TONSL基因复合杂合变异所致海绵状脊椎干骺端发育不良1例患儿的分析

Analysis of a child with SPONASTRIME dysplasia due to compound heterozygous variants of TONSL gene

目的探讨1例海绵状脊椎干骺端发育不良(SD)患儿的临床特征及遗传学病因。方法选取2022年8月因"身材矮小"就诊于临沂市人民医院的1例SD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(WES),并对候选变异进行Sanger测序验证。结果患儿为9月龄女性,表现为身材矮小、面中部发育不良、关节松弛、膝内翻、长骨干骺端不规则、腰椎扁平伴凹陷等。WES显示其TONSL基因存在c.3088G>T(p.Glu1030*)和c.3053G>A(p.Arg1018His)复合杂合变异,分别遗传自表型正常的父亲和母亲,且既往均未见报道。根据美国医学遗传学与基因组学学会(ACMG)相关指南,c.3088G>T被判定为可能致病性变异(PVS1+PM2_Supporting),c.3053G>A被判定为临床意义未明变异(PM2_Supporting+PM3+PP3)。结论TONSL基因的c.3088G>T及c.3053G>A复合杂合变异可能是上述患儿的遗传学病因。上述发现为患儿的临床诊断与遗传咨询提供了依据。

Objective To explore the clinical features and genetic etiology of a child with SPONASTRIME dysplasia(SD).Methods A 9-month-old female who had presented at the Linyi People′s Hospital in August 2022 for short stature was selected as the study subject.Clinical data of the child were collected,and whole exome sequencing(WES)was carried out.Sanger sequencing was used for validating the candidate variants.Results The child has manifested short stature,mid-face hypoplasia,joint laxity,internal knee rotation,irregularities in the metaphysis of long bones,and flat and concave lumbar vertebrae.WES revealed that she has harbored compound heterozygous variants of the TONSL gene,namely c.3088G>T(p.Glu1030*)and c.3053G>A(p.Arg1018His),which were inherited from her phenotypically normal parents.Neither variant was reported previously.Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG),the c.3088G>T variant was classified as likely pathogenic(PVS1+PM2_Supporting),whilst the c.3053G>A was classified as a variant of uncertain significance(PM2_Supporting+PM3+PP3).Conclusion The c.3088G>T and c.3053G>A compound heterozygous variants of the TONSL gene probably underlay the pathogenesis in this patient.Above finding has facilitated the clinical diagnosis and genetic counseling for her family.