摘要目的:对1例伴有眼部异常的脑小血管病患儿进行遗传学分析，以明确其致病原因。方法:选取2022年5月28日于宁波市妇女儿童医院就诊的1例患儿为研究对象。收集相关临床资料，采集患儿及其父母外周血样并提取基因组DNA，对患儿基因组DNA进行全外显子组测序(WES)并筛选可疑变异，应用Sanger测序进行家系验证，并对变异进行生物信息学分析。本研究已通过宁波大学附属妇女儿童医院医学伦理委员会的审查(批准号：EC2020-048)。结果:①患儿为7岁女性，患有癫痫。②WES检测显示患儿携带 COL4A1基因c.1792G>A(p.G598S)杂合错义变异，Sanger测序显示其父母均为野生型。根据美国医学遗传学与基因组学学会(ACMG)制定的《遗传变异分类标准与指南》，该变异被判定为可能致病性(PS2＋PM1＋PM2_Supporting＋PP3)。③经生物信息学相关软件预测，COL4A1蛋白第598位甘氨酸在不同物种间高度保守；变异型COL4A1蛋白(p.G598S)第598位丝氨酸与599位天冬氨酸产生了新的氢键。 结论:COL4A1基因c.1792G>A(p.G598S)杂合错义变异可能是上述伴眼部异常的脑小血管病患儿的遗传学病因。

abstractsObjective:To explore the genetic etiology of a child with brain small vessel disease 1 with ocular anomalies.Methods:A child who was adwstted to Ningbo Women and Children′s Hospital on May 28, 2022, was selected for the study. Clinical data were collected, and peripheral blood samples from the child and her parents were obtained for genomic DNA extraction. Whole exome sequencing (WES) was performed to screen for pathogenic variants. Candidate variants were validated via Sanger sequencing and subjected to bioinformatic analysis. This study was approved by the Medical Ethics Committee of Ningbo Women and Children′s Hospital (Ethics No. EC2020-048).Results:① The child was a 7-year-old female with a diagnosis of epilepsy. ② WES revealed that she has carried a heterozygous missense variant in the COL4A1 gene: c. 1792G>A (p.Gly598Ser). Sanger sequencing confirmed that her parents both had the wild-type genotype for this variant. Based on American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Interpretation of Sequence Variants, the variant were predicted to be a likely pathogenic (PS2+ PM1+ PM2_Supporting+ PP3). ③ Bioinformatics predicted that amino acid 598 was highly conserved in different species, formed hydrogen bond with Asp599 after becoming Ser598. Conclusion:The heterozygous missense variant of the COL4A1 gene c. 1792G>A (p.G598S) could be the pathogenic cause of this child with Brain small vessel disease 1 with ocular anomalies.