全外显子测序揭示 GNRHR 基因中的一个新的无义变异导致巴基斯坦一个家族的正常嗅觉型促性腺激素低下性性腺功能减退症。

Whole Exome Sequencing Revealed a Novel Nonsense Variant in the GNRHR Gene Causing Normosmic Hypogonadotropic Hypogonadism in a Pakistani Family.

机构信息

The First Affiliated Hospital of USTC, Division of Molecular Medicine, Hefei National Laboratory for Physical Sciences at Microscale, USTC-SJH Joint Center for Human Reproduction and Genetics, The CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Life Sciences, University of Science and Technology of China, Hefei, China,

出版信息

Horm Res Paediatr. 2019;91(1):9-16. doi: 10.1159/000497114. Epub 2019 Apr 4.

DOI:10.1159/000497114

PMID:30947225

Abstract

BACKGROUND

Congenital hypogonadotropic hypogonadism (CHH) is a heterogeneous disorder characterized by delayed or loss of puberty and infertility due to functional deficiency in the hypothalamic gonadotropin-releasing hormone (GnRH). CHH can be classified into 2 subtypes on the basis of olfaction: Kallmann syndrome and normosmic CHH (nCHH). The spectrum of genetic variants causing CHH is continually expanding. Here, we recruited a consanguineous Pakistani family having 2 male and 2 female infertile patients diagnosed with idiopathic nCHH.

AIMS

The aim of this study was to investigate the genetic cause of nCHH in the family.

METHODS

Clinical and physical analyses were performed for the patients. Genetic analysis was carried out using whole exome and Sanger sequencing.

RESULTS

Clinical and physical investigations confirmed low levels of gonadotropins and failure of secondary sexual development in the patients. Genetic analysis identified a novel nonsense mutation (chr4: g.68619942G>A, c.112C>T, p.Arg38*) in the gonadotropin-releasing hormone receptor gene (GNRHR) recessively co-segregating with nCHH in this family. All the patients are homozygous and their parents are heterozygous carriers, while normal siblings are heterozygous carriers or wild-type for this mutation, indicating that the identified mutation is pathogenic for nCHH in the family.

CONCLUSION

We report the first homozygous nonsense mutation in the GNRHR gene (chr4: g. 68619942G>A, c.112C>T, p. Arg38*) that is associated with familial nCHH. Hence, our study displayed a good correlation of the genotype and phenotype of nCHH patients.

摘要

背景

先天性低促性腺激素性性腺功能减退症（CHH）是一种异质性疾病，其特征为青春期延迟或缺失以及不育，这是由于下丘脑促性腺激素释放激素（GnRH）的功能缺陷所致。CHH 可以根据嗅觉分为 2 个亚型：卡尔曼综合征和正常嗅觉 CHH（nCHH）。导致 CHH 的遗传变异谱在不断扩大。在这里，我们招募了一个有血缘关系的巴基斯坦家庭，该家庭有 2 名男性和 2 名女性不育患者，被诊断为特发性 nCHH。

目的

本研究旨在探讨该家族 nCHH 的遗传原因。

方法

对患者进行临床和体格分析。使用全外显子组和 Sanger 测序进行遗传分析。

结果

临床和体格检查证实患者的促性腺激素水平较低，第二性征发育不良。遗传分析确定了一种新的无义突变（chr4：g.68619942G>A，c.112C>T，p.Arg38*），该突变在 GnRH 受体基因（GNRHR）中隐性共分离，与该家族中的 nCHH 相关。所有患者均为纯合子，其父母均为杂合子携带者，而正常兄弟姐妹为该突变的杂合子携带者或野生型，表明该突变与家族性 nCHH 相关。