Department of Zoology, Government Postgraduate College Dargai, Malakand 23060, Pakistan.
Higher Education Department, Government of Khyber Pakhtunkhwa, Peshawar 24550, Pakistan.
Genes (Basel). 2023 Jan 27;14(2):328. doi: 10.3390/genes14020328.
Charcot-Marie-Tooth disease (CMT) and autosomal recessive spastic ataxia of Charlevoix-Saguenay type (ARSACS) are large heterogeneous groups of sensory, neurological genetic disorders characterized by sensory neuropathies, muscular atrophies, abnormal sensory conduction velocities, and ataxia. CMT2EE (OMIM: 618400) is caused by mutations in (OMIM: 137960), CMT4F (OMIM: 614895) is caused by (OMIM: 605725), CMTX1 (OMIM: 302800) is caused by mutations in (OMIM: 304040), and ARSACS (OMIM: 270550) is caused by mutations in (OMIM: 604490). In this study, we enrolled four families: DG-01, BD-06, MR-01, and ICP-RD11, with 16 affected individuals, for clinical and molecular diagnoses. One patient from each family was analyzed for whole exome sequencing and Sanger sequencing was done for the rest of the family members. Affected individuals of families BD-06 and MR-01 show complete CMT phenotypes and family ICP-RD11 shows ARSACS type. Family DG-01 shows complete phenotypes for both CMT and ARSACS types. The affected individuals have walking difficulties, ataxia, distal limb weakness, axonal sensorimotor neuropathies, delayed motor development, pes cavus, and speech articulations with minor variations. The WES analysis in an indexed patient of family DG-01 identified two novel variants: c.83G>T (p.Gly28Val) in and c.4934G>C (p.Arg1645Pro) in . In family ICP-RD11, a recurrent mutation that causes ARSACS, c.262C>T (p.Arg88Ter) in , was identified. Another novel variant, c.231C>A (p.Arg77Ter) in , which causes CMT4F, was identified in family BD-06. In family MR-01, a hemizygous missense variant c.61G>C (p.Gly21Arg) in was identified in the indexed patient. To the best of our knowledge, there are very few reports on , , , and causing CMT and ARSACS phenotypes in the Pakistani population. Our study cohort suggests that whole exome sequencing can be a useful tool in diagnosing complex multigenic and phenotypically overlapping genetic disorders such as Charcot-Marie-Tooth disease (CMT) and spastic ataxia of Charlevoix-Saguenay type.
腓骨肌萎缩症（CMT）和常染色体隐性痉挛性共济失调型夏科-马里-图什病（ARSACS）是一组大型感觉神经遗传性疾病，其特征为感觉神经病、肌肉萎缩、感觉神经传导速度异常和共济失调。CMT2EE（OMIM：618400）由 （OMIM：137960）中的突变引起，CMT4F（OMIM：614895）由 （OMIM：605725）中的突变引起，CMTX1（OMIM：302800）由 （OMIM：304040）中的突变引起，而 ARSACS（OMIM：270550）由 （OMIM：604490）中的突变引起。在这项研究中，我们招募了四个家庭：DG-01、BD-06、MR-01 和 ICP-RD11，共有 16 名受影响的个体进行临床和分子诊断。对每个家庭的一名患者进行全外显子组测序，对其余家庭成员进行 Sanger 测序。BD-06 家族和 MR-01 家族的受影响个体表现出完全的 CMT 表型，而 ICP-RD11 家族表现出 ARSACS 型。DG-01 家族的个体表现出 CMT 和 ARSACS 型的完全表型。受影响的个体有行走困难、共济失调、远端肢体无力、轴索性感觉运动神经病、运动发育迟缓、高弓足和言语发音轻微变化。在 DG-01 家族的一名索引患者中，WES 分析发现了两个新的变异： 中的 c.83G>T（p.Gly28Val）和 中的 c.4934G>C（p.Arg1645Pro）。在 ICP-RD11 家族中，发现了导致 ARSACS 的重复突变 c.262C>T（p.Arg88Ter）在 中。在 BD-06 家族中发现了另一个新的变异 c.231C>A（p.Arg77Ter）在 中，导致 CMT4F。在 MR-01 家族中，在索引患者中发现了 中的半合子错义变异 c.61G>C（p.Gly21Arg）。据我们所知，在巴基斯坦人群中，很少有关于 、 、 和 引起 CMT 和 ARSACS 表型的报道。我们的研究队列表明，全外显子组测序可以成为诊断复杂的多基因和表型重叠遗传疾病（如腓骨肌萎缩症（CMT）和夏科-马里-图什型痉挛性共济失调）的有用工具。
