Sin3A基因变异致Witteveen-Kolk综合征遗传学分析

Genetic analysis of Witteveen-Kolk syndrome caused by Sin3A variation

目的 探讨开关不敏感3转录调节因子家族成员A(Sin3A)基因变异导致的Witteveen-Kolk综合征临床表型和遗传学特点。方法 收集1例发育迟缓患儿的临床资料,对患儿及其父母进行全外显子基因测序,采用Sanger测序验证可疑变异,并进行家系分析。结合文献分析Witteveen-Kolk综合征的临床特征和基因变异特点。结果 Witteveen-Kolk综合征患儿临床表现主要为轻中度智力障碍或发育迟缓、特殊面容(长脸、前额突出、鼻梁凹陷、长人中等)、身材矮小。颅脑磁共振成像(MRI)显示不同程度的脑畸形。全外显子基因测序结果显示,患儿Sin3A基因存在移码变异c.803dupC(p.Leu269Thrfs*37)(杂合)。Sanger测序证实存在变异位点,患儿父母该位点均为正常基因型。gnomAD等对照人群数据库未收录该变异位点,根据美国医学遗传学和基因组学学会(ACMG)/美国分子病理学学会(AMP)指南归类为“致病性”变异。结论 Sin3A基因变异可导致Witteveen-Kolk综合征。基因检测可明确生长发育迟缓伴特殊面容患儿的病因。

Objective To investigate the clinical phenotypes and genetic characteristics of Witteveen-Kolk syndrome caused by switch-insensitive 3 transcription regulator family member A(Sin3A)variation.Methods The clinical data of a child with developmental delay were collected,and whole-exome sequencing was used to determine the child and his parents.The suspected variations were verified by Sanger sequencing.The clinical characteristics and variation characteristics of Witteveen-Kolk syndrome were analyzed based on literature.Results The main clinical manifestations of Witteveen-Kolk syndrome were mild to moderate mental retardation or developmental delay,special facial features(long face,prominent forehead,sunken nose bridge,long philtrum)and short stature.Brain magnetic resonance imaging(MRI)showed different degrees of brain malformations.Sin3A c.803dupC(p.Leu269Thrfs*37)(heterozygous)frameshift variation was found by whole-exome sequencing.Sanger sequencing showed that the parents of the child had normal genotypes at this locus.The variation was not included in gnomAD and other control population databases,which was classified as"pathogenic"variation according to American College of Medical Genetics and Genomics(ACMG)/the Association for Molecular Pathology(AMP)variation classification criteria.Conclusions Sin3A variation can lead to Witteveen-Kolk syndrome.Genetic testing can confirm the etiology diagnosis of children with developmental delay and special facial features.