PIGN基因变异所致多发先天畸形-肌张力低下-癫痫综合征1例患儿的遗传学分析

Genetic analysis of a child with Multiple congenital anomalies-hypotonia-seizures syndrome 1 due to variant of PIGN gene

目的分析1例多发先天畸形-肌张力低下-癫痫综合征1(MCAHS1)患儿的临床表型及遗传学病因。方法收集2023年3月因"间断肢体抽动2年"就诊于青岛大学附属医院的1例MCAHS1患儿的临床资料。采集患儿及其父母的外周血样,对患儿进行全外显子组测序。对候选变异进行Sanger测序家系验证。根据美国医学遗传学与基因组学学会(ACMG)相关指南对变异进行致病性分析。结果患儿为2岁男性,表现为特殊面容、肢体畸形、肌张力低下、运动智力发育落后及癫痫发作。全外显子组测序发现其携带PIGN基因复合杂合变异:c.963G>A(p.Q321=)和c.994A>T(p.I332F),分别遗传自表型正常的母亲与父亲。根据ACMG相关指南,c.963G>A变异判定为致病性(PVS1+PM2_Supporting+PM3),c.994A>T变异判定为意义未明(PM2_Supporting+PP3)。结论本研究发现的PIGN基因变异位点扩展了MCAHS1的变异谱,有助于明确其基因型与表型的对应关系。

Objective To analyze the clinical phenotype and genetic etiology of a child with Multiple congenital anomalies-hypotonia-seizures syndrome 1(MCAHS1).Methods Clinical data of a 2-year-old boy who had presented at the Affiliated Hospital of Qingdao University in March 2023 for"intermittent limb twitching for 2 years"was collected.Peripheral blood samples were collected from the child and his parents for whole-exome sequencing(WES).Candidate variants were verified by Sanger sequencing and bioinformatic analysis based on the guidelines from the American College of Medical Genetics and Genomics(ACMG).Results The child had manifested with distinctive facial features,limb deformities,hypotonia,motor and intellectual delays,and epileptic seizures.WES revealed that he has harbored compound heterozygous variants of the PIGN gene,namely c.963G>A(p.Q321=)and c.994A>T(p.I332F),which were inherited from his phenotypically normal mother and father,respectively.Based on the ACMG guidelines,the c.963G>A was classified as a pathogenic variant(PVS1+PM2_Supporting+PM3),whilst the c.994A>T was classified as a variant of uncertain significance(PM2_Supporting+PP3).Conclusion Above discovery has expanded the mutational spectrum of the PIGN gene variants associated with MCAHS1,which may facilitate delineation of its genotype-phenotype correlation.