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

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

Author information

1
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, jafarustc@mail.ustc.edu.cn.
2
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.
3
Armed Forces Institute of Pathology (AFIP), Combined Military Hospital (CMH), Rawalpindi, Pakistan.
4
Department of Andrology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.

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.

KEYWORDS:

Congenital hypogonadotropic hypogonadism; GNRHR; Gonadotropin-releasing hormone; Nonsense mutation; Normosmic hypogonadotropic hypogonadism

PMID:
30947225
DOI:
10.1159/000497114

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