 patients presenting with early onset neuromuscular disorders from unknown genetic origin were tested by NGS for 579 nuclear genes associated with myopathy. In 21 of the 43 patients, the definite genetic causes were identified (48.8%). yieldNext-generation sequencing-based molecular diagnosis of neonatal hypotonia in Chinese Population PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Wang et al 2016)In 186 neonates with hypotonia, the authors identified the genetic causes for 117 neonates by traditional detection methods or targeted NGS, achieving a high solving rate of 62.9%. = neuromuscular disease, MPS = massive parallel sequencing, WES = whole exome sequencing* Categorise study design, for example meta-analysis, randomised trials, non-randomised trial or observational study, study of diagnostic accuracy, etc. **Provide high level information including population numbers and whether patients are being recruited or in post-recruitment, including providing the trial registration number to allow for tracking purposes.*** If the publication is a follow-up to an initial publication, please advise.Identify yet to be published research that may have results available in the near future that could be relevant in the consideration of your application by MSAC (limiting these to the English language only). Please do not attach full text articles, this is just intended to be a summary.Type of study design*Title of research (including any trial identifier if relevant)Short description of research (max 50 words)**Website link to research (if available)Date***1.Case seriesGenetic Study of Familial and Sporadic ALS/Motor Neuron Disease, Miyoshi Myopathy and Other Neuromuscular DisordersNCT01459302, USAThe purpose of this study is to identify additional genes that may cause or put a person at risk for either ALS, other forms of motor neuron disease, Miyoshi Myopathy and Other NMD in the hopes of improving diagnosis and treatment. Study Completion Date October 2018* Categorise study design, for example meta-analysis, randomised trials, non-randomised trial or observational study, study of diagnostic accuracy, etc. **Provide high level information including population numbers and whether patients are being recruited or in post-recruitment.***Date of when results will be made available (to the best of your knowledge).PART 5 – CLINICAL ENDORSEMENT AND CONSUMER INFORMATIONList all appropriate professional bodies / organisations representing the group(s) of health professionals who provide the service (please attach a statement of clinical relevance from each group nominated):Royal College of Pathologists of Australasia (RCPA)Human Genetics Society of Australasia (HGSA)List any professional bodies / organisations that may be impacted by this medical service (i.e. those who provide the comparator service):It should be noted that the RCPA provides other services used in the diagnostic workup of patients suspected of having a neuromuscular disorder including: histology/immunohistochemistry/Western blot of muscle biopsy samples, testing serum levels of the enzyme, creatine kinase and analysis of the PMP22 gene for constitutional genetic abnormalities causing peripheral neuropathy.Other professional bodies:Royal Australasian College of General PractitionersRoyal Australasian College of Physicians - Paediatrics & Child Health DivisionAustralia and New Zealand Association of NeurologistsList the relevant consumer organisations relevant to the proposed medical service (please attach a letter of support for each consumer organisation nominated):Australasian Neuromuscular NetworkMuscular Dystrophy AustraliaList the relevant sponsor(s) and / or manufacturer(s) who produce similar products relevant to the proposed medical service:Not applicableNominate two experts who could be approached about the proposed medical service and the current clinical management of the service(s):Name of expert 1: REDACTEDName of expert 2: REDACTEDName of expert 3: REDACTEDPlease note that the Department may also consult with other referrers, proceduralists and disease specialists to obtain their insight.PART 6 – POPULATION (AND PRIOR TESTS), INTERVENTION, COMPARATOR, OUTCOME (PICO)PART 6a – INFORMATION ABOUT THE PROPOSED POPULATIONDefine the medical condition, including providing information on the natural history of the condition and a high-level summary of associated burden of disease in terms of both morbidity and mortality:Neuromuscular disorders (NMDs) are a broad range of generally progressive disorders affecting the peripheral nervous system, muscle and neuromuscular junctions that present with a high level of clinical and genetic heterogeneity, and overlapping phenotypes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GYXR0YWhpPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48
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ADDIN EN.CITE.DATA (Fattahi et al 2017). The common aspect of all NMD is abnormal muscle function with associated clinical burden. At the most severe end of the spectrum onset can be in utero leading to foetal akinesia, paralysis or reduced movement in utero ADDIN EN.CITE <EndNote><Cite><Author>Beecroft</Author><Year>2018</Year><RecNum>137</RecNum><DisplayText>(Beecroft et al 2018)</DisplayText><record><rec-number>137</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1544578042">137</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Beecroft, S. J.</author><author>Lombard, M.</author><author>Mowat, D.</author><author>McLean, C.</author><author>Cairns, A.</author><author>Davis, M.</author><author>Laing, N. G.</author><author>Ravenscroft, G.</author></authors></contributors><auth-address>Centre for Medical Research, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Western Australia, Australia.
Harry Perkins Institute of Medical Research, QQ Block, QEII Medical Centre, Nedlands, Western Australia, Australia.</auth-address><titles><title>Genetics of neuromuscular fetal akinesia in the genomics era</title><secondary-title>J Med Genet</secondary-title></titles><periodical><full-title>J Med Genet</full-title></periodical><pages>505-514</pages><volume>55</volume><number>8</number><dates><year>2018</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0022-2593</isbn><accession-num>29959180</accession-num><urls><related-urls><url>;(Beecroft et al 2018). Paediatric patients may present with early onset symptoms that include a delay in motor milestones, hypotonia, abnormal gait characteristics, frequent falls, respiratory difficulties, and difficulty ascending stairs or arising from the floor. Late onset or adult patients may present with loss of strength, fatigue, episodic weakness, muscle cramps, falls and difficulties with speech and swallowing PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0RvbmFsZDwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+
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ADDIN EN.CITE.DATA (McDonald 2012). Many inherited NMDs are multi-systemic, involving cardiac, respiratory, and other organ systems ADDIN EN.CITE <EndNote><Cite><Author>Kassardjian</Author><Year>2016</Year><RecNum>105</RecNum><IDText>27554703</IDText><DisplayText>(Kassardjian et al 2016)</DisplayText><record><rec-number>105</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1535426211">105</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kassardjian, C. D.</author><author>Amato, A. A.</author><author>Boon, A. J.</author><author>Childers, M. K.</author><author>Klein, C. J.</author></authors></contributors><auth-address>Policy Department, American Association of Neuromuscular & Electrodiagnostic Medicine, Rochester, Minnesota, USA.</auth-address><titles><title>The utility of genetic testing in neuromuscular disease: A consensus statement from the AANEM on the clinical utility of genetic testing in diagnosis of neuromuscular disease</title><secondary-title>Muscle Nerve</secondary-title></titles><periodical><full-title>Muscle Nerve</full-title></periodical><pages>1007-1009</pages><volume>54</volume><number>6</number><edition>2016/08/25</edition><keywords><keyword>Consensus</keyword><keyword>Genetic Testing</keyword><keyword>Humans</keyword><keyword>Neuromuscular Diseases/ diagnosis/ genetics</keyword><keyword>Societies, Medical/standards</keyword><keyword>United States</keyword><keyword>Aanem</keyword><keyword>Nm</keyword><keyword>neuromuscular</keyword><keyword>neuromuscular disease</keyword><keyword>neuromuscular medicine</keyword></keywords><dates><year>2016</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1097-4598 (Electronic)
0148-639X (Linking)</isbn><accession-num>27554703</accession-num><urls><related-urls><url>;(Kassardjian et al 2016). The significant life-long morbidities of NMD are frequently severely disabling and associated with premature mortality. The clinical and genetic heterogeneities of NMDs make disease diagnosis complicated and expensive, often involving multiple tests ADDIN EN.CITE <EndNote><Cite><Author>Ankala</Author><Year>2015</Year><RecNum>62</RecNum><IDText>25380242</IDText><DisplayText>(Ankala et al 2015)</DisplayText><record><rec-number>62</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1531722525">62</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ankala, A.</author><author>da Silva, C.</author><author>Gualandi, F.</author><author>Ferlini, A.</author><author>Bean, L. J.</author><author>Collins, C.</author><author>Tanner, A. K.</author><author>Hegde, M. R.</author></authors></contributors><auth-address>Department of Human Genetics, Emory University School of Medicine, Atlanta, GA.</auth-address><titles><title>A comprehensive genomic approach for neuromuscular diseases gives a high diagnostic yield</title><secondary-title>Ann Neurol</secondary-title></titles><periodical><full-title>Ann Neurol</full-title></periodical><pages>206-14</pages><volume>77</volume><number>2</number><edition>2014/11/08</edition><keywords><keyword>Computational Biology/methods</keyword><keyword>Genetic Testing/ methods</keyword><keyword>Genomics/ methods</keyword><keyword>Humans</keyword><keyword>Neuromuscular Diseases/ diagnosis/ genetics</keyword><keyword>Polymorphism, Single Nucleotide/genetics</keyword></keywords><dates><year>2015</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1531-8249 (Electronic)
0364-5134 (Linking)</isbn><accession-num>25380242</accession-num><urls><related-urls><url>;(Ankala et al 2015). While historically treatment options for NMD were poor, new developments offer curative interventions or improvements decreasing morbidity and mortality ADDIN EN.CITE <EndNote><Cite><Author>Dowling</Author><Year>2018</Year><RecNum>124</RecNum><IDText>28889642</IDText><DisplayText>(Dowling et al 2018)</DisplayText><record><rec-number>124</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1537155677">124</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dowling, J. J.</author><author>D. Gonorazky H</author><author>Cohn, R. D.</author><author>Campbell, C.</author></authors></contributors><auth-address>Division of Neurology, Hospital for Sick Children, Toronto, Ontario, Canada.
Program for Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
Departments of Paediatrics and Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Department of Pediatrics, Clinical Neurological Sciences, Epidemiology, Western University, London, Ontario, Canada.</auth-address><titles><title>Treating pediatric neuromuscular disorders: The future is now</title><secondary-title>Am J Med Genet A</secondary-title></titles><periodical><full-title>Am J Med Genet A</full-title></periodical><pages>804-841</pages><volume>176</volume><number>4</number><edition>2017/09/11</edition><keywords><keyword>Charcot-Marie-Tooth disease</keyword><keyword>congenital myopathies</keyword><keyword>muscular dystrophies</keyword><keyword>neuromuscular disorders</keyword></keywords><dates><year>2018</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1552-4833 (Electronic)
1552-4825 (Linking)</isbn><accession-num>28889642</accession-num><urls><related-urls><url>;(Dowling et al 2018). However, novel treatments for NMD are guided by the underlying molecular pathology and establishment of a specific genetic diagnosis.Neuromuscular disorders can be roughly allocated into four categories: muscle disorders such as Duchenne muscular dystrophy (DMD); motor neuron disorders including spinal muscular atrophies (SMAs); neuropathies such as Charcot-Marie-Tooth disease (CMT); and neuromuscular junction disorders ADDIN EN.CITE <EndNote><Cite><Author>Arnold</Author><Year>2012</Year><RecNum>70</RecNum><IDText>22938877</IDText><DisplayText>(Arnold & Flanigan 2012)</DisplayText><record><rec-number>70</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1532399268">70</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Arnold, W. D.</author><author>Flanigan, K. M.</author></authors></contributors><auth-address>Division of Neuromuscular Disorders, Department of Neurology, Wexner Medical Center at the Ohio State University, The Ohio State University, 395 W. 12th Avenue, 7th Floor, Columbus, OH 43210, USA. William.Arnold@osumc.edu</auth-address><titles><title>A practical approach to molecular diagnostic testing in neuromuscular diseases</title><secondary-title>Phys Med Rehabil Clin N Am</secondary-title></titles><periodical><full-title>Phys Med Rehabil Clin N Am</full-title></periodical><pages>589-608</pages><volume>23</volume><number>3</number><keywords><keyword>Charcot-Marie-Tooth Disease/diagnosis/genetics</keyword><keyword>*Genetic Testing</keyword><keyword>Humans</keyword><keyword>*Molecular Diagnostic Techniques</keyword><keyword>Motor Neuron Disease/diagnosis/genetics</keyword><keyword>Muscular Dystrophies/diagnosis/genetics</keyword><keyword>Neuromuscular Diseases/*diagnosis/*genetics</keyword><keyword>Pedigree</keyword></keywords><dates><year>2012</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1558-1381 (Electronic)
1047-9651 (Linking)</isbn><accession-num>22938877</accession-num><urls><related-urls><url>;(Arnold & Flanigan 2012) It should be noted that genetic heterogeneity exists not only for NMDs as a group but also within the subgroups. For example, there are over 20 genes implicated in autosomal recessive limb-girdle muscular dystrophy ADDIN EN.CITE <EndNote><Cite><Author>Efthymiou</Author><Year>2016</Year><RecNum>101</RecNum><IDText>27588584</IDText><DisplayText>(Efthymiou et al 2016)</DisplayText><record><rec-number>101</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1535426211">101</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Efthymiou, S.</author><author>Manole, A.</author><author>Houlden, H.</author></authors></contributors><auth-address>aDepartment of Molecular NeurosciencebMRC Centre for Neuromuscular Diseases.</auth-address><titles><title>Next-generation sequencing in neuromuscular diseases</title><secondary-title>Curr Opin Neurol</secondary-title></titles><periodical><full-title>Curr Opin Neurol</full-title></periodical><pages>527-36</pages><volume>29</volume><number>5</number><edition>2016/09/03</edition><keywords><keyword>Exome</keyword><keyword>Genome</keyword><keyword>High-Throughput Nucleotide Sequencing</keyword><keyword>Humans</keyword><keyword>Neuromuscular Diseases/ diagnosis/genetics</keyword></keywords><dates><year>2016</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1473-6551 (Electronic)
1350-7540 (Linking)</isbn><accession-num>27588584</accession-num><urls><related-urls><url>;(Efthymiou et al 2016). The common features of types of neuromuscular disorders are summarised in REF _Ref523315770 \h Table 1. They tend to be mostly genetic in origin, can be inherited as autosomal dominant, autosomal recessive, X-linked or mitochondrial traits, however, de novo pathogenic variants are relatively common (up to 30% for DMD ADDIN EN.CITE <EndNote><Cite><Author>Darras</Author><Year>2018</Year><RecNum>25</RecNum><DisplayText>(Darras et al 2018)</DisplayText><record><rec-number>25</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1530505219">25</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Darras, B.T.</author><author>Urion, D.K.</author><author>Ghosh, P.S.</author></authors><secondary-authors><author>Adam, M.P.</author><author>Ardinger, H.H.</author><author>Pagon, R.A.</author></secondary-authors></contributors><titles><title>Dystrophinopathies</title><secondary-title>GeneReviews?</secondary-title></titles><volume>2018</volume><number>2nd July</number><dates><year>2018</year></dates><pub-location>Seattle</pub-location><publisher>University of Washington</publisher><urls><related-urls><url>;(Darras et al 2018)) ADDIN EN.CITE <EndNote><Cite><Author>Laing</Author><Year>2012</Year><RecNum>60</RecNum><IDText>22468856</IDText><DisplayText>(Laing 2012)</DisplayText><record><rec-number>60</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1531722525">60</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Laing, N. G.</author></authors></contributors><auth-address>Centre for Medical Research, University of Western Australia, Western Australian Institute for Medical Research, Nedlands, Western Australia, Australia. nlaing@cyllene.uwa.edu.au</auth-address><titles><title>Genetics of neuromuscular disorders</title><secondary-title>Crit Rev Clin Lab Sci</secondary-title></titles><periodical><full-title>Crit Rev Clin Lab Sci</full-title></periodical><pages>33-48</pages><volume>49</volume><number>2</number><edition>2012/04/04</edition><keywords><keyword>Humans</keyword><keyword>Mutation</keyword><keyword>Neuromuscular Diseases/ genetics</keyword></keywords><dates><year>2012</year><pub-dates><date>Mar-Apr</date></pub-dates></dates><isbn>1549-781X (Electronic)
1040-8363 (Linking)</isbn><accession-num>22468856</accession-num><urls><related-urls><url>;(Laing 2012). Approximately 761 different NMD disorders exist associated with >500 known genes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GYXR0YWhpPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48
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ADDIN EN.CITE.DATA (Fattahi et al 2017) (see Neuromuscular Disorders Gene Table website musclegenetable.fr).Table SEQ Table \* ARABIC 1Common features of hereditary neuromuscular disorders ADDIN EN.CITE <EndNote><Cite><Author>Arnold</Author><Year>2012</Year><RecNum>70</RecNum><IDText>22938877</IDText><DisplayText>(Arnold & Flanigan 2012)</DisplayText><record><rec-number>70</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1532399268">70</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Arnold, W. D.</author><author>Flanigan, K. M.</author></authors></contributors><auth-address>Division of Neuromuscular Disorders, Department of Neurology, Wexner Medical Center at the Ohio State University, The Ohio State University, 395 W. 12th Avenue, 7th Floor, Columbus, OH 43210, USA. William.Arnold@osumc.edu</auth-address><titles><title>A practical approach to molecular diagnostic testing in neuromuscular diseases</title><secondary-title>Phys Med Rehabil Clin N Am</secondary-title></titles><periodical><full-title>Phys Med Rehabil Clin N Am</full-title></periodical><pages>589-608</pages><volume>23</volume><number>3</number><keywords><keyword>Charcot-Marie-Tooth Disease/diagnosis/genetics</keyword><keyword>*Genetic Testing</keyword><keyword>Humans</keyword><keyword>*Molecular Diagnostic Techniques</keyword><keyword>Motor Neuron Disease/diagnosis/genetics</keyword><keyword>Muscular Dystrophies/diagnosis/genetics</keyword><keyword>Neuromuscular Diseases/*diagnosis/*genetics</keyword><keyword>Pedigree</keyword></keywords><dates><year>2012</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1558-1381 (Electronic)
1047-9651 (Linking)</isbn><accession-num>22938877</accession-num><urls><related-urls><url>;(Arnold & Flanigan 2012)Neuromuscular disorderCommon featuresMyopathiesMuscular dystrophyUsually proximal predominant weaknessDistal myopathyDistal muscle weaknessCongenital myopathyEarly onset with mostly static or slowly progressive weaknessMetabolic myopathySlowly progressive or dynamic symptoms of weakness ± exertional rhabdomyolysis and muscle contractureMitochondrial myopathiesWeakness ± other systemic features of mitochondrial cytopathyMuscle channelopathyFluctuating symptoms of muscle stiffness (myotonia) or weaknessMotor neuronProximal spinal muscular atrophyLower motor neuron dysfunction with proximal muscle weaknessFamilial amyotrophic lateral sclerosisMixed lower and upper motor neuron dysfunction Distal spinal muscular atrophyDistal muscle weaknessSpinobulbar muscular atrophyLower motor neuron dysfunction with proximal limb and bulbar weaknessNeuropathyCharcot-Marie-ToothDistal sensory loss and muscle weaknessHereditary sensory & autonomic neuropathySensory loss, variable autonomic dysfunction, usually less prominent weaknessDistal hereditary motor neuropathyDistal weakness, occasional mild sensory lossFocal/multifocal neuropathyRecurrent bouts of focal sensory loss and weaknessNerve channelopathyGeneralised neuropathy with variable features of sensory loss or painNeuromuscular junction disorderCongenital myasthenic syndromesFluctuating weaknessIt is impossible to describe the clinical characteristics of all neuromuscular disorders within the confines of this application. The disease burden and epidemiology are presented below in accordance with the major NMD categories. Muscle disorders (myopathies) Possibly the best characterised myopathies are the muscular dystrophies Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). DMD and BMD are X-linked recessive disorders, and therefore occur mostly in males. They are caused by mutations in the DMD gene ADDIN EN.CITE <EndNote><Cite><Author>Flanigan</Author><Year>2014</Year><RecNum>3</RecNum><IDText>25037084</IDText><DisplayText>(Flanigan 2014)</DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1529989303">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Flanigan, K. M.</author></authors></contributors><auth-address>Center for Gene Therapy, Room 3014, The Research Institute of Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43209, USA. Electronic address: kevin.flanigan@.</auth-address><titles><title>Duchenne and Becker muscular dystrophies</title><secondary-title>Neurol Clin</secondary-title></titles><periodical><full-title>Neurol Clin</full-title></periodical><pages>671-88, viii</pages><volume>32</volume><number>3</number><edition>2014/07/20</edition><keywords><keyword>Dystrophin/genetics/metabolism</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Muscular Dystrophy, Duchenne/ diagnosis/genetics/metabolism/ therapy</keyword><keyword>Becker muscular dystrophy</keyword><keyword>Duchenne muscular dystrophy</keyword><keyword>Dystrophin</keyword><keyword>Exon skipping</keyword></keywords><dates><year>2014</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1557-9875 (Electronic)
0733-8619 (Linking)</isbn><accession-num>25037084</accession-num><urls></urls><electronic-resource-num>10.1016/j.ncl.2014.05.002</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Flanigan 2014), which encodes dystrophin, a protein primarily located in skeletal and cardiac muscles ADDIN EN.CITE <EndNote><Cite><Author>NIH</Author><Year>2017</Year><RecNum>56</RecNum><DisplayText>(NIH 2017)</DisplayText><record><rec-number>56</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1530591160">56</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>NIH,</author></authors></contributors><titles><title>DMD gene</title></titles><volume>2018</volume><number>3rd July</number><dates><year>2017</year></dates><pub-location>Maryland, USA</pub-location><publisher>U.S. National Library of Medicine</publisher><urls><related-urls><url>;(NIH 2017). The incidence of DMD is approximately 1:5,000 live births PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SeWRlcjwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Ryder et al 2017). DMD presents with delayed motor milestones in early childhood, with a rapid progressive deterioration of muscle tissue and resultant weakness occurring before the teen years. Cardiomyopathy affects almost all DMD patients and is a common cause of death, usually by 20-30 years of age. BMD is a less common and less severe form of disease than DMD, with a highly variable phenotype characterised by later-onset skeletal muscle weakness, presenting typically between 5-15 years of age. BMD patients tend to live longer than those with DMD, with heart failure from cardiomyopathy being a common cause of death usually in the mid-40s ADDIN EN.CITE <EndNote><Cite><Author>Darras</Author><Year>2018</Year><RecNum>25</RecNum><DisplayText>(Darras et al 2018)</DisplayText><record><rec-number>25</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1530505219">25</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Darras, B.T.</author><author>Urion, D.K.</author><author>Ghosh, P.S.</author></authors><secondary-authors><author>Adam, M.P.</author><author>Ardinger, H.H.</author><author>Pagon, R.A.</author></secondary-authors></contributors><titles><title>Dystrophinopathies</title><secondary-title>GeneReviews?</secondary-title></titles><volume>2018</volume><number>2nd July</number><dates><year>2018</year></dates><pub-location>Seattle</pub-location><publisher>University of Washington</publisher><urls><related-urls><url>;(Darras et al 2018). Other muscular dystrophies besides dystrophinopathes include:Congenital muscular dystrophy: a heterogeneous group of early-onset muscular dystrophies. Affected children are usually symptomatic at birth or in the first 6 months. Congenital muscular dystrophy is characterised by hypotonia, muscle weakness, and reduced deep tendon reflexes, with or without joint contractures. Feeding and respiratory insufficiency are common; additional features may include microcephaly, eye anomalies, cerebral malformation, joint laxity, muscle atrophy, or hypertrophy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWg8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (Mah et al 2016; Menezes & North 2012).Emery-Dreifuss muscular dystrophies are associated with joint contractions, scapulo-peroneal weakness, and cardiac involvement with variable severity and progression, frequently leading to premature mortality ADDIN EN.CITE <EndNote><Cite><Author>Bonne</Author><Year>2014</Year><RecNum>127</RecNum><IDText>24755165</IDText><DisplayText>(Bonne 2014)</DisplayText><record><rec-number>127</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1537162506">127</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bonne, G.</author></authors></contributors><auth-address>Sorbonne Universites, UPMC Univ Paris 06, INSERM U974, CNRS FRE 3617, Center of Research in Myology, Institut de Myologie, Paris F-75013, France; Assistance Publique-Hopitaux de Paris, Groupe Hospitalier Pitie-Salpetriere, U.F. Cardiogenetique et Myogenetique, Service de Biochimie Metabolique, Paris F-75013, France. Electronic address: g.bonne@institut-.</auth-address><titles><title>Nuclear envelope proteins in health and diseases</title><secondary-title>Semin Cell Dev Biol</secondary-title></titles><periodical><full-title>Semin Cell Dev Biol</full-title></periodical><pages>93-4</pages><volume>29</volume><edition>2014/04/24</edition><keywords><keyword>Humans</keyword><keyword>Male</keyword><keyword>Membrane Proteins/ metabolism</keyword><keyword>Muscular Dystrophy, Emery-Dreifuss/genetics/pathology</keyword><keyword>Nuclear Envelope/ metabolism</keyword><keyword>Nuclear Lamina/ metabolism/pathology</keyword><keyword>Nuclear Proteins/ metabolism</keyword></keywords><dates><year>2014</year><pub-dates><date>May</date></pub-dates></dates><isbn>1096-3634 (Electronic)
1084-9521 (Linking)</isbn><accession-num>24755165</accession-num><urls></urls><electronic-resource-num>10.1016/j.semcdb.2014.04.023</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Bonne 2014).Facioscapulohumeral muscular dystrophy Type 1 (FSHD1) is a relatively common muscular dystrophy caused by deletion of an exact number of the 3.3kb D4Z4 repeats close to the telomere of the long arm of chromosome 4 ADDIN EN.CITE <EndNote><Cite><Author>Hewitt</Author><Year>1994</Year><RecNum>143</RecNum><IDText>7987304</IDText><DisplayText>(Hewitt et al 1994)</DisplayText><record><rec-number>143</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1562717877">143</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hewitt, J. E.</author><author>Lyle, R.</author><author>Clark, L. N.</author><author>Valleley, E. M.</author><author>Wright, T. J.</author><author>Wijmenga, C.</author><author>van Deutekom, J. C.</author><author>Francis, F.</author><author>Sharpe, P. T.</author><author>Hofker, M.</author><author>et al.,</author></authors></contributors><auth-address>School of Biological Sciences, University of Manchester, UK.</auth-address><titles><title>Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy</title><secondary-title>Hum Mol Genet</secondary-title></titles><periodical><full-title>Hum Mol Genet</full-title></periodical><pages>1287-95</pages><volume>3</volume><number>8</number><edition>1994/08/01</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Animals</keyword><keyword>Base Sequence</keyword><keyword>Chromosome Mapping</keyword><keyword>Cloning, Molecular</keyword><keyword>Genes, Homeobox/genetics</keyword><keyword>Humans</keyword><keyword>In Situ Hybridization, Fluorescence</keyword><keyword>Molecular Sequence Data</keyword><keyword>Muscular Dystrophies/ genetics</keyword><keyword>Repetitive Sequences, Nucleic Acid</keyword><keyword>Restriction Mapping</keyword></keywords><dates><year>1994</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0964-6906 (Print)
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ADDIN EN.CITE.DATA (Mah et al 2016; Menezes & North 2012).It should be noted that myotonic dystrophy (DM1), an autosomal dominant dystrophy associated with clinical myotonia, progressive muscular weakness, and extra-muscular manifestations such as cardiac arrhythmia and endocrine dysfunction, is not detected by the genetic panel described in this application, and will therefore not be discussed further. Myotonic dystrophy is caused by the expansion of CTG repeats in the DMPK gene and is best diagnosed/detected with the use of triplet primed PCR ADDIN EN.CITE <EndNote><Cite><Author>Kumara</Author><Year>2018</Year><RecNum>157</RecNum><DisplayText>(Kumara et al 2018)</DisplayText><record><rec-number>157</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1562735307">157</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kumara, A.</author><author>Agarwala, S.</author><author>Pradhan, S.</author></authors></contributors><titles><title>Molecular and clinical spectrum of type 1 myotonic dystrophy</title><secondary-title>Gene Reports</secondary-title></titles><periodical><full-title>Gene Reports</full-title></periodical><pages>34-41</pages><volume>11</volume><dates><year>2018</year></dates><urls></urls><electronic-resource-num>;(Kumara et al 2018).Congenital myopathiesThe congenital myopathies are another large group of muscle disorders, usually presenting at birth, though presentation may be in utero causing foetal akinesia or may be much later in life. Many of the causative genes for the congenital myopathies code for protein components of the sarcomere PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYXZlbnNjcm9mdDwvQXV0aG9yPjxZZWFyPjIwMTU8L1ll
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ADDIN EN.CITE.DATA (Ravenscroft et al 2015). Motor neuron disorders Motor neuron disorders include spinal muscular atrophies (SMAs) and amyotrophic lateral sclerosis (ALS), also known as motor neurone disease, or Lou Gehrig's disease. SMA is one of the most common fatal childhood disorders with prevalence in the general population of 1:6,000 to 1:10,000 live births per year ADDIN EN.CITE <EndNote><Cite><Author>Pearn</Author><Year>1978</Year><RecNum>125</RecNum><IDText>745211</IDText><DisplayText>(Pearn 1978)</DisplayText><record><rec-number>125</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1537161419">125</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pearn, J.</author></authors></contributors><titles><title>Incidence, prevalence, and gene frequency studies of chronic childhood spinal muscular atrophy</title><secondary-title>J Med Genet</secondary-title></titles><periodical><full-title>J Med Genet</full-title></periodical><pages>409-13</pages><volume>15</volume><number>6</number><edition>1978/12/01</edition><keywords><keyword>Child, Preschool</keyword><keyword>England</keyword><keyword>Female</keyword><keyword>Gene Frequency</keyword><keyword>Genes, Recessive</keyword><keyword>Genetic Carrier Screening</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Muscular Atrophy/epidemiology/ genetics</keyword><keyword>Sex Factors</keyword></keywords><dates><year>1978</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0022-2593 (Print)
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ADDIN EN.CITE.DATA (Arnold et al 2015; Menezes & North 2012). Genomic testing cannot detect the classic SMA caused by deletion of SMN1 due to the variable copy number of SMN1 and the closely related neighbouring SMN2, but can detect the other SMAs. ALS is characterised by the degeneration of motor neurons in the brain, brainstem and spinal cord that control voluntary and involuntary muscles. Presenting symptoms include limb weakness, weakness of speaking, swallowing and breathing muscles, in addition to muscle spasticity, loss of dexterity and difficulty walking. Most ALS cases are sporadic but 5-10% of cases are familial ADDIN EN.CITE <EndNote><Cite><Author>Bhatt</Author><Year>2016</Year><RecNum>130</RecNum><IDText>27720006</IDText><DisplayText>(Bhatt 2016)</DisplayText><record><rec-number>130</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1542599247">130</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bhatt, J. M.</author></authors></contributors><auth-address>Department of Neurology, New York University School of Medicine, 240 East 38th Street, 20th Floor, New York, NY 10016, USA. Electronic address: jaydeep.bhatt@.</auth-address><titles><title>The Epidemiology of Neuromuscular Diseases</title><secondary-title>Neurol Clin</secondary-title></titles><periodical><full-title>Neurol Clin</full-title></periodical><pages>999-1021</pages><volume>34</volume><number>4</number><edition>2016/10/11</edition><keywords><keyword>Cost of Illness</keyword><keyword>Global Health</keyword><keyword>Humans</keyword><keyword>Neuromuscular Diseases/classification/ epidemiology/genetics</keyword><keyword>Public Health</keyword><keyword>Risk Factors</keyword><keyword>Burden of disease</keyword><keyword>Epidemiology</keyword><keyword>Neuromuscular disease</keyword></keywords><dates><year>2016</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1557-9875 (Electronic)
0733-8619 (Linking)</isbn><accession-num>27720006</accession-num><urls></urls><electronic-resource-num>10.1016/j.ncl.2016.06.017</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Bhatt 2016). The disease ultimately leads to atrophy and impairment of the limb muscles with a proportion of patients progressing to dysphagia, ventilatory compromise, and sialorrhea. Although ALS can affect people of any age, symptoms are usually noted at around 60 years; however, for inherited cases this is usually younger (50 years), with an average survival from onset to death of 2-4 years ADDIN EN.CITE <EndNote><Cite><Author>Khairoalsindi</Author><Year>2018</Year><RecNum>117</RecNum><IDText>30159171</IDText><DisplayText>(Khairoalsindi & Abuzinadah 2018)</DisplayText><record><rec-number>117</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1535941933">117</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Khairoalsindi, O. A.</author><author>Abuzinadah, A. R.</author></authors></contributors><auth-address>Umm Al-Qura University, College of Medicine, Makkah, Saudi Arabia.
King Abdulaziz University, Internal Medicine Department, Neurology Division, Jeddah, Saudi Arabia.</auth-address><titles><title>Maximizing the Survival of Amyotrophic Lateral Sclerosis Patients: Current Perspectives</title><secondary-title>Neurol Res Int</secondary-title></titles><periodical><full-title>Neurol Res Int</full-title></periodical><pages>6534150</pages><volume>2018</volume><edition>2018/08/31</edition><dates><year>2018</year></dates><isbn>2090-1852 (Print)
2090-1860 (Linking)</isbn><accession-num>30159171</accession-num><urls><related-urls><url>;(Khairoalsindi & Abuzinadah 2018). Juvenile ALS is a very rare severe motor neuron disease that is characterised by progressive upper and lower motor neuron degeneration. Onset of JALS occurs during early childhood at a mean age of 6.5 years (range 3-20 years). Patients develop motor neuron degeneration leading to facial muscle spasticity, spastic dysarthria, and spastic gait, with mild atrophy of the legs and hands observed in some cases ADDIN EN.CITE <EndNote><Cite><Author>Orphanet</Author><Year>2018</Year><RecNum>139</RecNum><DisplayText>(Orphanet 2018)</DisplayText><record><rec-number>139</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1544588103">139</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Orphanet</author></authors></contributors><titles><title>Juvenile amyotrophic lateral sclerosis</title><secondary-title>The portal for rare diseases and orphan drugs</secondary-title></titles><volume>2018</volume><number>12th December</number><dates><year>2018</year></dates><publisher>Orphanet</publisher><urls><related-urls><url>(s)/group%20of%20diseases=Juvenile-amyotrophic-lateral-sclerosis&title=Juvenile%20amyotrophic%20lateral%20sclerosis&search=Disease_Search_Simple</url></related-urls></urls></record></Cite></EndNote>(Orphanet 2018).Peripheral neuropathies Charcot-Marie-Tooth disease (CMT), which is the most common form of inherited peripheral neuropathy, is the most prevalent hereditary neuromuscular disorder with prevalence of approximately 1:2,500 ADDIN EN.CITE <EndNote><Cite><Author>Baets</Author><Year>2014</Year><RecNum>120</RecNum><IDText>25110935</IDText><DisplayText>(Baets et al 2014)</DisplayText><record><rec-number>120</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1535945901">120</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Baets, J.</author><author>De Jonghe, P.</author><author>Timmerman, V.</author></authors></contributors><auth-address>aNeurogenetics Group bPeripheral Neuropathy Group, VIB-Department of Molecular Genetics cLaboratory of Neurogenetics, Institute Born-Bunge dDepartment of Neurology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.</auth-address><titles><title>Recent advances in Charcot-Marie-Tooth disease</title><secondary-title>Curr Opin Neurol</secondary-title></titles><periodical><full-title>Curr Opin Neurol</full-title></periodical><pages>532-40</pages><volume>27</volume><number>5</number><edition>2014/08/12</edition><keywords><keyword>Charcot-Marie-Tooth Disease/diagnosis/genetics/therapy</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Genetic Testing</keyword><keyword>Humans</keyword></keywords><dates><year>2014</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1473-6551 (Electronic)
1350-7540 (Linking)</isbn><accession-num>25110935</accession-num><urls></urls><electronic-resource-num>10.1097/wco.0000000000000131</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Baets et al 2014). CMT is a genetically heterogeneous group of inherited neuropathies, associated with sequence or copy-number variations in over 80 genes coding for proteins with strategic functions in Schwann cell or peripheral axon development and physiology, including myelin proteins, transcription factors, cytoskeletal components, and mitochondrial proteins. In Western countries with mixed ethnicities, autosomal dominant and X-linked dominant forms of CMT disease predominate. More than 90% of CMT disease cases with a molecular diagnosis are associated with pathogenic variants in 4 genes: PMP22, GJB1, MFN2, and MPZ ADDIN EN.CITE <EndNote><Cite><Author>Saporta</Author><Year>2014</Year><RecNum>121</RecNum><IDText>25299278</IDText><DisplayText>(Saporta 2014)</DisplayText><record><rec-number>121</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1535945955">121</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Saporta, M. A.</author></authors></contributors><titles><title>Charcot-Marie-Tooth disease and other inherited neuropathies</title><secondary-title>Continuum (Minneap Minn)</secondary-title></titles><periodical><full-title>Continuum (Minneap Minn)</full-title></periodical><pages>1208-25</pages><volume>20</volume><number>5 Peripheral Nervous System Disorders</number><edition>2014/10/10</edition><keywords><keyword>Charcot-Marie-Tooth Disease/ diagnosis/ genetics</keyword><keyword>Genetic Testing/methods/trends</keyword><keyword>Humans</keyword><keyword>Peripheral Nervous System Diseases/ diagnosis/ genetics</keyword></keywords><dates><year>2014</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1538-6899 (Electronic)
1080-2371 (Linking)</isbn><accession-num>25299278</accession-num><urls></urls><electronic-resource-num>10.1212/01.CON.0000455885.37169.4c</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Saporta 2014). Severity of symptoms and life expectancy varies widely. CMT is characterised by progressive distal weakness and wasting, a high stepping gait, foot deformities, absent deep tendon reflexes and distal sensory loss, with symptoms usually beginning in early childhood or early adulthood, but can also be late onset ADDIN EN.CITE <EndNote><Cite><Author>Menezes</Author><Year>2012</Year><RecNum>67</RecNum><IDText>22050238</IDText><DisplayText>(Menezes & North 2012)</DisplayText><record><rec-number>67</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1531722525">67</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Menezes, M. P.</author><author>North, K. N.</author></authors></contributors><auth-address>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.</auth-address><titles><title>Inherited neuromuscular disorders: pathway to diagnosis</title><secondary-title>J Paediatr Child Health</secondary-title></titles><periodical><full-title>J Paediatr Child Health</full-title></periodical><pages>458-65</pages><volume>48</volume><number>6</number><edition>2011/11/05</edition><keywords><keyword>Diagnosis, Differential</keyword><keyword>Genetic Testing</keyword><keyword>Humans</keyword><keyword>Medical History Taking</keyword><keyword>Muscular Dystrophies/diagnosis/genetics</keyword><keyword>Neuromuscular Diseases/ diagnosis/genetics</keyword><keyword>Physical Examination</keyword></keywords><dates><year>2012</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1440-1754 (Electronic)
1034-4810 (Linking)</isbn><accession-num>22050238</accession-num><urls><related-urls><url>;(Menezes & North 2012). CMT overlaps clinically with other disorders affecting the peripheral nerve, including some hereditary spastic paraplegias, leukodystrophies and motor neuron disorders, such as juvenile ALS. Neuromuscular junction disordersPathogenic variants in genes encoding proteins which form, regulate or function at the neuromuscular junction are associated with congenital myasthenic syndromes (CMS). CMS usually presents in infancy with a mixture of static and episodic weakness in the facial and limb/girdle muscles. The genetic heterogeneity is underlined by variants in 12 genes, with those in the acetylcholine receptor subunit epsilon (CHRNE) being the most prevalent ADDIN EN.CITE <EndNote><Cite><Author>Beeson</Author><Year>2016</Year><RecNum>126</RecNum><IDText>27472506</IDText><DisplayText>(Beeson 2016)</DisplayText><record><rec-number>126</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1537161893">126</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Beeson, D.</author></authors></contributors><auth-address>Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, The John Radcliffe Hospital, Oxford, UK.</auth-address><titles><title>Congenital myasthenic syndromes: recent advances</title><secondary-title>Curr Opin Neurol</secondary-title></titles><periodical><full-title>Curr Opin Neurol</full-title></periodical><pages>565-71</pages><volume>29</volume><number>5</number><edition>2016/07/30</edition><keywords><keyword>Glycosylation</keyword><keyword>Humans</keyword><keyword>Mutation</keyword><keyword>Myasthenic Syndromes, Congenital/ genetics/metabolism</keyword><keyword>Neuromuscular Junction/ genetics/metabolism</keyword><keyword>Receptors, Cholinergic/ genetics/metabolism</keyword><keyword>Synaptic Transmission/genetics</keyword></keywords><dates><year>2016</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1473-6551 (Electronic)
1350-7540 (Linking)</isbn><accession-num>27472506</accession-num><urls></urls><electronic-resource-num>10.1097/wco.0000000000000370</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Beeson 2016). Different pathogenic variants result in various pathogenetic disease mechanisms where therapeutic options depend on accurate identification of the underlying molecular aetiology ADDIN EN.CITE <EndNote><Cite><Author>Dowling</Author><Year>2018</Year><RecNum>124</RecNum><IDText>28889642</IDText><DisplayText>(Dowling et al 2018)</DisplayText><record><rec-number>124</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1537155677">124</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dowling, J. J.</author><author>D. Gonorazky H</author><author>Cohn, R. D.</author><author>Campbell, C.</author></authors></contributors><auth-address>Division of Neurology, Hospital for Sick Children, Toronto, Ontario, Canada.
Program for Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada.
Departments of Paediatrics and Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Department of Pediatrics, Clinical Neurological Sciences, Epidemiology, Western University, London, Ontario, Canada.</auth-address><titles><title>Treating pediatric neuromuscular disorders: The future is now</title><secondary-title>Am J Med Genet A</secondary-title></titles><periodical><full-title>Am J Med Genet A</full-title></periodical><pages>804-841</pages><volume>176</volume><number>4</number><edition>2017/09/11</edition><keywords><keyword>Charcot-Marie-Tooth disease</keyword><keyword>congenital myopathies</keyword><keyword>muscular dystrophies</keyword><keyword>neuromuscular disorders</keyword></keywords><dates><year>2018</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1552-4833 (Electronic)
1552-4825 (Linking)</isbn><accession-num>28889642</accession-num><urls><related-urls><url>;(Dowling et al 2018). Some variants in these genes, including the acetylcholine receptor subunit genes result in foetal akinesia ADDIN EN.CITE <EndNote><Cite><Author>Beecroft</Author><Year>2018</Year><RecNum>137</RecNum><DisplayText>(Beecroft et al 2018)</DisplayText><record><rec-number>137</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1544578042">137</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Beecroft, S. J.</author><author>Lombard, M.</author><author>Mowat, D.</author><author>McLean, C.</author><author>Cairns, A.</author><author>Davis, M.</author><author>Laing, N. G.</author><author>Ravenscroft, G.</author></authors></contributors><auth-address>Centre for Medical Research, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Western Australia, Australia.
Harry Perkins Institute of Medical Research, QQ Block, QEII Medical Centre, Nedlands, Western Australia, Australia.</auth-address><titles><title>Genetics of neuromuscular fetal akinesia in the genomics era</title><secondary-title>J Med Genet</secondary-title></titles><periodical><full-title>J Med Genet</full-title></periodical><pages>505-514</pages><volume>55</volume><number>8</number><dates><year>2018</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0022-2593</isbn><accession-num>29959180</accession-num><urls><related-urls><url>;(Beecroft et al 2018).Specify any characteristics of patients with the medical condition, or suspected of, who are proposed to be eligible for the proposed medical service, including any details of how a patient would be investigated, managed and referred within the Australian health care system in the lead up to being considered eligible for the service:Due to the heterogeneous nature of NMDs patients may present with many different clinical features as previously mentioned, with onset occurring at all stages of life from before birth, at birth, early to mid-childhood, right up to late adult onset. Paediatric patients suspected of having an NMD would usually be referred by their general practitioner to a paediatrician, who may then consult with a range of professions including physical therapists, neurologists and cardiologists, in addition to geneticists and genetic counsellors. Patients would undergo numerous diagnostic tests (described below) in order to ascertain a diagnosis including blood tests, physical assessments of gait and movement, muscle biopsies, electromyography (EMG), magnetic resonance imaging (MRI) or nerve conduction studies and in some cases, cardiological assessments. Adult patients would similarly be referred by their general practitioner to a neurologist. Define and summarise the current clinical management pathway before patients would be eligible for the proposed medical service (supplement this summary with an easy to follow flowchart [as an attachment to the Application Form] depicting the current clinical management pathway up to this point):The diagnosis of neuromuscular disorders traditionally involves taking a detailed patient and family history, conducting a clinical and neurophysiological assessment, followed by a pathological evaluation of muscle and/or nerve biopsy and sequential testing of individual genes ( REF _Ref530402908 \h Figure 1 REF _Ref523748009 \h ) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UZW9oPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Schofield et al 2017) Note: complementary investigations would be ordered based on the presenting phenotype of the patient. Not all complementary investigations would be conducted on all patients.The congenital myopathies are classified based on structural abnormalities on muscle biopsy, while protein abnormalities on immunohistochemistry and immunoblotting aid classification of the muscular dystrophies ADDIN EN.CITE <EndNote><Cite><Author>Menezes</Author><Year>2012</Year><RecNum>67</RecNum><IDText>22050238</IDText><DisplayText>(Menezes & North 2012)</DisplayText><record><rec-number>67</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1531722525">67</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Menezes, M. P.</author><author>North, K. N.</author></authors></contributors><auth-address>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.</auth-address><titles><title>Inherited neuromuscular disorders: pathway to diagnosis</title><secondary-title>J Paediatr Child Health</secondary-title></titles><periodical><full-title>J Paediatr Child Health</full-title></periodical><pages>458-65</pages><volume>48</volume><number>6</number><edition>2011/11/05</edition><keywords><keyword>Diagnosis, Differential</keyword><keyword>Genetic Testing</keyword><keyword>Humans</keyword><keyword>Medical History Taking</keyword><keyword>Muscular Dystrophies/diagnosis/genetics</keyword><keyword>Neuromuscular Diseases/ diagnosis/genetics</keyword><keyword>Physical Examination</keyword></keywords><dates><year>2012</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1440-1754 (Electronic)
1034-4810 (Linking)</isbn><accession-num>22050238</accession-num><urls><related-urls><url>;(Menezes & North 2012).A clinical history would include the following details:PregnancyPolyhydramnios, intrauterine movements and contracturesBirthCongenital hip dislocation, contractures, absent flexion creasesMedications given to mother (magnesium sulphate, opioids and anaesthetic agents)Neonatal period and infancyRespiratory distressHypotonia and floppinessSucking and swallowing difficultiesDistribution of the weaknessProximal, distal or globalFacial or bulbar weaknessOphthalmoplegiaFamily historyConsanguinityFamily history of a NMD and pedigree ADDIN EN.CITE <EndNote><Cite><Author>Menezes</Author><Year>2012</Year><RecNum>67</RecNum><IDText>22050238</IDText><DisplayText>(Menezes & North 2012)</DisplayText><record><rec-number>67</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1531722525">67</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Menezes, M. P.</author><author>North, K. N.</author></authors></contributors><auth-address>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.</auth-address><titles><title>Inherited neuromuscular disorders: pathway to diagnosis</title><secondary-title>J Paediatr Child Health</secondary-title></titles><periodical><full-title>J Paediatr Child Health</full-title></periodical><pages>458-65</pages><volume>48</volume><number>6</number><edition>2011/11/05</edition><keywords><keyword>Diagnosis, Differential</keyword><keyword>Genetic Testing</keyword><keyword>Humans</keyword><keyword>Medical History Taking</keyword><keyword>Muscular Dystrophies/diagnosis/genetics</keyword><keyword>Neuromuscular Diseases/ diagnosis/genetics</keyword><keyword>Physical Examination</keyword></keywords><dates><year>2012</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1440-1754 (Electronic)
1034-4810 (Linking)</isbn><accession-num>22050238</accession-num><urls><related-urls><url>;(Menezes & North 2012).A full list of recommended and potentially useful investigative tests is summarised in REF _Ref530404834 \h Table 2.DMD/BMD: The mean age of patients with suspected DMD/BMD at first clinical presentation/evaluation is 3.6 years, with a mean age at diagnosis of 4.9 years. Creatine kinase (CK) levels are elevated in both DMD and BMD patients due to the increased permeability of the sarcolemmal membrane, therefore patients suspected of DMD or BMD should have CK levels measured. It should be noted that elevated serum CK levels are present at birth in DMD/BMD patients, which offers the opportunity for newborn screening of the disorder ADDIN EN.CITE <EndNote><Cite><Author>Flanigan</Author><Year>2014</Year><RecNum>3</RecNum><IDText>25037084</IDText><DisplayText>(Flanigan 2014)</DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1529989303">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Flanigan, K. M.</author></authors></contributors><auth-address>Center for Gene Therapy, Room 3014, The Research Institute of Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43209, USA. Electronic address: kevin.flanigan@.</auth-address><titles><title>Duchenne and Becker muscular dystrophies</title><secondary-title>Neurol Clin</secondary-title></titles><periodical><full-title>Neurol Clin</full-title></periodical><pages>671-88, viii</pages><volume>32</volume><number>3</number><edition>2014/07/20</edition><keywords><keyword>Dystrophin/genetics/metabolism</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Muscular Dystrophy, Duchenne/ diagnosis/genetics/metabolism/ therapy</keyword><keyword>Becker muscular dystrophy</keyword><keyword>Duchenne muscular dystrophy</keyword><keyword>Dystrophin</keyword><keyword>Exon skipping</keyword></keywords><dates><year>2014</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1557-9875 (Electronic)
0733-8619 (Linking)</isbn><accession-num>25037084</accession-num><urls></urls><electronic-resource-num>10.1016/j.ncl.2014.05.002</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Flanigan 2014). A raised level of creatine kinase should result in referral to a neuromuscular specialist, with input from a geneticist or genetic counsellor. The gold standard of diagnosis (and for differentiating between DMD and BMD) remains muscle biopsy. Biopsy may reveal histological changes such as fibrosis, with immunohistochemical or western blot analysis used to quantify the level, including absence of dystrophin, the protein product of the DMD gene ADDIN EN.CITE <EndNote><Cite><Author>Flanigan</Author><Year>2014</Year><RecNum>3</RecNum><IDText>25037084</IDText><DisplayText>(Flanigan 2014)</DisplayText><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1529989303">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Flanigan, K. M.</author></authors></contributors><auth-address>Center for Gene Therapy, Room 3014, The Research Institute of Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43209, USA. Electronic address: kevin.flanigan@.</auth-address><titles><title>Duchenne and Becker muscular dystrophies</title><secondary-title>Neurol Clin</secondary-title></titles><periodical><full-title>Neurol Clin</full-title></periodical><pages>671-88, viii</pages><volume>32</volume><number>3</number><edition>2014/07/20</edition><keywords><keyword>Dystrophin/genetics/metabolism</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Muscular Dystrophy, Duchenne/ diagnosis/genetics/metabolism/ therapy</keyword><keyword>Becker muscular dystrophy</keyword><keyword>Duchenne muscular dystrophy</keyword><keyword>Dystrophin</keyword><keyword>Exon skipping</keyword></keywords><dates><year>2014</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1557-9875 (Electronic)
0733-8619 (Linking)</isbn><accession-num>25037084</accession-num><urls></urls><electronic-resource-num>10.1016/j.ncl.2014.05.002</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>(Flanigan 2014). Genetic sequencing has replaced the requirement for initial muscle biopsy. Diagnosis is based on these results combined with the clinical symptoms described above in Q24. Treatment for DMD or BMD would not be commenced until a definitive diagnosis by genetic sequencing PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaXJua3JhbnQ8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFy
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ADDIN EN.CITE.DATA (Birnkrant et al 2018b).Motor neuron disorders, neuropathies and congenital myasthenic syndrome: Serum CK may be normal to moderately raised (up to 5x normal) in SMAs and the congenital myopathies. Electromyography (EMG) and nerve conduction studies may help to differentiate neurogenic from myopathic weakness and to assist in the classification of neuropathy as demyelinating, axonal or intermediate and as sensorimotor or primarily motor or sensory neuropathy. The presence of a decrement in muscle action potential on repetitive nerve stimulation at low rates (2–5 Hz) is useful in identifying those with congenital or acquired myasthenia. Prolonged runs of motor unit potentials with a waxing and waning frequency and amplitude, described as resembling the sound of a motorcycle or chainsaw, may be heard on insertion of the needle electrode on EMG in older patients with myotonic dystrophy. A muscle biopsy may show evidence of chronic denervation, dystrophic change or structural abnormalities. The presence of small angular fibres, fibre-type grouping and type 2 fibre atrophy indicates chronic denervation as seen in SMAs and CMT. On the other hand, in the congenital and limb-girdle dystrophies, the muscle biopsy is characterised by diffuse variation in fibre size, necrotic and regenerating fibres and fibrosis. Nerve biopsy sections and teased fibre preparations are useful in the evaluation of neuropathies that remain genetically unclassified and may show evidence of axonal degeneration or demyelination, helping to more precisely target genetic studies. Patients with an initial clinical diagnosis of SMA based on history and clinical examination, would undergo first a single gene test for the common SMN1 deletion, bypassing other investigations including muscle or nerve biopsy ADDIN EN.CITE <EndNote><Cite><Author>Menezes</Author><Year>2012</Year><RecNum>67</RecNum><IDText>22050238</IDText><DisplayText>(Menezes & North 2012)</DisplayText><record><rec-number>67</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1531722525">67</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Menezes, M. P.</author><author>North, K. N.</author></authors></contributors><auth-address>Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.</auth-address><titles><title>Inherited neuromuscular disorders: pathway to diagnosis</title><secondary-title>J Paediatr Child Health</secondary-title></titles><periodical><full-title>J Paediatr Child Health</full-title></periodical><pages>458-65</pages><volume>48</volume><number>6</number><edition>2011/11/05</edition><keywords><keyword>Diagnosis, Differential</keyword><keyword>Genetic Testing</keyword><keyword>Humans</keyword><keyword>Medical History Taking</keyword><keyword>Muscular Dystrophies/diagnosis/genetics</keyword><keyword>Neuromuscular Diseases/ diagnosis/genetics</keyword><keyword>Physical Examination</keyword></keywords><dates><year>2012</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1440-1754 (Electronic)
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ADDIN EN.CITE.DATA (Schofield et al 2017)Neonatal/early infantile presentationEarly childhood presentationEssential investigationsBlood collection x2Blood collection x2Creatine kinaseCreatine kinaseLactate LactateAmmoniaAmmoniaUrine metabolic screenUrine metabolic screenDNA extraction and storageDNA extraction and storageChromosomal microarrayChromosomal microarrayInvestigations that may be considered depending on presentationVery long chain fatty acidsThyroid function studiesThyroid function studiesMyotonic dystrophy (DM1)Plasma amino acidsSMN1 exon copy number (SMA)Myotonic dystrophyMRI brain +/- anaesthetic and day stay admissionSMN1 exon copy number (SMA)Muscle MRI scan +/- anaesthetic and day stay admissionPrader Willi syndromeDystrophin MLPAAcetylcholine receptor antibodiesOphthalmology reviewAntibody screen for congenital infectionConnective tissue dysplasia clinic reviewLumbar puncture with lactate, amino acids and neurotransmittersHead ultrasound scanMRI brain +/- anaesthetic and day stay admissionOphthalmology reviewMLPA = multiplex ligation dependent probe amplificationPART 6b – INFORMATION ABOUT THE INTERVENTIONDescribe the key components and clinical steps involved in delivering the proposed medical service:There are four parts to the proposed medical service:1) Gene panel testing to identify pathogenic variants for genetic neuromuscular disorders in patients where clinical criteria or a family history indicate that genetic testing is warranted.2) Cascade testing of family members: using mutation-specific detection of a clinically actionable pathogenic variant previously identified in a biological relative. 3) Prenatal genetic testing using mutation-specific detection of a clinically actionable pathogenic variant(s) previously identified in a relative.4) Prenatal genetic testing for NMD using gene panels: for a suspected NMD in the prenatal period with no previous genetic testing performed in the family, after appropriate counsellingFor postnatal diagnostic or cascade testing, the patient would be required to provide a sample containing nucleated cells for DNA extraction (for example, peripheral blood, saliva, buccal swab, etc.). Testing in the prenatal period either due to a known familial cause of NMD or to a clinically suspected NMD with no prior family history requires an amniotic fluid (20ml) or chorionic villi (20mg) sample be obtained. 1) Gene panel testing to identify pathogenic variants for genetic neuromuscular disorders in patients where clinical criteria or a family history indicate that genetic testing is warranted.The proposed intervention is targeted gene panel analysis of multiple known neuromuscular disease genes using NGS to identify pathogenic variants for genetic neuromuscular disorders in patients where clinical criteria or a family history indicate that genetic testing is warranted. Over 500 disease genes are currently known for neuromuscular disorders (see Gene Table of Neuromuscular Disorders website musclegenetable.fr) and this number is increasing each year as new disease genes are being identified. Known disease genes are being associated with an increased spread of clinical phenotypes (diseases), especially through the use of diagnostic panels or diagnostic exome sequencing PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZWVjcm9mdDwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+
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ADDIN EN.CITE.DATA (Beecroft et al 2017; Cabrera-Serrano et al 2015). In addition, genes previously associated with only relatively mild dominant disease have been shown to be associated with severe disease through either recessive mutations PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aYWhhcmlldmE8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFy
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ADDIN EN.CITE.DATA (Kariminejad et al 2017). As NMDs can be difficult to categorise, a broad panel of genes is considered a better option in order to capture as many causative pathogenic variants as possible. Reducing the number of known disease genes on each panel would reduce the diagnostic yield ADDIN EN.CITE <EndNote><Cite><Author>Laing</Author><Year>2012</Year><RecNum>60</RecNum><IDText>22468856</IDText><DisplayText>(Laing 2012)</DisplayText><record><rec-number>60</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1531722525">60</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Laing, N. G.</author></authors></contributors><auth-address>Centre for Medical Research, University of Western Australia, Western Australian Institute for Medical Research, Nedlands, Western Australia, Australia. nlaing@cyllene.uwa.edu.au</auth-address><titles><title>Genetics of neuromuscular disorders</title><secondary-title>Crit Rev Clin Lab Sci</secondary-title></titles><periodical><full-title>Crit Rev Clin Lab Sci</full-title></periodical><pages>33-48</pages><volume>49</volume><number>2</number><edition>2012/04/04</edition><keywords><keyword>Humans</keyword><keyword>Mutation</keyword><keyword>Neuromuscular Diseases/ genetics</keyword></keywords><dates><year>2012</year><pub-dates><date>Mar-Apr</date></pub-dates></dates><isbn>1549-781X (Electronic)
1040-8363 (Linking)</isbn><accession-num>22468856</accession-num><urls><related-urls><url>;(Laing 2012). The proposal is to use two separate panels: a “myopathy” panel for myogenic disorders and a “neuropathy” panel which covers central and peripheral nervous system disorders. Based on clinical criteria, patients will be triaged to undergo testing with either the myopathy or neuropathy panel, usually not both; however in some circumstances patients may require testing with both panels.To maximise the rate of diagnosis, all known myopathy or neuropathy associated genes with mutations detectable by NGS should be included on the panels. The lists of genes included on the current PathWest Laboratory Medicine Neurogenetic Unit myopathy and neuropathy panels are given in Appendix A (318 genes and 375 genes on the myopathy and neuropathy panels, respectively. See Gene Table of Neuromuscular Disorders: musclegenetable.fr). The panels need to be iterated at appropriate intervals with the newly identified disease genes.Note that some genes are included on both the myopathy and neuropathy panels because variants in some genes can cause what appear to be both myopathic or neuropathic phenotypes. For example, pathogenic variants in MYH7 encoding slow muscle fibre myosin cause myogenic disorders, including Laing distal myopathy. However, Laing distal myopathy is almost invariably diagnosed clinically as a peripheral neuropathy since that is what it closely resembles and peripheral neuropathy is much more common than distal myopathy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW1vbnQ8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Beecroft et al 2017). In addition, it should be noted that whilst most patients will present and be tested at a young age, testing should not be restricted to a paediatric population as many important variants, such as variants in ACTA1 that encode skeletal muscle alpha actin, may be identified at any stage in development, including adulthood.Using targeted panels removes some of the issues associated with whole exome analysis, including minimising the risk of incidental findings. In addition, panels are superior to whole exome sequencing or whole genome sequencing for myopathy testing due to the presence of triplicated regions in both NEB and TTN. In order to identify the pathogenic variants in these triplicated regions it is advantageous to have a very high depth of coverage which is easily achieved using targeted panels (Mark Davis et al unpublished data). Work flowThe proposed workflow for the diagnosis of suspected genetic NMD patients is summarised in REF _Ref530403130 \h Figure 2. Following referral by a general practitioner to a paediatrician or neurologist, the patient would undergo standard clinical examination to determine if they were candidates for having a genetic NMD. Any patient suspected of having a genetic NMD would follow one of two pathways:i) As described in Question 24, the mutations that cause some NMDs, such as facioscapulohumeral muscular dystrophy type 1 (FSHD1), myotonic dystrophy type 1 (DM1), spinal muscular atrophy type 1 (SMN1), are not currently detectable using NGS. Therefore, if there is a strong suspicion on clinical grounds that the patient has one of the disorders not detected by NGS, they should undergo analysis for those single disorders. It should be noted that these individual gene/mutation tests are currently funded either by the patient or by some State health department genetic services as there is no public funding in the form of MBS item numbers for these tests.If the single disease gene testing is negative, then the patient would undergo analysis using either the myopathic or the neuropathic gene panel, depending on clinical phenotype. ii) Patients with a suspected NMD other than those that require a separate single gene/mutation test would go straight to testing using either the myopathy or neuropathy gene panel, depending on the clinical phenotype. 2) Cascade genetic testing of family members: for a clinically actionable pathogenic variant(s) previously identified in a biological relative. Family members of a patient with an NMD where genetic testing has identified the causative variant(s) should receive genetic counselling to establish who is at risk of having the family causative variant(s). Variant-specific genetic testing, using Sanger sequencing or other technologies such as MLPA, should then be performed for relatives identified as being at risk of having the causative variant(s) identified in the index case.Testing of parents may be used to establish appropriate segregation of recessive variants identified in the index case, to test whether a pathogenic variant has arisen de novo in the index case, or whether a parent is a somatic mosaic for the pathogenic variant. Variant-specific testing may also be used to test affected siblings and for affected relatives in the extended family. It could also be used for pre-symptomatic testing for late-onset disorders in apparently unaffected relatives. Family members identified as carriers of the family pathogenic variant(s) may then be faced with future reproductive choices to consider, including pre-implantation genetic diagnosis or prenatal genetic testing through chorionic villus or amniotic fluid sampling. For some mutations, carriers may also require clinical assessment and follow-up especially regarding cardiomyopathy.3) Prenatal genetic testing: using mutation-specific detection of a clinically actionable pathogenic variant(s) previously identified in a relativePrenatal genetic testing for a clinically actionable pathogenic variant(s) should be offered for any future pregnancies after appropriate counselling. The mutation-specific testing would most often use Sanger sequencing to identify the causative pathogenic variant(s) previously identified in the family proband. 4) Prenatal genetic testing for NMD using gene panels: for a suspected NMD in the prenatal period with no previous genetic testing performed in the family, after appropriate counselling. Where there is a high degree of suspicion that a woman may be carrying a fetus with a NMD e.g. suspected foetal akinesia detected by prenatal ultrasound, consideration should be given to a prenatal gene panel testing in the context of an index patient (fetus). 3810-38100Patient referred to paediatrician/consultant neurologistDetailed clinical examination for neuromuscular disordersComprehensive neurological examinationMuscle weakness/hypertoniaPresence of specific signs (i.e. contractures, calf hypertrophy etc)Presence of complications (i.e. respiratory failure, cardiomyopathy etc)± metabolic studies, ± electrophysiology, ± imagingDifferentials that require single gene tests:eg. SMN1, myotonic dystrophy (DM1), FSHD1Suspected genetic NMD disorderPanel testing: myopathy or neuropathy panel depending on clinical phenotypeUnderlying molecular cause identifiedAppropriate patient/family managementNo underlying molecular cause identifiedConsider other investigations including muscle biopsy or MRI if appropriateReanalyse the data at appropriate intervals as the pathogenic status of variants are changed. If negative, then panel testingPatient referred to paediatrician/consultant neurologistDetailed clinical examination for neuromuscular disordersComprehensive neurological examinationMuscle weakness/hypertoniaPresence of specific signs (i.e. contractures, calf hypertrophy etc)Presence of complications (i.e. respiratory failure, cardiomyopathy etc)± metabolic studies, ± electrophysiology, ± imagingDifferentials that require single gene tests:eg. SMN1, myotonic dystrophy (DM1), FSHD1Suspected genetic NMD disorderPanel testing: myopathy or neuropathy panel depending on clinical phenotypeUnderlying molecular cause identifiedAppropriate patient/family managementNo underlying molecular cause identifiedConsider other investigations including muscle biopsy or MRI if appropriateReanalyse the data at appropriate intervals as the pathogenic status of variants are changed. If negative, then panel testingFigure SEQ Figure \* ARABIC 2Proposed molecular approach to diagnosis of NMD patientsNote: this schematic is a visual aid, depicting the testing pathway; however, it is unlikely that a laboratory would run an individual panel for each disorder e.g. one panel would be used to test for motor neuron, peripheral neuropathies and neuromuscular junction disorders (NMJD)Does the proposed medical service include a registered trademark component with characteristics that distinguishes it from other similar health components?N/AIf the proposed medical service has a prosthesis or device component to it, does it involve a new approach towards managing a particular sub-group of the population with the specific medical condition?N/AIf applicable, are there any limitations on the provision of the proposed medical service delivered to the patient (i.e. accessibility, dosage, quantity, duration or frequency):One off diagnostic test, noting that patients who test negative may undergo retesting at a future date if the test is expanded to include new genes.The sequence data may also be reanalysed as the status of variants may change from variants of uncertain significance (VUS) (Class 3) to likely pathogenic (Class 4) or pathogenic (Class 5) with time PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWNoYXJkczwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+
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ADDIN EN.CITE.DATA (Richards et al 2015). Data reanalysis for variant re-classification is formally requested by a clinician if new clinical evidence becomes available in the disease evolution or if clinical re-assessment is aligned with new literature to suggest potential disease causality of a specific, previously unclassified variant. Data reanalysis may also be prompted by the laboratory in liaison with the requesting clinician if a new gene has been associated with a relevant particular phenotype or if a new clinical association has been reported for a previously known NMD gene. In recent years, WA Health has reported approximately 5 occasions where a new variant was identified after reanalysis under these circumstances. If applicable, identify any healthcare resources or other medical services that would need to be delivered at the same time as the proposed medical service:Although genetic counselling is a critical component of genomic testing, it is unlikely that counselling would occur prior to, or at the same time as the genetic test due to long waiting lists. The requesting specialist, whether a paediatrician, neurologist or other specialist, may triage the patient to counselling at the same time as requesting the genetic test while explaining the test procedure, benefits and limitations, and potential consequences of test results to the patient/family members. Alternatively, the requesting specialist may triage the patient to counselling after a definitive genetic diagnosis is obtained. Patients may need to be referred to a neurologist for some diagnostic tests, and some may require referral to a cardiologist for diagnosis/treatment of cardiomyopathy.If applicable, advise which health professionals will primarily deliver the proposed service:Depending on age of onset, a specialist paediatrician, neurologist, or in the case of women considering pregnancy and requiring prenatal testing, a maternal-fetal medicine specialist, would normally request the service. A pathologist or an appropriately qualified medical scientist would perform the service and provide the clinical report, including interpretation of the results.If applicable, advise whether the proposed medical service could be delegated or referred to another professional for delivery:N/AIf applicable, specify any proposed limitations on who might deliver the proposed medical service, or who might provide a referral for it:Consideration should be given to restricting those who can provide a referral for this service to a specialised setting: specialist paediatricians, consultant neurologists, clinical geneticists or fetal-maternal specialist. If applicable, advise what type of training or qualifications would be required to perform the proposed service as well as any accreditation requirements to support service delivery:Testing would be delivered only by NATA Accredited Pathology Laboratories (as defined in MBS Pathology table) by referral only by registered Medical Practitioners (non-pathologists) in line with other tests in the MBS Pathology Table. Interpretation of results would be provided by approved practising pathologists or medical scientists(a) Indicate the proposed setting(s) in which the proposed medical service will be delivered (select all relevant settings): FORMCHECKBOX Inpatient private hospital FORMCHECKBOX Inpatient public hospital FORMCHECKBOX Outpatient clinic FORMCHECKBOX Emergency Department FORMCHECKBOX Consulting rooms FORMCHECKBOX Day surgery centre FORMCHECKBOX Residential aged care facility FORMCHECKBOX Patient’s home FORMCHECKBOX Laboratory FORMCHECKBOX Other – please specify below FORMTEXT Specify further details hereWhere the proposed medical service is provided in more than one setting, please describe the rationale related to each:N/AIs the proposed medical service intended to be entirely rendered in Australia? FORMCHECKBOX Yes FORMCHECKBOX No – please specify belowPART 6c – INFORMATION ABOUT THE COMPARATOR(S)Nominate the appropriate comparator(s) for the proposed medical service, i.e. how is the proposed population currently managed in the absence of the proposed medical service being available in the Australian health care system (including identifying health care resources that are needed to be delivered at the same time as the comparator service):The nominated comparator is no genetic testing.A number of diagnostic tests, such as serum creatine kinase testing, electro-diagnostic studies including electromyography (EMG) and nerve conduction studies or muscle biopsy can be performed as part of the clinical work up of patients suspected of having an NMD. However, these tests cannot deliver a definitive diagnosis. Muscle biopsy may in some cases provide a strong suggestion of which disease is involved: for example, in Duchenne muscular dystrophy if dystrophin levels are sufficiently reduced PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0RvbmFsZDwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+
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ADDIN EN.CITE.DATA (McDonald 2012), however, it cannot identify the precise pathogenic variant in the patient. EMG may define the disease in a patient as a congenital myasthenic syndrome but not which genetic subtype. Therefore these diagnostic tests cannot be considered true comparators. Only the identification of the precise disease-causing mutation in the patient in the correct gene can accurately determine which NMD a patient has ADDIN EN.CITE <EndNote><Cite><Author>Laing</Author><Year>2012</Year><RecNum>60</RecNum><IDText>22468856</IDText><DisplayText>(Laing 2012)</DisplayText><record><rec-number>60</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1531722525">60</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Laing, N. G.</author></authors></contributors><auth-address>Centre for Medical Research, University of Western Australia, Western Australian Institute for Medical Research, Nedlands, Western Australia, Australia. nlaing@cyllene.uwa.edu.au</auth-address><titles><title>Genetics of neuromuscular disorders</title><secondary-title>Crit Rev Clin Lab Sci</secondary-title></titles><periodical><full-title>Crit Rev Clin Lab Sci</full-title></periodical><pages>33-48</pages><volume>49</volume><number>2</number><edition>2012/04/04</edition><keywords><keyword>Humans</keyword><keyword>Mutation</keyword><keyword>Neuromuscular Diseases/ genetics</keyword></keywords><dates><year>2012</year><pub-dates><date>Mar-Apr</date></pub-dates></dates><isbn>1549-781X (Electronic)
1040-8363 (Linking)</isbn><accession-num>22468856</accession-num><urls><related-urls><url>;(Laing 2012). Therefore, the nominated comparator is no genetic testing.Does the medical service that has been nominated as the comparator have an existing MBS item number(s)? FORMCHECKBOX Yes (please provide all relevant MBS item numbers below) FORMCHECKBOX No There are MBS item numbers for some of the tests that can be performed to characterise NMDs. There are no MBS item numbers for Sanger sequencing any NMD genes or WEA or WGS for neuromuscular disorders. Muscle biopsy may give an indication of which disease may be involved. Item number 30075: DIAGNOSTIC BIOPSY OF LYMPH GLAND, MUSCLE OR OTHER DEEP TISSUE OR ORGAN, as an independent procedure, if the biopsy specimen is sent for pathological examination. Fee: $149.75Item number 72846: Immunohistochemical examination of biopsy material by immunofluorescence, immunoperoxidase or other labelled antibody techniques with multiple antigenic specificities per specimen - 1 to 3 antibodies except those listed in 72848. Fee $59.60Item number 72844: Enzyme histochemistry of skeletal muscle for investigation of primary degenerative or metabolic muscle diseases or of muscle abnormalities secondary to disease of the central or peripheral nervous system - 1 or more tests. Fee: $30.75Define and summarise the current clinical management pathways that patients may follow after they receive the medical service that has been nominated as the comparator (supplement this summary with an easy to follow flowchart [as an attachment to the Application Form] depicting the current clinical management pathway that patients may follow from the point of receiving the comparator onwards including health care resources):The comparator is no genetic testing. Therefore, the clinical management pathway follows that as described in REF _Ref530402908 \h Figure 1, the conventional care pathway with potential diagnostic tests as described in Q26. There are multiple issues with trying to summarise all the clinical management pathways NMD patients may follow. The difficulties arise mainly from the spectra of diseases diagnosed by the myopathy and neuropathy panels. One example of a care pathway for a child diagnosed with DMD is given below. However, due to the heterogeneous nature of NMDs it should be noted that the care pathways for all NMDs involve a multi-disciplinary approach, including counselling and referral to a neuromuscular specialist in addition to paediatricians, physiotherapists, respiratory therapists and cardiologists. The clinical care pathways and which services would be required are different for the different categories of NMDs; however, psychosocial care for patients and family members should occur at all stages of disease progression PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaXJua3JhbnQ8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFy
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ADDIN EN.CITE.DATA (Birnkrant et al 2018b; Birnkrant et al 2018c). DMD: Early stage management of DMD while the child is still ambulatory includes:Physiotherapy for advice on stretching, to prevent contracturesLater, knee-foot-ankle orthoses may help prolong walkingSerial casting of the ankles may be helpful (may prevent the need for surgical release of the Achilles tendon).Glucocorticoid therapy, which may prolong ambulation by 6-24 months, preserve upper limb and respiratory function, and avoid the need for scoliosis surgerynote of caution as these may be associated with side-effects including osteoporosis and vertebral fracturesPrednisone or prednisolone 0·75 mg/kg per day is the usual treatment, or de?azacort 0·9 mg/kg per dayOptimisation of bone healthvitamin D and calcium dietary advice or supplements.bisphosphonates if vertebral fracture occurs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaXJua3JhbnQ8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFy
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ADDIN EN.CITE.DATA (Birnkrant et al 2018a). Female carriers should also be offered family planning options including pre-implantation genetic diagnosis or prenatal genetic testing through chorionic villus or amniotic fluid sampling for male pregnancies.(a) Will the proposed medical service be used in addition to, or instead of, the nominated comparator(s)? FORMCHECKBOX In addition to FORMCHECKBOX Instead ofIf instead of please outline the extent of which the current service/comparator is expected to be substituted:All patients presenting with a clinical suspicion of an NMD should be referred on for mutational analysis after initial clinical tests. This would negate the need to perform an invasive and painful skeletal muscle biopsy in all cases for whom a definitive molecular diagnosis is obtained. Only those cases that return a negative genetic testing result should undergo a muscle biopsy.Define and summarise how current clinical management pathways (from the point of service delivery onwards) are expected to change as a consequence of introducing the proposed medical service including variation in health care resources (Refer to Question 39 as baseline):Genetic testing plays a role in the diagnosis, appropriate investigation, and monitoring of NMDs. A definitive diagnosis by mutational analysis will negate the need to perform many other downstream diagnostic tests, including invasive procedures such as muscle or nerve biopsies (and the associated Western blot or immunohistochemistry), which carry a small but recognised morbidity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0RvbmFsZDwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+
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ADDIN EN.CITE.DATA (McDonald 2012). Other expensive testing may also be avoided, including nerve or muscle imaging, and blood and cerebrospinal fluid testing. In determining the index case, additional testing of other family members for other disorders may be avoided. In the absence of gene panel testing, patients may undergo time consuming and expensive sequential Sanger sequencing (so called “diagnosis by sequencing” and not MBS listed) of the most likely candidate genes in relation to the suspected clinical phenotype in a bid to confirm a diagnosis. This, as described above (Q 38) is not feasible for all of the now identified NMD genes. Panel testing maximises the chance of identifying the causative variant(s) in a patient, with a genetic diagnosis potentially changing the clinical diagnosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZWVjcm9mdDwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+
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ADDIN EN.CITE.DATA (Misaka et al 2019; Yoshihisa et al 2018) Prior to genomic diagnosis, it was not possible to analyse these mutations because of the size and repetitive nature of the gene. With genomic diagnosis sudden cardiac death due to dilated cardiomyopathy can be prevented (personal communication WA Health). Similarly, diagnosis of mutations in LMNA (Lamin A/C), a neuromuscular junction defect allows close monitoring of cardiac rhythm to prevent sudden cardiac death (personal communication WA Health).Referral to a cardiologist for investigation and consideration of implantation of a defibrillator or pacemaker in a patient with limb girdle muscular dystrophy.Quality of life may also be improved with a definitive diagnosis that may prompt screening for treatable comorbidities such as cataracts or diabetes in a patient with myotonic muscular dystrophy.Detecting mutations in the ABCD1 gene indicates that Addison’s disease should be considered, which may be potentially life-saving (personal communication WA Health).Identification of an AT mutation in an atypical adult ataxia telangiectasia patient indicates breast cancer screening should be investigated. In one family this led to the detection of early breast cancer in both the 25 year-old patient and her carrier mother. Without a genetic diagnosis, clinical indicators alone would not have led to this diagnosis in a patient with no telangiectasia (personal communication WA Health).It should be noted; however, that many of these interventions are variant-specific. Treatment of the wrong variant with the wrong drug will result in a worsening of the disorder.There is clinical utility for family members to know about an inherited disorder, because the specific genetic diagnosis helps to predict the pattern of inheritance. This information is critical for genetic counselling, specifically informing family planning discussions, as well as discussions around prenatal diagnosis or early diagnosis of asymptomatic family members, as well as providing patient access to specific disease support groups. Without a genetic diagnosis, physicians or genetic counsellors cannot adequately educate patients or predict risks in a manner that helps guide family planning or diagnostic decisions ADDIN EN.CITE <EndNote><Cite><Author>Kassardjian</Author><Year>2016</Year><RecNum>105</RecNum><IDText>27554703</IDText><DisplayText>(Kassardjian et al 2016)</DisplayText><record><rec-number>105</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1535426211">105</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kassardjian, C. D.</author><author>Amato, A. A.</author><author>Boon, A. J.</author><author>Childers, M. K.</author><author>Klein, C. J.</author></authors></contributors><auth-address>Policy Department, American Association of Neuromuscular & Electrodiagnostic Medicine, Rochester, Minnesota, USA.</auth-address><titles><title>The utility of genetic testing in neuromuscular disease: A consensus statement from the AANEM on the clinical utility of genetic testing in diagnosis of neuromuscular disease</title><secondary-title>Muscle Nerve</secondary-title></titles><periodical><full-title>Muscle Nerve</full-title></periodical><pages>1007-1009</pages><volume>54</volume><number>6</number><edition>2016/08/25</edition><keywords><keyword>Consensus</keyword><keyword>Genetic Testing</keyword><keyword>Humans</keyword><keyword>Neuromuscular Diseases/ diagnosis/ genetics</keyword><keyword>Societies, Medical/standards</keyword><keyword>United States</keyword><keyword>Aanem</keyword><keyword>Nm</keyword><keyword>neuromuscular</keyword><keyword>neuromuscular disease</keyword><keyword>neuromuscular medicine</keyword></keywords><dates><year>2016</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1097-4598 (Electronic)
0148-639X (Linking)</isbn><accession-num>27554703</accession-num><urls><related-urls><url>;(Kassardjian et al 2016). PART 6d – INFORMATION ABOUT THE CLINICAL OUTCOMESummarise the clinical claims for the proposed medical service against the appropriate comparator(s), in terms of consequences for health outcomes (comparative benefits and harms):Public funding of genetic testing for the diagnosis of NMDs would provide equity of access. Currently some patients are accessing genomic testing for NMDs on a user-pays basis by sending samples overseas to Invitae at a cost of up to US$1,500. It should be noted that this panel only contains 109 genes, and therefore may leave many patients without a diagnosis. Importantly, this testing is not covered by the same quality assurance processes as Australian NATA accredited laboratories are subject to and there have been poor outcomes with low “hit” rates reported. NMD gene panel testing is currently tested in a Centre of Excellence in Western Australia.Providing a definitive diagnosis gives certainty to patients and families. The importance of being able to give the family disease a name through accurate molecular diagnosis cannot be overemphasised. The family now knows what disease they have and knowing what disease they have provides closure ADDIN EN.CITE <EndNote><Cite><Author>Basel</Author><Year>2017</Year><RecNum>159</RecNum><DisplayText>(Basel & McCarrier 2017)</DisplayText><record><rec-number>159</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1562739751">159</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Basel, D.</author><author>McCarrier, J.</author></authors></contributors><auth-address>Department of Pediatrics, Medical College of Wisconsin, Children's Hospital of Wisconsin, 9000 West Wisconsin Avenue, MS 716, Milwaukee, WI 53226, USA. Electronic address: dbasel@mcw.edu.
Department of Pediatrics, Medical College of Wisconsin, Children's Hospital of Wisconsin, 9000 West Wisconsin Avenue, MS 716, Milwaukee, WI 53226, USA.</auth-address><titles><title>Ending a Diagnostic Odyssey: Family Education, Counseling, and Response to Eventual Diagnosis</title><secondary-title>Pediatr Clin North Am</secondary-title><alt-title>Pediatric clinics of North America</alt-title></titles><periodical><full-title>Pediatr Clin North Am</full-title></periodical><pages>265-272</pages><volume>64</volume><number>1</number><edition>2016/11/30</edition><keywords><keyword>Child</keyword><keyword>Decision Making</keyword><keyword>Genetic Counseling</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Genetic Testing/*methods</keyword><keyword>Humans</keyword><keyword>Rare Diseases/*diagnosis/*genetics</keyword></keywords><dates><year>2017</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0031-3955</isbn><accession-num>27894449</accession-num><urls></urls><electronic-resource-num>10.1016/j.pcl.2016.08.017</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider><language>eng</language></record></Cite></EndNote>(Basel & McCarrier 2017). It stops the family being in limbo. It stops them being in the dark as to what their disease is. It provides clarity as to the pattern of inheritance and therefore clarity of prognosis and clarity as to the risk of a couple having further affected children. Having an accurate molecular diagnosis also restores reproductive confidence. One example of this that we have written about was when the deletions of SMN1 responsible for spinal muscular atrophy were first identified in 1995 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWZlYnZyZTwvQXV0aG9yPjxZZWFyPjE5OTU8L1llYXI+
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ADDIN EN.CITE.DATA (Lefebvre et al 1995). When the WA laboratory could first perform prenatal diagnosis for the deletions, we were inundated with an avalanche of WA families wanting prenatal diagnosis, families who had put off having any further children until their disease could be tested for ADDIN EN.CITE <EndNote><Cite><Author>Laing</Author><Year>2012</Year><RecNum>60</RecNum><DisplayText>(Laing 2012)</DisplayText><record><rec-number>60</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1531722525">60</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Laing, N. G.</author></authors></contributors><auth-address>Centre for Medical Research, University of Western Australia, Western Australian Institute for Medical Research, Nedlands, Western Australia, Australia. nlaing@cyllene.uwa.edu.au</auth-address><titles><title>Genetics of neuromuscular disorders</title><secondary-title>Crit Rev Clin Lab Sci</secondary-title></titles><periodical><full-title>Crit Rev Clin Lab Sci</full-title></periodical><pages>33-48</pages><volume>49</volume><number>2</number><edition>2012/04/04</edition><keywords><keyword>Humans</keyword><keyword>Mutation</keyword><keyword>Neuromuscular Diseases/ genetics</keyword></keywords><dates><year>2012</year><pub-dates><date>Mar-Apr</date></pub-dates></dates><isbn>1549-781X (Electronic)
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ADDIN EN.CITE.DATA (Schofield et al 2017).The main consequences of introducing genetic testing for the diagnosis of NMDs include:?Early identification and early commencement of treatment of affected probands, resulting in an improved quality of life and an increased survival time;?Early identification and early commencement of treatment of affected relatives; andCarriers would be positively identified and offered surveillance and family planning options for any future pregnancies.Please advise if the overall clinical claim is for: FORMCHECKBOX Superiority FORMCHECKBOX Non-inferiorityBelow, list the key health outcomes (major and minor – prioritising major key health outcomes first) that will need to be specifically measured in assessing the clinical claim of the proposed medical service versus the comparator:Direct evidence: Safety Outcomes: Adverse events from testing: physical and/or psychological harms from genetic testingClinical Effectiveness Outcomes: Quality of life, morbidity, increased survival timeCost-effectivenessIndirect evidence:Analytical validity: test failure rate, sensitivity, specificity, concordance, unsatisfactory or uninterpretable results, diagnostic yieldClinical validity: predictive or prognostic valueTherapeutic efficacy: time to diagnosis, change in patient management (earlier access to treatment), change in detection and treatment of family members (earlier detection of and management of relatives due to genetic testing, impact on family planning) Therapeutic effectiveness: effect of change in management (e.g. increased time to mortality, improved quality of life).PART 7 – INFORMATION ABOUT ESTIMATED UTILISATIONEstimate the prevalence and/or incidence of the proposed population:Australian data on the incidence and prevalence of NMDs are lacking. The cross-sectional analysis by Norwood et al (2009) was conducted in the northern counties of England and may therefore be generalisable to Australia. However, prevalence studies are likely to underestimate those diseases that lead to early death, such as DMD, as prevalence reflects both incidence and duration. Norwood et al included all registered patients with genetic muscle diseases diagnosed and currently seen by the neuromuscular team at the UK’s Institute of Human Genetics. Patients with inherited disorders such as mitochondrial and metabolic myopathies, ion channel disorders, congenital myasthenic syndromes and hereditary motor and sensory neuropathies as well as those with acquired neuromuscular disease including inflammatory myopathies, myasthenia gravis and motor neuron diseases were excluded. A total of 1,105 patients were identified for inclusion, representing 31 different disease entities. Diagnostic clarity achieved through careful delineation of clinical features supported by histological, immunological and genetic analysis enabled a definitive diagnosis in 75.7% of patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ob3J3b29kPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48
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ADDIN EN.CITE.DATA (Norwood et al 2009).Despite the exclusion of common groups such as hereditary motor and sensory neuropathy (40/100,000) and mitochondrial disorders (9.2/100,000), the combined prevalence was 37.0/100,000. Following that group were patients diagnosed with the dystrophinopathies making up 22.9% (8.46/100,000) of the clinic population. A point prevalence of 7.29 (95% CI [5.98, 8.79]) and 8.29 (95% CI [6.90, 9.88]) per 100,000 males was reported for BMD and DMD, respectively. Limb girdle muscular dystrophy, comprised 6.2% of the clinic population with a combined prevalence of 2.27/100 000. In addition, patients were diagnosed with 12 other muscle disorders, which ranged from a point prevalence of 0.89/100,000 for the group of congenital muscular dystrophies, to conditions with only two affected individuals in a population of three million. The X-linked form of Emery–Dreifuss muscular dystrophy and Ullrich muscular dystrophy had a prevalence of 0.13/100 000, making both very rare. Bethlem myopathy was relatively more common with a prevalence of 0.77/100 000 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ob3J3b29kPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48
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ADDIN EN.CITE.DATA (Norwood et al 2009).IncidenceThere is a paucity of data on the incidence of NMDs in Australia. In 2015, the Western Australian registry of developmental anomalies reported the incidence of “muscular dystrophies and myopathy” as approximately 0.2/1,000 or 1/5,000 live births, ADDIN EN.CITE <EndNote><Cite><Author>Bhatt</Author><Year>2016</Year><RecNum>130</RecNum><IDText>27720006</IDText><DisplayText>(Bhatt 2016)</DisplayText><record><rec-number>130</rec-number><foreign-keys><key app="EN" db-id="waxaxvrdgtwrrmepz2r5pa9mezettsdr0z0a" timestamp="1542599247">130</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bhatt, J. M.</author></authors></contributors><auth-address>Department of Neurology, New York University School of Medicine, 240 East 38th Street, 20th Floor, New York, NY 10016, USA. Electronic address: jaydeep.bhatt@.</auth-address><titles><title>The Epidemiology of Neuromuscular Diseases</title><secondary-title>Neurol Clin</secondary-title></titles><periodical><full-title>Neurol Clin</full-title></periodical><pages>999-1021</pages><volume>34</volume><number>4</number><edition>2016/10/11</edition><keywords><keyword>Cost of Illness</keyword><keyword>Global Health</keyword><keyword>Humans</keyword><keyword>Neuromuscular Diseases/classification/ epidemiology/genetics</keyword><keyword>Public Health</keyword><keyword>Risk Factors</keyword><keyword>Burden of disease</keyword><keyword>Epidemiology</keyword><keyword>Neuromuscular disease</keyword></keywords><dates><year>2016</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1557-9875 (Electronic)
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ADDIN EN.CITE.DATA (Matthews et al 2016). Using the number of live births in Australia to estimate the size of the at-risk population would yield an approximate incidence of 62 affected live born individuals each year, based on the 311,104 births registered in 2016. When compared to world-wide incidence data, this estimate is very close to the incidence of DMD, and therefore likely to be an underestimation of the true incidence of NMDs in Australia. In addition, the true incidence is likely to be higher due to the number of (currently) undiagnosed cases.Two recent systematic reviews have estimated incidence rates for 13 neuromuscular disorders (see REF _Ref530480971 \h Table 3), which, as individual disorders, are rare, but as a group they are not, with an overall incidence rate ranging from 11.95 to 82.8 per 100,000 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaGF0dDwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Bhatt 2016; Deenen et al 2015). Similarly, this is an underestimation due to the number of NMDs without incidence data.Table SEQ Table \* ARABIC 3Global incidence rates for 13 neuromuscular disorders PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaGF0dDwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Bhatt 2016; Deenen et al 2015)DisorderIncidence range per 100,000Anterior horn cellsType I spinal muscular atrophy3.53 to 9.8All spinal muscular atrophy3.53 to 14.9Amyotrophic lateral sclerosis0.42 to 5.3Peripheral nerveChronic inflammatory demyelinating polyneuropathy0.35 to 1.6Guillain-Bare syndrome0.4 to 3.0Friedreich Ataxia2.7 to 6.19Neuromuscular junctionMyasthenia Gravis0.3 to 2.8 (11.8 reported by one study in Japan)Lambert-Eaton myasthenic syndrome0.05MuscularDuchene muscular dystrophy 2.0 to 34.7 per 100,000 malesBecker muscular dystrophy1.06 to 7.2 per 100,000 malesLimb-girdle muscular dystrophy0.7Polymyositis0.27 to 3.80Dermatomyositis0.08 to 1.78Inclusion body myositis0.09 to 0.79TOTAL11.95 to 82.8Estimate the number of times the proposed medical service(s) would be delivered to a patient per year:Once in a lifetime diagnostic test if a definitive diagnosis is obtained.How many years would the proposed medical service(s) be required for the patient?N/AEstimate the projected number of patients who will utilise the proposed medical service(s) for the first full year:Genetic testing for NMDs is currently predominantly conducted in Western Australia for patients from Queensland, NSW, South Australia, Victoria and Western Australia. Although the number of tests conducted in WA Is not inclusive of all NMD patients in Australia, it does represent a significant majority. In addition, a number of prevalent, undiagnosed patients may also seek to use the proposed service.Data from the previous two years (2017 and 2018) of testing patients with a suspected NMD with an NGS panel are summarised below. The number of cascade tests conducted is dependent on the number of index cases found to be positive. In 2017 and 2018, 29% and 23.7% of patients suspected of having an NMD were found to be positive for a NMD identified by the NGS panel, respectively. These numbers resulted in 1.12 and 1.3, respectively, family members per index case seeking cascade testing. The expected numbers for the following 3-years were calculated using the slight increase in the number of tests performed from 2017 to 2018 (an increase of 8.4%). The estimated number of cascade tests performed will be based on the number of positive index cases – an average of the number of positives was used to estimate this (26.35%). Similarly, the estimated number of cascade tests used the average number of tests performed per index case (1.21). It is difficult to estimate the number of prenatal diagnoses, however, the numbers are expected to remain low.It is expected that uptake of testing should remain relatively constant over the next three years.Table SEQ Table \* ARABIC 4Number of tests conducted in Western Australia in previous 2 years, and expected number of tests for the next 3 yearsPopulation to be tested20172018Expected2019Expected2020Expected2021Index cases944276 +ve1023242 +ve110829312003161300342Cascade testing310330354382413Prenatal diagnosis1319Estimate the anticipated uptake of the proposed medical service over the next three years factoring in any constraints in the health system in meeting the needs of the proposed population (such as supply and demand factors) as well as provide commentary on risk of ‘leakage’ to populations not targeted by the service:There are four parts to the proposed medical service:1) Gene panel testing to identify pathogenic variants for genetic neuromuscular disorders in patients where clinical criteria or a family history indicate that genetic testing is warranted.2) Cascade testing of family members: using mutation-specific detection of a clinically actionable pathogenic variant previously identified in a first-degree relative. 3) Prenatal genetic testing using mutation-specific detection of a clinically actionable pathogenic variant(s) previously identified in a relative.4) Prenatal genetic testing for NMD using gene panels: for a suspected NMD in the prenatal period with no previous genetic testing performed in the family, after appropriate counselling.There is minimal risk of leakage associated with items 1 and 4; however, items 2 and 3 may result in item numbers for cascade testing and prenatal testing of relatives of any proband with a causal variant or variants identified by any technique, including single gene/mutation detection. The item number should specify that the gene panel must be the testing method that was used to identify the familial variant.PART 8 – COST INFORMATIONIndicate the likely cost of providing the proposed medical service. Where possible, please provide overall cost and breakdown:Cost of index case testing: $1,200Cost of variant-specific cascade testing: $450The cost of prenatal testing for a documented familial gene variant, including sampling cost followed by genetic analysis, and maternal cell contamination: $1,000The cost of prenatal testing, including sampling cost followed by genetic analysis, and maternal cell contamination: $ 1,600Note: The scheduled fees (100%) stated in the item number descriptors below reflect current costs to perform these analyses. If the scheduled fees are set at these prices, then an 85% reimbursement would result in the need for considerable out-of-pocket payments by patients, with the potential for a lack of equity in access for some patients/families.In addition to the costs outlined above, prenatal genetic testing would utilise either:Chorionic villus sampling, usually after 11 weeks into the pregnancy. MBS item number 16603: CHORIONIC VILLUS SAMPLING, by any route. Fee: $121.85 Benefit: 75% = $91.40 85% = $103.60;Amniocentesis, which isn't usually carried out until 15 to 16 weeks of pregnancyMBS item number 16606: Fetal blood sampling, using interventional techniques from umbilical cord or fetus, including fetal neuromuscular blockade and amniocentesis, (Anaes.) Fee: $243.25 Benefit: 75% = $182.45 85% = $206.80The cost of pre-implantation genetic diagnosis may also be considered (MSAC application 1165).Specify how long the proposed medical service typically takes to perform:Diagnostic testing would take between 4 - 12 weeks, with carrier testing taking 4 - 6 weeks. Due to workload commitments, the normal turnaround time for testing is 2-4 months (90% of tests requested would fall into this timeline), however urgent cases can be processed in 1-2 weeks.Prenatal testing for known familial variant(s) 4 -7 days. If public funding is sought through the MBS, please draft a proposed MBS item descriptor to define the population and medical service usage characteristics that would define eligibility for MBS funding.Item number AAAA Category 6 (Pathology Services) – Group P7 GeneticsCharacterisation of a germline gene variant(s) by a gene panel in a patient presenting with clinical symptoms suggestive of a genetic neuromuscular disorder other than those associated with variants that are not detected by massively parallel sequencing, and after exclusion of non-genetic causes, requested by a specialist or consultant physician.Fee: $ 1,200 Benefit: 75% = 825.00 85% = 935.00Item number BBBBCategory 6 (Pathology Services) – Group P7 GeneticsDetection of a single identified gene variant in a biological relative of a patient with a documented pathogenic germline gene variant for a neuromuscular disorder identified by item number AAAA, requested by a specialist or consultant physician who manages the treatment of the patient. Fee: $ 450.00 Benefit: 75% = 337.50 85% = 382.50Item number CCCC Category 6 (Pathology Services) – Group P7 GeneticsPrenatal detection of a familial gene variant(s) for a neuromuscular disorder previously identified in an index patient in the family by item number AAAA, including maternal cell contamination assessment, requested by a specialist or consultant physician who manages the treatment of the patient.Fee: $ 1,000.00 Benefit: 75% = $750.0085% =$ 850.00 Item number DDDDCategory 6 (Pathology Services) – Group P7 GeneticsPrenatal detection of an unknown germline gene variant(s) for a suspected genetic neuromuscular disorder using a gene panel, after exclusion of non-genetic causes, and including maternal cell contamination assessment, requested by a specialist or consultant physician who manages the treatment of the patient.Fee: $ 1,600.00 Benefit: 75% = $750.0085% =$ 850.00 Appendix A: Muscular panelAARS2AMPD1C8orf22CHRNDCOL6A3DPAGT1FHL1GYG1ISPDLDB3MPZMYL12ANUP88PIEZO2PRELPABHD5ANKRD1CA3CHRNECOLQDPM1FHL3GYS1ITGA7LDHAMRPL3MYL2OBSCNPIGYPREPLACAD9ANKRD2CACNA1SCHRNGCOX14DPM2FKBP14HACD1ITGA9LIMS2MSTNMYL3OPA1PIP5K1CPRXACADVLANO5CAPN3CHST14COX6A2DPM3FKRPHADHAKBTBD13LMNAMTM1MYL4ORAI1PLECPTRFACTA1APODCASQ1CKMCOX6B1DYSFFKTNHADHBKCNA1LMOD2MTMR14MYLPFP4HA1PLOD1PYGMACTC1ASCC1CAV3CKMT2CPT2ECEL1FLNAHBBKCNJ2LMOD3MUSKMYO18BPABPN1PMP22PYROXD1ACTN2ATP1A2CCDC78CLCN1CRYABEDN3FLNCHIST1H3HKIF21ALPIN1MUSTN1MYOD1PBLDPNPLA2RAPSNADCY6ATP2A1CD99CLDN11CYC1EGR2GAAHNRNPA1KLHL31LRP4MYBPC1MYOTPDE4DIPPOGLUT1RBCK1ADGRG6ATP5A1CEP89CMYA5DAG1EMDGAPDHHNRNPA2B1KLHL40LYZMYBPC3MYOZ1PDK4POLGRMND1ADSSL1B3GALNT2CFL2CNTN1DCST2ENO3GBE1HNRNPDLKLHL41MAGEL2MYF6NALCNPDLIM3POLG2RRM2BAGKB3GALT6CHATCNTNAP1DESERBB3GFPT1HRASKLHL9MBMYH13NDUFAF1PFKMPOMGNT1RYR1AGLB4GAT1CHCHD10COL12A1DLK1ETFDHGGPS1HSPB6KYMEG3MYH14NDUFAF2PGAM2POMGNT2SCN4AAGRNBAG3CHD7COL13A1DMDFARS2GLE1HSPB7L1CAMMEGF10MYH2NEBPGK1POMKSDHAAIFM1BIN1CHKACOL1A1DNA2FBN2GMPPBHSPB8LAMA2MGME1MYH3NEFLPGM1POMT1SEPN1ALDOABVESCHKBCOL3A1DNAJB6FBXL4GNEHSPG2LAMB2MICU1MYH7NFU1PHKA1POMT2SGCAALG14C10orf2CHRNA1COL6A1DNM2FDX1LGOLGA2IGF2LAMP2MMP1MYH8NNATPHKBPOSTNSGCBALG2C12orf65CHRNB1COL6A2DOK7FGF7GREM1ISCULARGEMMP28MYL1NRAPPHOX2APPP1R27SGCDSGCGSLC25A4SMCHD1SRPK3SURF1TANGO2TIA1TNNC2TNNT3TPM2TRIP4UNC80XIRP2SLC18A3SLC25A42SNAP25STAC3SYNE1TAZTK2TNNI1TNPO3TPM3TRPV4UQCRC2ZBTB42SLC19A3SLC25A6SOX10STIM1SYNE2TBCKTMEM43TNNI2TNXBTRAPPC11TTNVCPZC4H2SLC22A5SLC28A2SPEGSTMN2SYNPO2TCAPTMEM5TNNT1TOR1AIP1TRIM32UBA1VMA21SLC25A20SLNSQSTM1SUCLA2SYT2TGFB3TNNC1TNNT2TP63TRIM63UNC79XIRP1Neuropathy panelAARSARFGEF2C19orf12DCXEXOSC8GFAPIKBKAPLYSTNTRK1POLR3BRTN2SLC52A2TBR1UBA1ABCB7ARHGEF10CACNA1ADDHD1FA2HGJB1INF2MAGOPA1POMGNT1RTTNSLC52A3TDP1UBA5ABCD1ARL6IP1CACNA1BDDHD2FAM126AGJB3ISPDMARSOPTNPOMGNT2RUBCNSLC5A7TECPR2UBQLN2ABHD12ARSACACNA1GDENRFAM134BGJC2ITPR1MARS2OTUD4POMKSACSSLC6A3TFGUNC79ACTBARSICACNB4DHTKD1FARS2GNALKARSMATR3PAFAH1B1POMT1SAMHD1SLC9A1THUNC80ACTG1ARXCCT5DNAJB2FAT3GNB4KCNA1MCPH1PANK2POMT2SBF1SNX14THAP1USP8ADARASAH1CDK5RAP2DNAJB5FAT4GOSR2KCNC3MED25PARK2PPP2R2BSBF2SOD1TNFAIP1VAMP1ADCK3ASCC1CENPJDNM2FBLN5GRID2KCND3MFN2PAX6PRDM12SCN11ASOX10TOR1AVAPBADGRG1ASPACEP152DNMT1FBXO38GRM1KCTD13MLC1PBLDPRKCGSCN1ASPASTTOR1AIP1VCPAFG3L2ASPMCHCHD10DRD2FGD4HACE1KIAA0196MMP28PCNTPRKRASCN9ASPG11TP63VLDLRAIFM1ATCAYCHMP2BDRP2FGF14HARSKIF1AMORC2PDK3PRNPSCYL1SPG20TPP1VPS13AAIMP1ATL1CLCN2DSTFIG4HEPACAMKIF1BMPZPDYNPRPHSEPT9SPG21TREX1VPS37AAKT1ATL3CLPPDYNC1H1FKRPHINT1KIF1CMR1PEX10PRPS1SETXSPG7TRIM2VRK1AKT3ATMCOASYEDN3FKTNHK1KIF21AMRE11APFN1PRRT2SGCESPRTRIP4WDR45ALDH18A1ATP1A3COL4A1EGR2FLNAHNRNPA1KIF2AMTMR2PGAP1PRXSH3TC2SPTBN2TRPV4WDR48ALDH3A2ATP2B3COL4A2EIF2B1FLRT1HNRNPA2B1KIF5AMTPAPPIK3R5PSAPSIGMAR1SPTLC1TSEN2WDR62ALS2ATP2B4COX6A1EIF2B2FLVCR1HNRNPUL1KIF5CMYH14PLA2G6PTENSIL1SPTLC2TSEN34WNK1AMPD2ATP6AP2CPT1CEIF2B3FTLHNRNPUL2KLC2MYH7PLEKHG5RAB3GAP2SLC12A6SPTLC3TSEN54WWOXANGATP7ACSF1REIF2B4FUSHOXD10KLC4NAGLUPLOD1RAB7ASLC16A2SQSTM1TTBK2YARSANO10ATRCTDP1EIF2B5FXNHPCAKTN1NDE1PLP1REEP1SLC17A5STUB1TTPAYWHAEANO3B3GALNT2CUL3ELOVL4GAD1HSPB1L1CAMNDRG1PMP2REEP2SLC18A3SYNE1TTRZBTB18AP4B1B4GALNT1CWF19L1ELOVL5GALCHSPB3LARGENEFLPMP22RELNSLC1A3SYT14TUBA1AZFRAP4E1BCAP31CYP2U1ENTPD1GANHSPB8LAS1LNGFPMPCARNASEH2BSLC20A2TAF1TUBBZFYVE26AP4M1BEAN1CYP7B1EOMESGARSHSPD1LITAFNIPA1PNKPRNASET2SLC25A46TARDBPTUBB2BZFYVE27AP4S1BICD2DARS2ERLIN1GBA2IBA57LMNANOP56PNPLA6RNF170SLC2A1TBCDTUBB3AP5Z1BSCL2DCAF8ERLIN2GCH1IFIH1LMNB1NOTCH3POLGRNF216SLC33A1TBK1TUBB4AAPTXC12orf65DCTN1EXOSC3GDAP1IGHMBP2LRSAM1NT5C2POLR3ARPIASLC52A1TBPTUBG1References ADDIN EN.REFLIST Ankala, A., da Silva, C. et al (2015). 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