期刊
GENETICS IN MEDICINE
卷 22, 期 9, 页码 1478-1488出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/s41436-020-0840-3
关键词
next-generation sequencing; targeted exome analysis; neuromuscular disease; limb-girdle weakness; genetic diagnosis
资金
- Sanofi Genzyme
- Ultragenyx
- LGMD2I Research Fund
- Samantha J. Brazzo Foundation
- LGMD2D Foundation
- Kurt+Peter Foundation
- Muscular Dystrophy UK
- Coalition to Cure Calpain 3
- National Human Genome Research Institute
- National Eye Institute
- National Heart, Lung, and Blood Institute [UM1 HG008900]
- National Human Genome Research Institute [R01 HG009141]
Purpose Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology. Methods Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions. Results We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants inCAPN3,DYSF,ANO5,DMD,RYR1,TTN,COL6A2, andSGCAcollectively accounted for over half of the solved cases; while variants in newer disease genes, such asBVESandPOGLUT1, were also found. The remaining well-characterized unsolved patients (48%) need further investigation. Conclusion Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes.
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