Genetic landscape and diagnostic outcomes of UK patients With congenital myopathies and muscular dystrophies over a 10-Year period

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Abstract

BACKGROUND AND OBJECTIVES: Congenital myopathies (CMYOs) and congenital muscular dystrophies (CMDs) are rare, clinically and genetically heterogeneous neuromuscular conditions characterized by muscle weakness, usually with onset at birth or in the first few months of life. Next-generation sequencing (NGS) has significantly enhanced diagnostic capabilities and transformed the diagnostic process for such rare conditions. The aim of this study was to describe the outcomes of NGS analysis and genotypic prevalence among patients with CMYO and CMD referred for diagnostic assessment to the National Highly Specialized Service (HSS) at the Dubowitz Neuromuscular Centre in London, United Kingdom, over a period of 10 years. METHODS: Diagnostic outcomes of all referrals to the HSS for NGS analysis of CMYO and/or CMD gene panels from 2014 to 2023 were included and reviewed. RESULTS: A total of 1,927 patients were referred to the service, and a total of 2,352 genetic analyses were completed over 10 years. Overall, 553 of 1,927 unrelated individuals (28.7%) had a genetic diagnosis of CMYO or CMD, due to pathogenic variant/s in one of 59 genes. A total of 345 patients had a diagnosis of CMYO and 208 had CMD. The most common CMYOs were due to pathogenic variants in RYR1 (23.8%), TTN (10.7%), MTM1 (10.4%), NEB (8.7%), SELENON (7.5%), ACTA1 (6.7%), or DNM2 (4.6%) genes. Pathogenic changes in further 27 CMYO genes were also identified. The most common CMDs were due to pathogenic variants in COL6A1 (20.7%), LAMA2 (15.4%), COL6A2 (13.5%), COL6A3 (7.2%), GMPPB (6.7%), POMGnT1 (6.3%), FKRP (6.3%), or LMNA (4.8%) genes. Pathogenic changes in further 17 CMD genes were also identified. A total of 1,374 patients remained undiagnosed. Of these, 78 patients (5.7%) carried a heterozygous pathogenic change in a recessive gene and 419 patients (30.5%) carried a variant of unknown significance, with variants in RYR1 (17.1%), NEB (14.2%), and TTN (12.7%) genes being the most frequent. DISCUSSION: This large, real-world cohort provides a comprehensive overview of the genetic distribution of CMYO and CMD in routine practice. Our findings offer a robust framework to guide diagnostic strategies, inform variant interpretation, and support clinical decision making in the genomic era.