非典型Stickler综合征I型三个家系的遗传分析及产前诊断

Genetic Analysis and Prenatal Diagnosis of Three Families with Nonsydromic Ocular Stickler Syndrome Type I

目的:分析非典型Stickler综合征I型患者的临床表现和遗传学病因,为患者基因诊断、遗传咨询、产前诊断提供理论依据。方法:实验研究。收集3个典型Stickler综合征I型家系患者的临床表型资料,采集患者及家系其他成员的外周血提取基因组DNA。应用全外显子组测序筛查可疑基因变异,对候选变异进行Sanger测序验证并检测家系全部受检者变异携带情况。通过人类基因变异数据库和PubMed数据库检索候选变异的致病性报道情况,依据美国医学遗传学和基因组学学院与分子病理学协会(ACMG)指南判断致病性及等级。依据先证者相关变异结果对孕妇行产前诊断。结果:纳入研究的3个家系均检测到Stickler综合征I型致病基因变异。家系1患者携带COL2A1基因c.1693C>T(p.R565C)杂合变异,家系2患者携带COL2A1基因c.2862C>T(p.G954=)杂合变异,家系3患者携带COL2A1基因c.2355+1G>A(splicing)杂合变异。这3个基因变异经保守性分析、功能预测并依据ACMG指南逐一打分判断为致病性变异。结论:全外显子组测序等分子遗传检测技术对非典型Stickler综合征I型的病因学诊断具有重要意义,本研究中3个家系患者均找到遗传学病因,在基因水平确诊非典型Stickler综合征I型。

Objective:To analyze the clinical manifestations and genetic etiology of nonsyndromic ocular Stickler syndrome type I(STLI)patients,and to provide them with the theoretical basis for gene diagnosis,genetic counseling and prenatal diagnosis.Methods:This was a experimental study.Clinical data from 3 families were collected and genomic DNA was extracted from the peripheral blood of patients and related subjects.Whole exome sequencing was used to screen suspicious gene mutations,and Sanger sequencing was used to verify the candidate mutations and investigate the mutation-carrying status of other members of the families.The Human Gene Mutation Database(HGMD)and PubMed databases were searched for the pathogenicity reports of the candidate gene mutations,and pathogenicity was judged according to The American College of Medical Genetics and Genomics(ACMG)guidelines.Results:Pathogenic gene variations for Stickler syndrome type I was detected in all 3 families.The patients in family 1 carried the heterozygous variation of COL2A1 c.1693C>T(p.R565C),a patient in family 2 carried the heterozygous variation of COL2A1 c.2862C>T(p.G954=),and a patient in family 3 carried the heterozygous variation of COL2A1 c.2355+1G>A(spilling).The three variants were identified through conservative analysis and functional prediction and then classified as pathogenic according to ACMG guidelines.Conclusions:Whole exome sequencing and other molecular genetic techniques are of great significance for the etiological diagnosis of atypical STL1.The cause of the disease in the patients of the families in this study was detected and effective genetic counseling and prenatal diagnosis was carried out.