目的探讨1个神经性肌强直与轴索型神经病(neuromyotonia and axonal neuropathy,NMAN)家系的临床及遗传学特点。方法收集先证者及其双亲的临床资料与外周血样,应用三联重复引物PCR联合毛细管电泳检测先证者强直性肌营养不良致病基因DMPK与ZNF9的动态突变;应用高通量测序筛查神经系统遗传病致病基因的变异,用Sanger测序验证检出的基因变异;应用Sanger测序分析双亲及100名非病个体的变异位点基因型;分析基因变异的致病性。结果未发现DMPK与ZNF9基因动态突变位点的异常扩展;测序结果显示先证者HINT1基因第3外显子存在c.335C>T(p.R119W)纯合错义变异,其表型正常的双亲均为上述变异的携带者,对照群体未检出该变异。基于ACMG指南的评价提示为致病性变异。结论在NMAN患者中发现的这个新的致病变异(c.335C>T,p.R119W)为HINT1基因与NMAN的关系提供了更多的证据,填补了中国人群HINT1基因突变谱的空白。
Objective To explore clinical and genetic features of a pedigree affected with autosomal recessive neuromyotonia and axonal neuropathy (NMAN). Methods For the proband and her parents, clinical data was collected, genomic DNA was extracted from peripheral blood samples. Triplet primed-PCR was carried out to detect dynamic mutation of DMPK and ZNF9 genes, which are responsible for myotonic dystrophy, by capillary electrophoresis. High-throughput sequencing was used to screen variants of candidate genes for Mendelian disorders involving the nervous system. Candidate variants were confirmed by Sanger sequencing. The genotype of the variant was determined in the parents and 100 healthy controls. Pathogenicity of the variant was assessed by ACMG criterion. Results Mutation of DMPK and ZNF9 genes was excluded. DNA sequencing has identified a homozygous missense variant (c.335C> T, p. R119W) in the HINT1 gene. Both parents were found to carry the variant. The same variant was not found among the healthy controls. According to the ACMG criterion, the missense variant was classified as a pathogenic variant. Conclusion The c. 335C>T (p.R119W) of the HINT1 gene probably underlie the disease in this pedigree. Above finding provided further evidence for the connection between HINT1 and NMAN and enriched the mutation spectrum of HINT1 gene.
Chinese Journal of Medical Genetics