Abstract：
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 MPV17 (OMIM: 137960), CMT4F (OMIM: 614895) is caused by PRX (OMIM: 605725), CMTX1 (OMIM: 302800) is caused by mutations in GJB1 (OMIM: 304040), and ARSACS (OMIM: 270550) is caused by mutations in SACS (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 MPV17 and c.4934G>C (p.Arg1645Pro) in SACS. In family ICP-RD11, a recurrent mutation that causes ARSACS, c.262C>T (p.Arg88Ter) in SACS, was identified. Another novel variant, c.231C>A (p.Arg77Ter) in PRX, which causes CMT4F, was identified in family BD-06. In family MR-01, a hemizygous missense variant c.61G>C (p.Gly21Arg) in GJB1 was identified in the indexed patient. To the best of our knowledge, there are very few reports on MPV17, SACS, PRX, and GJB1 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.
摘要：
Charlevoix-Saguenay型（ARSACS）的Charcot-Marie-Tooth病（CMT）和常染色体隐性遗传性痉挛性共济失调是感觉上的大量异质群体，以感觉神经病变为特征的神经遗传疾病，肌肉萎缩,异常的感觉传导速度，和共济失调.CMT2EE（OMIM：618400）是由MPV17（OMIM：137960）中的突变引起的，CMT4F(OMIM:614895)是由PRX(OMIM:605725)引起的,CMTX1（OMIM：302800）是由GJB1（OMIM：304040）中的突变引起的，ARSACS(OMIM:270550)是由SACS(OMIM:604490)中的突变引起的。在这项研究中,我们纳入了4个家庭：DG-01、BD-06、MR-01和ICP-RD11，有16个受影响的个体，用于临床和分子诊断。对来自每个家庭的一名患者进行全外显子组测序分析,并对其余家庭成员进行Sanger测序。家庭BD-06和MR-01的受影响个体显示完整的CMT表型，家庭ICP-RD11显示ARSACS类型。家族DG-01显示CMT和ARSACS类型两者的完整表型。受影响的个人有行走困难，共济失调,远端肢体无力，轴突感觉运动神经病,电机发育延迟，pescavus,和言语表达有微小的变化。在DG-01家族的索引患者中进行的WES分析鉴定出两个新的变体：c.83G>T（p。Gly28Val）在MPV17和c.4934G>C（p。Arg1645Pro）在SACS中。在家族ICP-RD11中，一种导致ARSACS的复发性突变，c.262C>T（p。Arg88Ter）在SACS中，已确定。另一种新颖的变体，c.231C>A（p。Arg77Ter）在PRX中，这导致了CMT4F，在BD-06家族中鉴定。在MR-01家族中，半合子错义变体c.61G>C（p。在有索引的患者中鉴定出GJB1中的Gly21Arg）。据我们所知,关于MPV17，SACS，PRX,GJB1在巴基斯坦人群中引起CMT和ARSACS表型。我们的研究队列表明，整个外显子组测序可以诊断复杂的多基因和表型重叠的遗传疾病，例如Charcot-Marie-Tooth病（CMT）和Charlevoix-Saguenay型的痉挛性共济失调。
