Zhang Wenyu, Qi Na, Guo Liangjie, Wang Hongdan, Gao Yue, Hou Qiaofang, Lou Guiyu
Department of Endocrinology and Metabolism, the Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People's Hospital), Zhengzhou, Henan 450003, China.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2023 Aug 10;40(8):966-972. doi: 10.3760/cma.j.cn511374-20220801-00510.
To investigate the clinical phenotype and genetic characteristics of a Chinese pedigree affected with Cohen syndrome.
A proband who was admitted to Zhengzhou People's Hospital on June 2, 2021 due to intellectual disability and developmental delay, in addition with her younger sister and other family members, were selected as the study subjects. Clinical data of the proband and her younger sister were collected. Genomic DNA was extracted from peripheral venous blood and chorionic villi samples. Chromosomal abnormalities were detected with chromosomal microarray analysis (CMA). Whole exome sequencing (WES) and Sanger sequencing were carried out to detect candidate variants in the proband. With RNA extracted from the peripheral blood samples, VPS13B gene transcripts and expression were analyzed by PCR and real-time quantitative PCR. Prenatal diagnosis was carried out at 12 weeks' gestation.
The proband was a 10-year-old female with clinical manifestations including development delay, obesity, severe myopia and peculiar facial features. Her sister was 3 years old with a similar phenotype. CMA revealed no chromosomal abnormality in the proband, while WES results revealed that the proband and her sister had both harbored compound heterozygous variants of the VPS13B gene, namely c.10076_10077delCA (p.T3359fs*29) and c.6940+1G>T, which were respectively inherited from their mother and father. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were classified as pathogenic (PVS1+PS4+PM4+PP1; PVS1+PM2_Supporting+PM3+PP1). In vivo splicing assay confirmed that the c.6940+1G>T variant has produced a frameshift transcript with skipping of exon 38. Compared with the control group, the expression of RNA in the peripheral blood of the proband's parents has decreased to 65% ~ 70% (P < 0.01), whilst that in the proband and her sister has decreased to 40% (P < 0.001). Prenatal diagnosis at 12 weeks of gestation has found that the fetus only harbored the heterozygous c.10076_ 10077delCA variant.
The c.10076_10077delCA (p.T3359fs*29) frameshift variant and c.6940+1G>T splicing variant probably underlay the Cohen syndrome in this pedigree. Genetic testing has facilitated the diagnosis of this disease.
研究一个患有科恩综合征的中国家系的临床表型和遗传特征。
选取一名于2021年6月2日因智力残疾和发育迟缓入住郑州市人民医院的先证者，以及她的妹妹和其他家庭成员作为研究对象。收集先证者及其妹妹的临床资料。从外周静脉血和绒毛膜绒毛样本中提取基因组DNA。采用染色体微阵列分析（CMA）检测染色体异常。对先证者进行全外显子组测序（WES）和桑格测序以检测候选变异。从外周血样本中提取RNA，通过PCR和实时定量PCR分析VPS13B基因转录本和表达情况。在妊娠12周时进行产前诊断。
先证者为一名10岁女性，临床表现包括发育迟缓、肥胖、重度近视和特殊面容。她的妹妹3岁，具有相似的表型。CMA检测显示先证者无染色体异常，而WES结果显示先证者及其妹妹均携带VPS13B基因的复合杂合变异，即c.10076_10077delCA（p.T3359fs*29）和c.6940+1G>T，分别遗传自她们的母亲和父亲。根据美国医学遗传学与基因组学学会（ACMG）的指南，这两个变异均被分类为致病性变异（PVS1+PS4+PM4+PP1；PVS1+PM2_Supporting+PM3+PP1）。体内剪接试验证实c.6940+1G>T变异产生了一个外显子38跳跃的移码转录本。与对照组相比，先证者父母外周血中RNA的表达下降至65%~70%（P<0.01），而先证者及其妹妹外周血中RNA的表达下降至40%（P<0.001）。妊娠12周时的产前诊断发现胎儿仅携带杂合的c.
