背景:先天性垂体功能减退症是一种遗传异质性疾病。全外显子组测序(WES)是对患有这种疾病的患者进行分子诊断的一种有前途的方法。
目的:对父母近亲出生的先天性垂体功能减退症患者进行WES,先天性垂体功能减退症患者队列中的CDH2筛查,和新型CDH2变体的功能测试。
方法:通过WES分析了先证者及其近亲父母的基因组DNA。评估拷贝数变体。对遗传变异进行了群体频率过滤(ExAC,1000个基因组,gnomad和ABraOM),致病性的计算机预测,和基因表达在垂体和/或下丘脑。通过Sanger测序筛选来自145名患者的基因组DNA的CDH2。
结果:一名GH缺乏的女性患者,TSH,ACTH,LH,FSH和异位垂体后叶腺含有罕见的纯合子c.865G>A(p。Val289Ile)在CDH2中的变体。为了确定CDH2中的p.Val289Ile变体是否影响细胞粘附特性,我们稳定转染L1成纤维细胞系,用亲脂性染料标记细胞,和量化聚合。在表达野生型CDH2的细胞中形成大的聚集体,但在用变体CDH2转染或未转染的细胞中聚集受损。
结论:在1例垂体功能减退症患者中发现了一个纯合的CDH2等位基因变体,和变异体外细胞聚集功能受损。在145名其他筛查CDH2变异的患者中未发现致病变异。因此,CDH2是垂体功能减退症的候选基因,需要在不同人群中进行检测。
UNASSIGNED: Congenital hypopituitarism is a genetically heterogeneous condition. Whole exome sequencing (WES) is a promising approach for molecular diagnosis of patients with this condition.
UNASSIGNED: The aim of this study is to conduct WES in a patient with congenital hypopituitarism born to consanguineous parents,
CDH2 screening in a cohort of patients with congenital hypopituitarism, and functional testing of a novel CDH2 variant.
UNASSIGNED: Genomic DNA from a proband and her consanguineous parents was analyzed by WES. Copy number variants were evaluated. The genetic variants were filtered for population frequency (ExAC, 1000 genomes, gnomAD, and ABraOM), in silico prediction of pathogenicity, and gene expression in the pituitary and/or hypothalamus. Genomic DNA from 145 patients was screened for
CDH2 by Sanger sequencing.
UNASSIGNED: One female patient with deficiencies in growth hormone, thyroid-stimulating hormone, adrenocorticotropic hormone, luteinizing hormone, and follicle-stimulating hormone and ectopic posterior pituitary gland contained a rare homozygous c.865G>A (p.Val289Ile) variant in CDH2. To determine whether the p.Val289Ile variant in CDH2 affects cell adhesion properties, we stably transfected L1 fibroblast lines, labeled the cells with lipophilic dyes, and quantified aggregation. Large aggregates formed in cells expressing wildtype CDH2, but aggregation was impaired in cells transfected with variant
CDH2 or non-transfected.
UNASSIGNED: A homozygous CDH2 allelic variant was found in one hypopituitarism patient, and the variant impaired cell aggregation function in vitro. No disease-causing variants were found in 145 other patients screened for
CDH2 variants. Thus, CDH2 is a candidate gene for hypopituitarism that needs to be tested in different populations.
UNASSIGNED: A female patient with hypopituitarism was born from consanguineous parents and had a homozygous, likely pathogenic, CDH2 variant that impairs cell aggregation in vitro. No other likely pathogenic variants in
CDH2 were identified in 145 hypopituitarism patients.