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Diagnostic yield of multi-gene panel for muscular dystrophies and other hereditary myopathies

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Abstract

Genetic testing is being considered the first-step in the investigation of hereditary myopathies. However, the performance of the different testing approaches is little known. The aims of the present study were to evaluate the diagnostic yield of a next-generation sequencing panel comprising 39 genes as the first-tier test for genetic myopathies diagnosis and to characterize clinical and molecular findings of families from southern Brazil. Fifty-one consecutive index cases with clinical suspicion of genetic myopathies were recruited from October 2014 to March 2018 in a cross-sectional study. The overall diagnostic yield of the next-generation sequencing panel was 52.9%, increasing to 60.8% when including cases with candidate variants. Multi-gene panel solved the diagnosis of 12/25 (48%) probands with limb-girdle muscular dystrophies, of 7/14 (50%) with congenital muscular diseases, and of 7/10 (70%) with muscular dystrophy with prominent joint contractures. The most frequent diagnosis for limb-girdle muscular dystrophies were LGMD2A/LGMD-R1-calpain3-related and LGMD2B/LGMD-R2-dysferlin-related; for congenital muscular diseases, RYR1-related-disorders; and for muscular dystrophy with prominent joint contractures, Emery-Dreifuss-muscular-dystrophy-type-1 and COL6A1-related-disorders. In summary, the customized next-generation sequencing panel when applied in the initial investigation of genetic myopathies results in high diagnostic yield, likely reducing patient’s diagnostic odyssey and providing important information for genetic counseling and participation in disease-specific clinical trials.

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The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors are grateful to the patients and families for their participation in this study and to the professionals who attended these individuals but were not directly involved in this research project.

Funding

The study was funded by the Fundo de Incentivo à Pesquisa e Eventos-HCPA (Grant Number: 17–0340) and by unrestricted research grant from PTC Therapeutics.

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Authors and Affiliations

  1. Graduate Program in Medicine: Medical Sciences, Universidade Federal Do Rio Grande Do Sul (UFRGS), Porto Alegre, Brazil

    Pablo Brea Winckler, Marco Antonnio Rocha Dos Santos, Márcia Lorena Fagundes Chaves & Jonas Alex Morales Saute

  2. Neurology Division, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil

    Pablo Brea Winckler, Marco Antonnio Rocha Dos Santos, Márcia Lorena Fagundes Chaves & Jonas Alex Morales Saute

  3. Medical Genetics Division, HCPA, Ramiro Barcelos, 2350, Porto Alegre, 90035-903, Brazil

    Bruna Cristine Chwal, Daniela Burguêz, Marcia Polese-Bonatto & Jonas Alex Morales Saute

  4. Departamento de Neurologia, Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brazil

    Edmar Zanoteli

  5. Graduate Program in Science in Gastroenterology and Hepatology, Universidade Federal Do Rio Grande Do Sul (UFRGS), Porto Alegre, Brazil

    Marina Siebert

  6. Unit of Laboratorial Research, Experimental Research Center, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil

    Marina Siebert

  7. BRAIN (Basic Research and Advanced Investigations in Neurosciences) Laboratory, Experimental Research Center, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, Brazil

    Marina Siebert

  8. Center for Individualized Medicine and Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA

    Filippo Pinto e Vairo

  9. Department of Internal Medicine, UFRGS, Porto Alegre, Brazil

    Márcia Lorena Fagundes Chaves & Jonas Alex Morales Saute

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  1. Pablo Brea Winckler
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10072_2022_5934_MOESM1_ESM.xlsx

Supplementary file1 Supplemental Table 1 Clinical, genetic, neurophysiological and neuropathological description of subjects. AA, amino acid; AD, autosomal dominant; AO, age at onset; AR, autosomal recessive; AWA, age at walking aid dependency; AWC, age at wheelchair dependency; CMD; congenital muscular diseases; DD, disease duration; DM, distal myopathy; DMD, Duchenne muscular dystrophy; EMG; electromyography; F, female; Fam, family; GMWS, modified Gardner-Medwin-Walton scale. IHC, immunohistochemistry; LGMD; limb-girdle muscular dystrophy; M, male; Max, maximum; MDJC, muscular dystrophy with prominent joint contractures; MM, metabolic myopathy; MRI, magnetic resonance imaging; NA, not available; SMA, spinal muscular atrophy; UA, ultrastructural analysis; *diagnosed based on clinical findings and family molecular diagnosis.# Not detected by the next-generation sequencing panel due to low coverage and detected by whole exome sequencing (XLSX 24 KB)

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Winckler, P.B., Chwal, B.C., Dos Santos, M.A.R. et al. Diagnostic yield of multi-gene panel for muscular dystrophies and other hereditary myopathies. Neurol Sci 43, 4473–4481 (2022). https://doi.org/10.1007/s10072-022-05934-y

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