Novel homozygous mutations in Pakistani families with Charcot\u2013Marie\u2013Tooth disease

Sumaira Kanwal,Yu Jin Choi,Jin Hee Park,Shazia Perveen,Hee Ji Choi,Rana Nuzhat,Byung-Ok Choi,Si On Lim,Ki Wha Chung,Aneela Khan

doi:10.1186/s12920-021-01019-5

Abstract

BackgroundCharcot–Marie–Tooth disease (CMT) is a group of genetically and clinically heterogeneous peripheral nervous system disorders. Few studies have identified genetic causes of CMT in the Pakistani patients.MethodsThis study was performed to identify pathogenic mutations in five consanguineous Pakistani CMT families negative for PMP22 duplication. Genomic screening was performed by application of whole exome sequencing.ResultsWe identified five pathogenic or likely pathogenic homozygous mutations in four genes: c.2599C > T (p.Gln867*) and c.3650G > A (p.Gly1217Asp) in SH3TC2, c.19C > T (p.Arg7*) in HK1, c.247delG (p.Gly83Alafs*44) in REEP1, and c.334G > A (p.Val112Met) in MFN2. These mutations have not been reported in CMT patients. Mutations in SH3TC2, HK1, REEP1, and MFN2 have been reported to be associated with CMT4C, CMT4G, dHMN5B (DSMA5B), and CMT2A, respectively. The genotype–phenotype correlations were confirmed in all the examined families. We also confirmed that both alleles from the homozygous variants originated from a single ancestor using homozygosity mapping.ConclusionsThis study found five novel mutations as the underlying causes of CMT. Pathogenic mutations in SH3TC2, HK1, and REEP1 have been reported rarely in other populations, suggesting ethnic-specific distribution. This study would be useful for the exact molecular diagnosis and treatment of CMT in Pakistani patients.

Highlights

Charcot–Marie–Tooth disease (CMT) is a group of genetically and clinically heterogeneous peripheral nervous system disorders
This study aimed to determine the genetic causes of CMT or related neuropathies using in Pakistani patients using whole exome sequencing (WES) and subsequent filtering of called variants
Motor nerve conduction velocities (MNCVs) of the median and ulnar nerves were determined by stimulating at the elbow and wrist while recording compound muscle action potentials (CMAPs) over the abductor pollicis brevis and adductor digiti quinti, respectively

Summary

Introduction

Charcot–Marie–Tooth disease (CMT) is a group of genetically and clinically heterogeneous peripheral nervous system disorders. Few studies have identified genetic causes of CMT in the Pakistani patients. Charcot–Marie–Tooth disease (CMT) and related neuropathies are a group of genetically and clinically heterogeneous peripheral neuropathies with a prevalence of approximately 1 in 2500 people [1]. Only a few studies have been performed to determine the genetic causes of CMT and related peripheral neuropathies in Pakistan [6,7,8,9]. Pakistani patients for whom genetic causes were identified exhibited unusually high frequencies of recessive homozygous mutations. The high rates of homozygous mutations in Pakistani patients can be attributed to the relatively frequent occurrence of consanguineous marriages

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