Clinical and genomic evaluation of 207 genetic myopathies in the Indian subcontinent

Objective Inherited myopathies comprise more than 200 different
individually rare disease-subtypes but when combined together have a high
prevalence of 1 in 6000 individuals across the world. Our goal was to
determine for the first time the clinical- and gene-variant spectrum of
genetic myopathies in a substantial cohort study of the Indian
subcontinent. Methods In this cohort-study, we performed the first large
clinical exome sequencing (ES) study with phenotype correlation on 207
clinically well-characterized inherited myopathy-suspected patients from
the Indian subcontinent with diverse ethnicities. Results
Clinical-correlation driven definitive molecular diagnosis was established
in 49% (101 cases; 95% CI, 42%-56%) of patients with the major
contributing pathogenicity in either of three genes, GNE (28%;
GNE-myopathy), DYSF (25%; Dysferlinopathy) and CAPN3 (19%; Calpainopathy).
We identified 65 variant alleles comprising 37 unique variants in these
three major genes. 78% of the DYSF patients were homozygous for the
detected pathogenic variant suggesting the need for carrier-testing for
autosomal-recessive disorders like Dysferlinopathy that are common in
India. We describe the observed clinical spectrum of myopathies including
uncommon and rare subtypes in India: Sarcoglycanopathies (SGCA/B/D/G),
Collagenopathy (COL6A1/2/3), Anoctaminopathy (ANO5), telethoninopathy
(TCAP), Pompe-disease (GAA), Myoadenylate-deaminase-deficiency-myopathy
(AMPD1), myotilinopathy (MYOT), laminopathy (LMNA), HSP40-proteinopathy
(DNAJB6), Emery-Dreifuss-muscular-dystrophy (EMD), Filaminopathy (FLNC),
TRIM32-proteinopathy (TRIM32), POMT1-proteinopathy (POMT1), and
Merosin-deficiency-congenital-muscular-dystrophy-type-1 (LAMA2). 13
Patients harbored pathogenic variants in >1 gene and had unusual
clinical features suggesting a possible role of synergistic-heterozygosity
/ digenic-contribution to disease presentation and progression.
Conclusions Application of clinically-correlated ES to myopathy diagnosis
has improved our understanding of the clinical and genetic spectrum of
different subtypes and their overlaps in Indian patients. This, in turn,
will enhance the global gene-variant-disease databases by including data
from developing countries/continents for more efficient clinically-driven
molecular diagnostics.