Polavarapu_2023_Brain__

Congenital myasthenic syndromes are a rare group of inherited disorders caused by gene defects associated with the neuromuscular junction and potentially treatable with commonly available medications such as acetylcholinesterase inhibitors and beta2 adrenergic receptor agonists. In this study we identify and genetically characterise the largest cohort of congenital myasthenic syndrome patients from India to date. Clinically suspected patients evaluated in a South Indian hospital between 2014-2019 underwent genetic testing either by standard diagnostic methods of gene panel testing or a two-step method of hotspot screening followed by whole-exome sequencing. In total 156 genetically diagnosed patients (141 families) have been characterised in this study and the mutational spectrum and genotype-phenotype correlation described. 87 males and 69 females were evaluated with an age of onset ranging from congenital to fourth decade (mean 6.6 +/- 9.8 years). The mean age at diagnosis was 19 +/- 12.8 (1-56 years) with a mean diagnostic delay of 12.5 +/- 9.9 (0-49 years). Disease-causing variants in 17 congenital myasthenic syndrome-associated genes were identified in 132 families (93.6%), while in nine families (6.4%) variants in genes not associated with congenital myasthenic syndromes were found. Overall, postsynaptic defects were most common (62.4%) followed by glycosylation defects (21.3%), synaptic basal lamina genes (4.3%) and presynaptic defects (2.8%). Other genes found in our cohort to cause neuromuscular junction defects (DES, TEFM) accounted for 2.8%. Among the individual congenital myasthenic syndrome genes, the most commonly affected gene was CHRNE (39.4%) followed by DOK7 (14.4%), DPAGT1 (9.8%), GFPT1 (7.6%), MUSK (6.1%), GMPPB (5.3%) and COLQ (4.5%). We identified 22 recurrent variants in this study, out of which eight were found to be geographically specific to the Indian subcontinent. Apart from the known common CHRNE variants p.E443Kfs*64 (11.4%) and DOK7 p.A378Sfs*30 (9.3%), we identified seven novel recurrent variants specific to this cohort including DPAGT1 p.T380I and DES c.1023 + 5G > A for which founder haplotypes are suspected. This study highlights the geographic differences in the frequencies of various causative congenital myasthenic syndrome genes and underlines the increasing significance of glycosylation genes (DPAGT1, GFPT1 and GMPPB) as a cause of neuromuscular junction defects. Myopathy and muscular dystrophy genes like GMPPB and DES presenting as gradually progressive limb girdle congenital myasthenic syndromes expand the phenotypic spectrum. The novel genes MACF1 and TEFM identified in this cohort add to the expanding list of genes with new mechanisms causing neuromuscular junction defects.