1. Targeted gene panel use in 2249 neuromuscular patients: the Australasian referral center experience
- Author
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Padma Sivadorai, Royston Ong, Nina Kresoje, Sarah J. Beecroft, Gianina Ravenscroft, Cheryl A Wise, Mark R. Davis, Daniel Trajanoski, Fathimath Faiz, Rachael M. Duff, Vanessa Atkinson, Kyle S. Yau, Kym Mina, Nicholas Pachter, Rebecca Gooding, Kristen J. Nowak, Phillipa J. Lamont, Macarena Cabrera-Serrano, Richard J.N. Allcock, Nigel G. Laing, The Fred Liuzzi Foundation, Australian Genomics, Fundación Alfonso Martín Escudero, Junta de Andalucía, National Health and Medical Research Council (Australia), and Department of Health (Australia)
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Neurology ,Neuromuscular disease ,Adolescent ,Referral ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Context (language use) ,Disease ,Cohort Studies ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Genetic Testing ,RC346-429 ,Child ,Referral and Consultation ,Exome ,Research Articles ,Disease burden ,Aged ,Aged, 80 and over ,business.industry ,General Neuroscience ,Australia ,High-Throughput Nucleotide Sequencing ,Infant ,Neuromuscular Diseases ,Middle Aged ,medicine.disease ,3. Good health ,030104 developmental biology ,Child, Preschool ,Female ,Neurology. Diseases of the nervous system ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Research Article ,RC321-571 ,New Zealand ,Cohort study - Abstract
[Objective] To develop, test, and iterate a comprehensive neuromuscular targeted gene panel in a national referral center., [Methods] We designed two iterations of a comprehensive targeted gene panel for neuromuscular disorders. Version 1 included 336 genes, which was increased to 464 genes in Version 2. Both panels used TargetSeqTM probe‐based hybridization for target enrichment followed by Ion Torrent sequencing. Targeted high‐coverage sequencing and analysis was performed on 2249 neurology patients from Australia and New Zealand (1054 Version 1, 1195 Version 2) from 2012 to 2015. No selection criteria were used other than referral from a suitable medical specialist (e.g., neurologist or clinical geneticist). Patients were classified into 15 clinical categories based on the clinical diagnosis from the referring clinician., [Results] Six hundred and sixty‐five patients received a genetic diagnosis (30%). Diagnosed patients were significantly younger that undiagnosed patients (26.4 and 32.5 years, respectively; P = 4.6326E‐9). The diagnostic success varied markedly between disease categories. Pathogenic variants in 10 genes explained 38% of the disease burden. Unexpected phenotypic expansions were discovered in multiple cases. Triage of unsolved cases for research exome testing led to the discovery of six new disease genes., [Interpretation] A comprehensive targeted diagnostic panel was an effective method for neuromuscular disease diagnosis within the context of an Australasian referral center. Use of smaller disease‐specific panels would have precluded diagnosis in many patients and increased cost. Analysis through a centralized laboratory facilitated detection of recurrent, but under‐recognized pathogenic variants., Research funding: The Fred Liuzzi Foundation, Australian Postgraduate Award, Australian Genomics Health Alliance. Grant Number: GNT1113531, Fundación Alfonso Martín Escudero, Junta de Andalucía‐Consejería de Salud. Grant Number: B‐0005‐2017, Australian National Health and Medical Research Council. Grant Numbers: APP1117510, APP1122952, APP1080587, Western Australian Department of Health Future Health’s WA Merit Award.
- Published
- 2020