Novel homozygous mutations in Pakistani families with recessive Charcot-Marie-Tooth disease

Abstract Background Charcot-Marie-Tooth disease (CMT) is a group of genetically and clinically heterogeneous peripheral nervous disorders. Few studies have identified genetic causes in the Pakistani CMT patients. Methods This 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 Results We 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. All the mutations were not reported in the CMT patients. Mutations in the SH3TC2, HK1, REEP1, and MFN2 have been reported to be implicated to 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 were originated from a single founder using homozygosity mapping. Conclusions This 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 will be useful for the exact molecular diagnosis and treatment in the Pakistani CMT patients.