Whole exome sequencing in 33 patients revealed 4 novel variants in 11 limbs-girdle muscular dystrophy families

Introduction: Muscular dystrophies (MD) are a large heterogeneous group of over 60 neuromuscular disorders caused by mutations in nearly 60 different genes. These conditions lead to varying degrees of neuromuscular dysfunctions, leading to muscular dystrophies-atrophies, gait abnormalities or waddling, tip-toe walking, difficulties in climbing stairs, dilated cardiomyopathy, and respiratory distresses. Methods: In this study, we for the first time examined 67 individuals from 11 families, of whom 33 were affected ranging from 4 to 30 years. Whole exome sequencing was conducted on an index patient from each family, and the causative variants were identified using our in-house data analysis pipeline. The candidate variants were further validated through Sanger sequencing in the family to confirm the segregation of the affected alleles. Results: Patients primarily showed progressive weakening of muscles, changes in muscle tone or structure and the development of an abnormal gait, eventually leading to loss of ambulation. The severity of the disease varied both within and between families. This study identified four novel pathogenic variants (COL6A1; c.1659_1665dup; p.Pro555_Asp557dup, DMD; 145.7Kb cytogenetic band Xp21.1 deletion, DMD: 40.3Kb cytogenetic band Xp21.1 duplication and HMGCR; c.1537C > T; p.Pro513Ser) and six recurrent variants (DMD; c.1032 T > A; p.Tyr344Ter, DMD; c.3923C > A; p.Ser1308Ter, CAPN3; c.379 + 3 A > G, DYSF; c.4251del; p.Ile1418SerfsTer47, ANO5; c.692G > T; p.Gly231Val. and LAMA2; c.1300C > T; p.Arg434Ter) in seven MDs associated genes (COL6A1, DMD, CAPN3, DYSF, HMGCR, ANO5, and LAMA2). Discussion: In this study, we identified four novel and six recurrent pathogenic variants in seven genes, expanding the genetic basis of MD and providing a valuable resource for further diagnostic and therapeutic approaches. These findings have significant implications for enhancing the understanding of MD pathogenesis and may guide the development of personalized therapeutic strategies for affected individuals. Overall, this study contributes to advancing the genetic diagnostics of MD and offers new avenues for therapeutic interventions, potentially improving patient outcomes.