Molecular genetic and clinical delineation of 22 patients with congenital hypogonadotropic hypogonadism

Aoyama, Kohei; Mizuno, Haruo; Tanaka, Tatsushi; Togawa, Takao; Negishi, Yutaka; Ohashi, Kei; Hori, Ikumi; Izawa, Masako; Hamajima, Takashi; Saitoh, Shinji

doi:10.1515/jpem-2017-0035

Cited by 18 publications

(31 citation statements)

References 23 publications

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“…15 AR AURKC CATSPER1 CCDC39 CFTR CHD7 DNAAF1 DNAAF2 DNAAF3 DNAH1 DNAH11 DNAH5 DNAI1 DNAI2 DPY19L2 DYX1C1 ETV5 FGF8 FGFR1 GNRHR HEATR2 HSF2 HYDIN KAL1 KISS1R LEP LEPR NANOS1 NELF NR5A1 PLCZ1 PROK2 PROKR2 RHOXF1 RHOXF2 RSPH1 RSPH4A RSPH9 SEPT12 SLC26A8 SOHLH2 SPATA16 SUN5 SYCE1 SYCP3 TAC3 TACR3 TEX11 USP26 WDR11 ZMYDN15 In previous studies, KISS1R was one of the major genes that implicated in IHH in the autosomal-recessive form. 16 Mutations of this gene have been identified in less than 5% of patients with normosmic IHH. 12 Up to now, at least 20 different mutations have been described in the literature, most of which were loss-of-function mutations and were found to have variable clinical manifestation.…”

Section: Discussionmentioning

confidence: 99%

Identification of KISS1R gene mutations in disorders of non‐obstructive azoospermia in the northeast population of China

Geng

Zhang

Liu

et al. 2019

Clinical Laboratory Analysis

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Background: Non-obstructive azoospermia (NOA), a serious phenotype of male spermatogenesis failure, is a multifactorial disease which is regulated by genetic, epigenetic, and environmental factors. Some gene structural variants have been demonstrated to be related to NOA. Loss-of-function mutations of KISS1R cause normosmic idiopathic hypogonadotropic hypogonadism (IHH) which result in azoospermia at the pre-testicular level. The objective of this research was to investigate genetic variants of KISS1R in NOA patients. Methods:The entire coding region of 52 spermatogenesis-associated genes (KISS1R included) was sequenced from 200 NOA patients. Mutation screening was performed to identify genetic variations of these genes by targeted exome sequencing. Sequencing data analysis was carried out by a series of bioinformatics tools.Candidate variants confirmation was performed by Sanger sequencing. Functional analysis of candidate variants was evaluated using SIFT and PolyPhen-2.Results: Three heterozygous missense variants in KISS1R were identified in three patients, respectively. No deleterious variations in other candidate genes were found in the three patients. Two of these three variants, p.A211T and p.G186E, had been reported in the ExAC and dbSNP database, respectively, while the other variant p.A301D was novel. These variants were all predicted to be likely pathogenic by in silico analysis. Conclusion:Our study revealed three heterozygous missense variants in KISS1R which expanded the mutation spectrum of KISS1R in infertile men with NOA in the northeast of China.

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Section: Discussionmentioning

confidence: 99%

Identification of KISS1R gene mutations in disorders of non‐obstructive azoospermia in the northeast population of China

Geng

Zhang

Liu

et al. 2019

Clinical Laboratory Analysis

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“…However, it was also reported that both dominant and recessive forms of CHH transmission were present in patients with TACR3 mutations and patients with heterozygous mutations were clinically similar to those with homozygous mutations . But most researches suggested that TACR3 was autosomal recessive inheritance, offsprings with heterozygous mutations were not affected …”

Section: Discussionmentioning

confidence: 99%

“…12 But most researches suggested that TACR3 was autosomal recessive inheritance, offsprings with heterozygous mutations were not affected. 13,17,18,21,25 The pathogenicity of the variant may be due to the dominant negative effect. Noel et al reported the mechanisms of another heterozygous mutation in TACR3 disrupting NK3R function in GnRH-deficient patients.…”

Section: Discussionmentioning

confidence: 99%

A novel stopgain mutation c.G992A (p.W331X) in TACR3 gene was identified in nonobstructive azoospermia by targeted next‐generation sequencing

Geng

Yang

Deng

et al. 2018

Clinical Laboratory Analysis

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Background Nonobstructive azoospermia (NOA) is one of the most severe forms of male infertility because of impaired spermatogenesis with the absence of spermatozoa in the ejaculate. The causes of this disease can be partly attributed to genetic factors. Some common structural variants and single nucleotide polymorphisms (SNPs) were reported to be associated with NOA. However, the underlying etiology and genetic mechanism(s) remain largely unclear. The aim of this study was to investigate the associated mutations of spermatogenic genes in Chinese infertile men with NOA. Methods The entire coding region of 25 genes associated with spermatogenesis was sequenced from 200 infertile men with NOA. Screening was carried out using the targeted exome sequencing to identify genetic variations and SNPs of the entire coding region of these genes. Results After the targeted exome sequencing data were filtered through several currently existing variation databases, a series of variations were found. In this paper, we report one novel stopgain variation c.G992A (p.W331X) in the exon 4 of TACR3 gene. The variant was heterozygous and categorized as pathogenic. Conclusion In conclusion, our study revealed a novel stopgain mutation c.G992A (p.W331X) in TACR3 which expanded the mutation spectrum of TACR3 in Chinese NOA infertile men and advanced our understanding of the genetic susceptibility to NOA.

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“…However, there is no consented gene list that should be offered for patients providing an accurate diagnosis for the majority of cases. After publication of the expert consensus 7 CHH gene panel testing studies were reported (Table 2) (Quaynor et al 2016;Aoyama et al 2017;Wang et al 2017;Cassatella et al 2018;Zhou et al 2018;Amato et al 2019;Kim et al 2019). In these studies, 25-261 genes were included as susceptibility genes of CHH.…”

Section: Testing Strategiesmentioning

confidence: 99%

“…Regarding phenotype-genotype correlation some authors reported inconclusive results and little co-segregation by analyzing pedigrees in their cohorts (Aoyama et al 2017;Zhou et al 2018), probably due to the complex genetic background of CHH. However, differences in genetic profile among populations are indicated in Chinese and Japanese cohorts (Aoyama et al 2017;Zhou et al 2018). Zhou et al reported that in Chinese population, cryptorchidism was the most common accompanying feature in addition to CHH, but no single gene in their panel showed association with this abnormality (Zhou et al 2018).…”

Section: Pathogenicity Of the Identified Variants Genotypephenotype mentioning

confidence: 99%

Molecular genetic diagnostics of hypogonadotropic hypogonadism: from panel design towards result interpretation in clinical practice

et al. 2020

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Congenital hypogonadotropic hypogonadism (CHH) is a clinically and genetically heterogeneous congenital disease. Symptoms cover a wide spectrum from mild forms to complex phenotypes due to gonadotropin-releasing hormone (GnRH) deficiency. To date, more than 40 genes have been identified as pathogenic cause of CHH. These genes could be grouped into two major categories: genes controlling development and GnRH neuron migration and genes being responsible for neuroendocrine regulation and GnRH neuron function. High-throughput, next-generation sequencing (NGS) allows to analyze numerous gene sequences at the same time. Nowadays, whole exome or whole genome datasets could be investigated in clinical genetic diagnostics due to their favorable cost-benefit. The increasing genetic data generated by NGS reveal novel candidate genes and gene variants with unknown significance (VUSs). To provide clinically valuable genetic results, complex clinical and bioinformatics work are needed. The multifaceted genetics of CHH, the variable mode of inheritance, the incomplete penetrance, variable expressivity and oligogenic characteristics further complicate the interpretation of the genetic variants detected. The objective of this work, apart from reviewing the currently known genes associated with CHH, was to summarize the advantages and disadvantages of the NGS-based platforms and through the authors' own practice to guide through the whole workflow starting from gene panel design, performance analysis and result interpretation. Based on our results, a genetic diagnosis was clearly identified in 21% of cases tested (8/38). Congenital hypogonadotropic hypogonadism (CHH) Congenital hypogonadotropic hypogonadism (CHH) as a clinically heterogeneous entity Congenital hypogonadotropic hypogonadism (CHH) is a genetic condition characterized by incomplete or absent puberty and infertility due to central (tertiary or hypothalamic) hypogonadism caused by gonadotropic hormonereleasing hormone (GnRH) deficiency. Three clinical forms are distinguished by the European consensus: (1) GnRH deficiency with defective sense of smell (Kallmann syndrome, KS), (2) isolated GnRH deficiency (normosmic CHH) and the third form when KS/CHH is part of a complex genetic syndrome (Boehm et al. 2015). CHH has an incidence of 1:125,000 in female and 1:30,000 in males indicating the male predominance (Stamou and Georgopoulos 2018). CHH has a heterogeneous clinical appearance, and lately the constitutional delay of growth and puberty (CDGP), the adultonset hypogonadotropic hypogonadism and the hypothalamic amenorrhea are also considered as a milder end of the Electronic supplementary material The online version of this article (

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Molecular genetic and clinical delineation of 22 patients with congenital hypogonadotropic hypogonadism

Abstract: The frequency of CHH genes in the Japanese was compatible with previous reports, except that CHD7 mutations might be more common. Furthermore, partial phenotype-genotype correlations were demonstrated in our cohort.

Cited by 18 publications

References 23 publications

Identification of KISS1R gene mutations in disorders of non‐obstructive azoospermia in the northeast population of China

Identification of KISS1R gene mutations in disorders of non‐obstructive azoospermia in the northeast population of China

A novel stopgain mutation c.G992A (p.W331X) in TACR3 gene was identified in nonobstructive azoospermia by targeted next‐generation sequencing

Molecular genetic diagnostics of hypogonadotropic hypogonadism: from panel design towards result interpretation in clinical practice

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