SPRED1基因变异所致Legius综合征3例的临床及遗传学分析

Clinical and genetic analysis of three children with Legius syndrome due to variants of SPRED1 gene

目的探讨3例Legius综合征患儿的临床表型及遗传学特征。方法选取2019年6月6日至2022年8月25日以性早熟或矮小症就诊于河南省儿童医院的3例疑似Legius综合征的患儿作为研究对象。收集患儿的临床资料,对其进行全外显子组测序,对候选变异进行Sanger测序家系验证。结果3例患儿(2女1男,年龄分别为4岁6个月、8岁、14岁8个月)均具有典型的咖啡斑,例1合并性早熟、例2和例3合并矮小症。基因检测提示患儿1携带SPRED1基因c.751C>T(p.Arg251Ter194)新发杂合变异,例2携带SPRED1基因c.229A>T(p.Lys77Ter368)杂合变异,例3携带SPRED1基因c.1044_1046delinsC(p.R349fs*11)杂合变异。根据美国医学遗传学与基因组学学会相关指南,c.751C>T(p.Arg251Ter194)判断为可能致病性变异(PVS1_Strong+PM2_Supporting+PM6),既往未见报道。例2、3均为已知的致病性变异。结论3例患儿均具有多处咖啡斑,同时伴有性早熟或矮小症,且均携带SPRED1基因变异,考虑为Legius综合征。

ObjectiveTo explore the clinical and genetic characteristics of three children with Leguis syndrome.MethodsThree children suspected as Legius syndrome at the Henan Children′s Hospital for precocious puberty or short stature from June 6,2019 to August 25,2022 were selected as the study subjects.Clinical data of the children were collected.All children were subjected to whole exome sequencing,and candidate variants were verified by Sanger sequencing.ResultsAll of the children(including 2 females and 1 male,and aged 4 years and 6 months,8 years,and 14 years and 8 months,respectively)had typical caféde lait spots.Child 1 also had precocious puberty,and children 2 and 3 had short statures.Genetic testing revealed that all of them had harbored heterozygous variants of the SPRED1 gene,including c.751C>T(p.Arg251Ter194)in child 1,c.229A>T(p.Lys77Ter368)in child 2,and c.1044_1046delinsC(p.R349fs*11)in child 3.Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG),the c.751C>T(p.Arg251Ter194)variant was predicted to be likely pathogenic,whilst the other two were known pathogenic variants.ConclusionAll of the three children were diagnosed with Leguis syndrome due to variants of the SPRED1 gene,which had manifested as multiple caféde lait spots in conjunct with precocious puberty or short statures.