why choose us

300×250 Ad Slot

Research Article: Genetic basis of Charcot-Marie-Tooth disease in Pakistani consanguineous families

Date Published: 2026-09-10

Abstract:
Charcot-Marie-Tooth (CMT) is a group of inherited neuromuscular disorders with diverse clinical features such as muscle weakness and atrophy of the distal regions, foot deformities, sensory loss and decreased or absent reflexes. With the diverse inheritance patterns including dominant, recessive, and X-linked, it exhibits significant genetic heterogeneity often overlapping with other neurological disorders. Whole exome sequencing (WES) has emerged as favorable diagnostic tool for such challenging disease entities. We recruited five Pakistani families that consisted of 14 affected individuals exhibiting representative symptoms of CMT such as severe muscle weakness of the lower limbs, muscles atrophy, claw hands and feet deformities. WES data analysis revealed two novel and two already reported homozygous missense variants in GDAP1 (NM_018972) c.1A?>?G (p. Met1Val), c.683A?>?G (p. Glu228Gly), c.734C?>?T (p. Thr245Ile) and c.811G?>?A (p. Gly271Arg) in families A–D, respectively. While a novel homozygous SBF2 variant c.2746G?>?C, p. (Gly916Arg) was identified in family E. Sanger sequencing confirm the segregation of all candidate variants in their respective pedigrees. Moreover, molecular modeling supports the destabilizing effect of these variants on final protein product of both GDAP1 and SBF2 by inducing modifications in overall conformation of the protein. The present study expands the mutation spectrum of the GDAP1 and SBF2 genes, with possible implications for improved understanding of disease pathophysiology. Furthermore, the current study highlights the importance of NGS, particularly WES, in achieving rapid and precise molecular genetic diagnosis for clinical purposes, especially in neuromuscular disorders of heterogeneous nature.

Introduction:
Charcot-Marie-Tooth (CMT) disease is the most common form of inherited neuromuscular disorder. The global prevalence of CMT is one in 2,500 ( 1 ). It exhibits substantial clinical heterogeneity, though main features include muscle weakness and atrophy of the distal regions, initially of the lower limbs and spreading to the upper limbs, foot deformities, and sensory loss and absent or decreased reflexes ( 1–3 ). Clinical sub classification of CMT is assigned on the basis of electrophysiological findings and these…

Read more

300×250 Ad Slot