Genetics of ncHH: from a peculiar inheritance of a novel GNRHR mutation to a comprehensive review of the literature

Cioppi, Francesca; Riera-Escamilla, Antoni; Manilall, Ashmeetha; Guarducci, E.; Todisco, Tommaso; Corona, Giovanni; Colombo, Federico; Bonomi, Marco; Flanagan, Colleen A.; Krausz, Csilla

doi:10.1111/andr.12563

Cited by 14 publications

(14 citation statements)

References 44 publications

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“…12 In the past few years, IHH has classically been categorized as a single-gene disease, 13 but the phenotypic presentation of this disease and its genetic background are highly heterogeneous. 14 A few genes that are involved in the pathogenesis of IHH have been identified at various sites, including TAC3, TACR3, GnRHR, FGFR1, GNRH1, FGF8, KISS1, and KISS1R. 11 However, these genetic defects account for less than 30% of patients with IHH.…”

Section: Discussionmentioning

confidence: 99%

“…Males can be clinically manifested as absent or incomplete puberty, small penis, cryptorchidism, and infertility . In the past few years, IHH has classically been categorized as a single‐gene disease, but the phenotypic presentation of this disease and its genetic background are highly heterogeneous . A few genes that are involved in the pathogenesis of IHH have been identified at various sites, including TAC3 , TACR3 , GnRHR , FGFR1 , GNRH1 , FGF8 , KISS1, and KISS1R .…”

Section: Discussionmentioning

confidence: 99%

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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%

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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“…Regarding FGFR1, nearly half, regarding PROK2/PROKR2, nearly twothird of the cases exhibit incomplete penetrance and variable expressivity that complicate the determination of inheritance (Maione et al 2018). Recently, a normosmic CHH patient was reported who inherited a pathogenic variant in GNRHR gene in a homozygous form due to the occurrence of uniparental isodisomy (Cioppi et al 2019). (Uniparental disomy-UPD is a non-Mendelian inheritance pattern when an individual has inherited two copies of a specific chromosome (or part of it) from a single parent.…”

Section: Genetic Background Of Chhmentioning

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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“…In many of these genes the phenomenon of allelic heterogeneity is displayed, where different mutations in the same gene lead to varying phenotypes along a range of disease severity. For example, complete loss-of-function mutations in the GNRHR gene are associated with severe hypogonadism due to exonic nonsense changes or even imprinting defects such as maternal uniparental isodisomy (Cioppi et al 2019), whereas mutations leading to partial deficiency show a wide spectrum of clinical manifestations including the 'fertile eunuch' phenotype, partial hypogonadotropic hypogonadism and isolated delayed puberty (Pitteloud et al 2001, Chevrier et al 2011, Vaaralahti et al 2011.…”

Section: Single Gene Defects Leading To Delayed and Disordered Pubertymentioning

confidence: 99%

Genetic regulation in pubertal delay

Howard

2019

Journal of Molecular Endocrinology

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Delayed puberty represents the clinical presentation of a final common pathway for many different pathological mechanisms. In the majority of patients presenting with significantly delayed puberty, there is a clear family history of delayed or disturbed puberty, and pubertal timing is known to be a trait with strong heritability. Thus, genetic factors clearly play a key role in determining the timing of puberty, and mutations in certain genes are recognised as responsible for delayed or absent puberty in a minority of patients. Through the identification of causal genetic defects such as these we have been able to learn a great deal about the pathogenesis of disrupted puberty and its genetic regulation. Firstly, deficiency in key genes that govern the development of the gonadotropin-releasing hormone system during fetal development may result in a spectrum of conditions ranging from isolated delayed puberty to absent puberty with anosmia. Secondly, a balance of inhibitory and excitatory signals, acting upstream of GnRH secretion, are vital for the correct timing of puberty. These act to repress the hypothalamic–pituitary–gonadal axis during mid-childhood and allow it to reactivate at puberty, and alterations in this equilibrium can cause delayed (or precocious) puberty. Thirdly, disturbances of energy metabolism inputs to the kisspeptin–GnRH system may also lead to late onset of puberty associated with changes in body mass.

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Genetics of ncHH: from a peculiar inheritance of a novel GNRHR mutation to a comprehensive review of the literature

Cited by 14 publications

References 44 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

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

Genetic regulation in pubertal delay

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