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. 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. 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. 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. 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 would be useful for the exact molecular diagnosis and treatment of CMT in Pakistani patients.

中文翻译：

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巴基斯坦 Charcot–Marie–Tooth 病家族的新纯合突变

Charcot-Marie-Tooth 病 (CMT) 是一组遗传和临床异质性周围神经系统疾病。很少有研究确定巴基斯坦患者 CMT 的遗传原因。进行这项研究的目的是鉴定对 PMP22 重复呈阴性的五个近亲巴基斯坦 CMT 家族的致病突变。通过应用全外显子组测序进行基因组筛选。我们在四个基因中鉴定出五个致病性或可能致病性纯合突变：SH3TC2 中的 c.2599C > T (p.Gln867*) 和 c.3650G > A (p.Gly1217Asp)，c.19C > T (p.Arg7*) REEP1 中的 HK1、c.247delG (p.Gly83Alafs*44) 和 MFN2 中的 c.334G > A (p.Val112Met)。这些突变尚未在 CMT 患者中报道。据报道，SH3TC2、HK1、REEP1 和 MFN2 的突变与 CMT4C、CMT4G、dHMN5B (DSMA5B)、和 CMT2A，分别。在所有检查的家庭中都证实了基因型 - 表型相关性。我们还使用纯合性作图证实了来自纯合变体的两个等位基因均源自单个祖先。这项研究发现五种新突变是 CMT 的根本原因。SH3TC2、HK1 和 REEP1 的致病性突变在其他人群中很少报道，表明存在种族特异性分布。该研究将有助于巴基斯坦患者 CMT 的精确分子诊断和治疗。SH3TC2、HK1 和 REEP1 的致病性突变在其他人群中很少报道，表明存在种族特异性分布。该研究将有助于巴基斯坦患者 CMT 的精确分子诊断和治疗。SH3TC2、HK1 和 REEP1 的致病性突变在其他人群中很少报道，表明存在种族特异性分布。该研究将有助于巴基斯坦患者 CMT 的精确分子诊断和治疗。