Titinopathies: Phenotype - genotype heterogeneity in an Indian cohort.

Introduction: Titinopathies are heterogenous group of disorders affecting the skeletal and cardiac muscles variably and caused by Titin ( gene mutations located in Chromosome 2. The manifestations extend from congenital to adult-onset myopathies. Here we describe the phenotype-genotype heterogeneity of patients with myopathy/muscular dystrophy associated with TTN variants in an Indian cohort.

Methods: A retrospective descriptive study of 12 patients diagnosed with primary muscle disease evaluated between 2016 and 2023 harboring rare variants.

Results: Eight patients were included (M:F ratio - 3:1). The median age at onset of entire cohort is 5 (range: birth- 33 years). The major clinical phenotypes were congenital myopathy [n = 3, 37.5%], juvenile onset myopathy [n = 3, 37.5%] and adult AD - Hereditary myopathy with early respiratory failure (HMERF) phenotype [n = 2, P6, P8; 25%]. Prominent / wide first interdigital space in feet in congenital and juvenile forms (c.38421_38437delinsC, c.106531 + 1G > A) was a novel feature. The variant c.95134T > C previously reported in HMERF in British population, was noted in two patients in our cohort and with GNE myopathy like phenotype in one. Muscle MRI done in congenital myopathy (c.26201-1G > A) showed fatty infiltration of anterior and posterior thigh with sparing of gracilis, adductor magnus and tibialis anterior.

Conclusion: This is the first Indian study with a large cohort demonstrating many novel mutations and clinical heterogeneity expanding the spectrum of titinopathies.