Department of Biosciences, COMSATS University Islamabad, Sahiwal, Pakistan.
Department of Biological Sciences, Kongju National University, 56 Gongjudaehakro, Gongju, 32588, Korea.
BMC Med Genomics. 2021 Jun 30;14(1):174. doi: 10.1186/s12920-021-01019-5.
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.
Charcot-Marie-Tooth 病（CMT）是一组具有遗传和临床异质性的周围神经系统疾病。很少有研究在巴基斯坦患者中确定 CMT 的遗传原因。
本研究旨在鉴定五个巴基斯坦近亲 CMTDNA 阴性的先证者家族中的致病突变。通过应用全外显子组测序进行基因组筛查。
我们在四个基因中发现了五个致病或可能致病的纯合突变：SH3TC2 中的 c.2599C>T(p.Gln867*)和 c.3650G>A(p.Gly1217Asp)，HK1 中的 c.19C>T(p.Arg7*)，REEP1 中的 c.247delG(p.Gly83Alafs*44)，以及 MFN2 中的 c.334G>A(p.Val112Met)。这些突变在 CMT 患者中尚未报道。SH3TC2、HK1、REEP1 和 MFN2 中的突变已被报道与 CMT4C、CMT4G、dHMN5B（DSMA5B）和 CMT2A 相关。在所有检查的家族中都证实了基因型-表型相关性。我们还通过纯合子作图证实了来自纯合变体的两个等位基因均源自一个单一祖先。
本研究发现了五个新的突变作为 CMT 的潜在原因。SH3TC2、HK1 和 REEP1 中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。本研究将有助于对巴基斯坦患者的 CMT 进行准确的分子诊断和治疗。
