MCPH1基因变异致原发性小头畸形患儿的表型及遗传学分析

Phenotypic and Genetic Analysis of Children with Primary Microcephaly Caused by MCPH1 Gene Mutation

目的对1例原发性小头畸形患儿进行临床分析和基因检测,以明确致病原因。方法对1例原发性小头畸形患儿的临床资料进行回顾性分析。采用下一代测序(NGS)技术对患儿进行全外显子基因检测,对变异位点采用Sanger测序法进行验证。对变异位点进行生物信息学分析。结果患儿主要的临床表现为小头畸形、下颌稍小、高腭弓、眼眦稍上斜、运动及认知发育落后。基因结果显示,患儿MCPH1基因存在第6外显子c.445G>A(Val149Lle)及第13外显子c.2312C>G(Pro771Arg)复合杂合变异。患儿父亲携带MCPH1基因c.445G>A杂合变异,母亲携带MCPH1基因c.2312C>G杂合变异,姐姐未检测到该变异。HGMD Pro、PubMed和ClinVar数据库无关于MCPH1基因c.445G>A和c.2312C>G变异的报道。ExAC数据库和千人基因组数据库中未收录MCPH1基因c.445G>A变异和c.2312C>G变异。Polyphen2、SIFT、Mutation Taster在线软件预测MCPH1基因c.445G>A变异为良性(BH4),MCPH1基因c.2312C>G变异为有害。根据美国医学遗传学与基因组学学会(ACMG)指南评估2个变异均为可能致病的变异。结论患儿临床表型高度符合小头畸形的诊断,但基因检测致病证据不充分。因此除MCPH1基因(8p23.1)区域突变外,可能还存在影响功能内含子区域的突变。

Objective To analyze the clinical features and detect the gene of a child with primary microcephaly,so as to identify the cause of the disease.Methods The clinical data of a child with primary microcephaly were analyzed retrospectively.Next generation sequencing(NGS)technology was used to detect the whole exon gene of children,and Sanger sequencing method was used to verify the mutation sites.Bioinformatics analysis was carried out on the mutation sites.Results The main clinical manifestations of the children were microcephaly,slightly smaller mandible,high palatal arch,slightly inclined canthus,and poor motor and cognitive development.Gene results showed that there was a compound heterozygous variation of exon 6 c.445G>A(Val149Lle)and exon 13 c.2312C>G(Pro771Arg)in MCPH1 gene.The father of the child carries c.445G>A heterozygous variation of MCPH1 gene,and the mother carries c.2312C>G heterozygous variation of MCPH1 gene.The sister does not detect this variation.HGMD Pro,PubMed and ClinVar databases have no reports on the c.445G>A and c.2312C>G variants of MCPH1 gene.The exAC database and the 1000 person genome database did not include the c.445G>A variation and c.2312C>G variation of MCPH1 gene.Polyphen_2、SIFT、Mutation Taster The online software predicts that the c.445G>A mutation of MCPH1 gene is benign(BH4),and the c.2312C>G mutation of MCPH1 gene is harmful.According to the guidelines of the American Society of Medical Genetics and Genomics(ACMG),the two variants were evaluated as possible pathogenic variants.Conclusion The clinical phenotypes of the children are highly consistent with the diagnosis of microcephaly,but the evidence of genetic detection is insufficient.Therefore,in addition to the mutations in the MCPH1 gene(8p23.1)region,there may also be mutations that affect the functional intron region.