全外显子组测序在9p缺失综合征诊断中的应用

Application of whole exome sequencing in 9p deletion syndrome

目的探讨1例具有子宫发育不全而无面容异常和智力语言障碍的XX核型女性9p缺失综合征患者的临床及分子细胞遗传学特征。方法对患者及其父母行外周血染色体G显带核型分析,并对患者行全外显子组测序,分析9p末端缺失相关的临床表现、分子细胞遗传学特征及两者之间可能的关联性。结果该例9p末端缺失女性患者的临床症状主要为原发性闭经、幼稚子宫、性激素异常、癫痫等,未见三角头畸形和智力语言障碍等常见的9p缺失综合征典型症状。核型分析结果为46,XX,del(9)(p23),其父母核型未见异常。全外显子组测序结果显示,患者在9p24.3-p23(24846~13022661)区域存在单拷贝缺失,缺失片段长度约为13.0 Mb,覆盖了61个已知基因,包括DMRT1、DMRT3、DMRT2、DOCK8、KANK1、FOXD4等多个与9p缺失综合征表型密切相关的关键基因,在染色体其他区域并未发现其他致病性拷贝数变异(CNV)、碱基插入和缺失。结论9p末端缺失导致DMRT1基因单倍剂量不足可能是患者幼稚子宫、原发性闭经的主要致病因素。全外显子组测序提供了与临床表型相关的基因型背景数据。

Objective To report the clinical and molecular cytogenetic characteristics of a XX female patient with 9p deletion syndrome.Methods Chromosome G-banding karyotyping was performed on the patient and her parents,and whole exome sequencing was performed on the patient.The clinical,molecular cytogenetic characteristics and distal deletions on chromosome 9p were analyzed.Results The patient presented with primary amenorrhea,infantile uterus,abnormal level of sex hormones and epilepsy,but without typical clinical features of 9p deletion syndrome such as trigonocephaly and mental retardation.Karyotyping analysis of the patient showed 46,XX,del(9)(p23),and her parents'karyotypes were normal.Whole exome sequencing showed the patient had a deletion on 9p24.3-p23(24846-13022661,13.0 Mb),which included critical genes such as DMRT1,DMRT3,DMRT2,DOCK8,KANK1,FOXD4(totally 61 genes).No other pathogenic copy number variation(CNV),base insertion and deletion were detected in other regions of chromosomes.Conclusions Haploinsufficiency of one or more genes on the terminal of chromosome 9p may underlie the disorders of sexual development of the patient.Whole exome sequencing provides genotypic data relevant to the clinical phenotypes.