Deciphering the Genetic Landscape of Unsolved Congenital Myopathies: A Multinational Research Approach.

Abstract

Background/Objectives: Congenital myopathies (CM) are a diverse group of inherited neuromuscular disorders most frequently characterized by muscle weakness and structural abnormalities on muscle biopsy. A significant proportion of CM cases remain genetically unsolved at a single-centre level, underscoring the necessity for comprehensive research approaches that leverage international collaborations. Method(s): We analysed exome sequencing and short-read genome sequencing data from unsolved CM cases across multiple centres in Europe, the USA, Asia, and Australia. This analysis was complemented by dedicated expert curation of clinical and histopathological data, along with curation of de novo variants and Variants of Uncertain Significance (VUS). We further explored genetic pathomechanisms through in vitro studies, and bulk and single nucleus RNA sequencing (snRNAseq). Result(s): We identified three novel forms of CM. (1) Loss-of-function variants in JPH1 were identified in three unrelated patients with striking bulbar and ocular involvement. (2) Biallelic variants in ASCC3 were identified in eight patients manifesting with a range of overlapping features including early-onset core myopathy, intellectual disability, and respiratory involvement. snRNAseq analysis highlighted the role of ASC-1 complex in translational homeostasis. (3) Our highly collaborative research revealed 12 unique missense variants in TUBA4A in 23 individuals, indicating a novel class of myopathy with de novo, autosomal dominant, and autosomal recessive inheritance. Previously, TUBA4A variants had been associated with FTD, ALS and ataxia. Thus, our study extends the phenotypic landscape of TUBA4A-related disease. Conclusion(s): These findings emphasise the critical role of international collaborations in enhancing genetic interpretation and identifying novel disease genes and genotype-phenotype relationships in neuromuscular disease research.