Complete Idiopathic Hypogonadotropic Hypogonadism due to Homozygous &lt;b&gt;&lt;i&gt;GNRH1&lt;/i&gt;&lt;/b&gt; Mutations in the Mutational Hot Spots in the Region Encoding the Decapeptide

Mengen, Eda; Tunç, Selma; Kotan, Leman Damla; Nalbantoğlu, Özlem; Demir, Korcan; Gürbüz, Fatih; Turan, İhsan; Seker, Gül; Yüksel, Bilgin; Topaloğlu, Ali Kemal

doi:10.1159/000441977

Cited by 21 publications

(21 citation statements)

References 24 publications

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“…Out of 310 patients with IHH, only one case was found, attesting to the rarity of mutations in this gene as a cause of IHH ( 70 ). We recently reported further GNRH1 mutations located in the region encoding the decapeptide which is the same region involved in earlier reported mutations ( 71 ).…”

Section: Introductionsupporting

confidence: 65%

Update on the Genetics of Idiopathic Hypogonadotropic Hypogonadism

Topaloğlu

2018

Jcrpe

104

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Traditionally, idiopathic hypogonadotropic hypogonadism (IHH) is divided into two major categories: Kallmann syndrome (KS) and normosmic IHH (nIHH). To date, inactivating variants in more than 50 genes have been reported to cause IHH. These mutations are estimated to account for up to 50% of all apparently hereditary cases. Identification of further causative gene mutations is expected to be more feasible with the increasing use of whole exome/genome sequencing. Presence of more than one IHH-associated mutant gene in a given patient/pedigree (oligogenic inheritance) is seen in 10-20% of all IHH cases. It is now well established that about 10-20% of IHH cases recover from IHH either spontaneously or after receiving some sex steroid replacement therapy. Moreover, there may be an overlap or transition between constitutional delay in growth and puberty (CDGP) and IHH. It has been increasingly observed that oligogenic inheritance and clinical recovery complicates the phenotype/genotype relationship in IHH, thus making it challenging to find new IHH-associated genes. In a clinical sense, recognizing those IHH genes and associated phenotypes may improve our diagnostic capabilities by enabling us to prioritize the screening of particular gene(s) such as synkinesia (ANOS1), dental agenesis (FGF8/FGFR1) and hearing loss (CHD7). Also, IHH-associated gene studies may be translated into new therapies such as for polycystic ovary syndrome. In a scientific sense, the most significant contribution of IHH-associated gene studies has been the characterization of the long-sought gonadotropin releasing hormone pulse generator. It appears that genetic studies of IHH will continue to advance our knowledge in both the biological and clinical domains.

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Section: Introductionsupporting

confidence: 65%

Update on the Genetics of Idiopathic Hypogonadotropic Hypogonadism

Topaloğlu

2018

Jcrpe

104

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“…GNRH1 has been considered for several years an obvious candidate for mutations in patients with nCHH, but so far only three different homozygous mutations have been described (Fig. 3C) (42,43,44). In our study, we identified a novel GNRH1 homozygous mutation located at the consensus splicing site region upstream the start of exon 2 (c.142-2A>C).…”

Section: Discussionmentioning

confidence: 67%

New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism

Amato

Montenegro

Lerário

et al. 2019

European Journal of Endocrinology

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Context Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. Several genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. The advent of next-generation sequencing (NGS) has allowed the simultaneous genotyping of several regions, faster, making possible the extension of the genetic knowledge of CHH. Objective Genetic characterization of a large cohort of Brazilian CHH patients. Design and patients A cohort of 130 unrelated patients (91 males, 39 females) with CHH (75 normosmic CHH, 55 Kallmann syndrome) was studied using a panel containing 36 CHH-associated genes. Results Potential pathogenic or probably pathogenic variants were identified in 43 (33%) CHH patients. The genes ANOS1, FGFR1 and GNRHR were the most frequently affected. A novel homozygous splice site mutation was identified in the GNRH1 gene and a deletion of the entire coding sequence was identified in SOX10. Deleterious variants in the IGSF10 gene were identified in two patients with reversible normosmic CHH. Notably, 6.9% of the patients had rare variants in more than one gene. Rare variants were also identified in SPRY4, IL17RD, FGF17, IGSF1 and FLRT3 genes. Conclusions This is a large study of the molecular genetics of CHH providing new genetic findings for this complex and heterogeneous genetic condition. NGS has been shown to be a fast, reliable and effective tool in the molecular diagnosis of congenital CHH and being able to targeting clinical genetic testing in the future.

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“…GNRH1, KISS1, TAC3) of the above-mentioned receptors are far more rare. Indeed, only 4 nCHH families carrying biallelic GNRH1 mutations have been reported (50)(51)(52), along with a few cases of nCHH/KS probands with monoallelic mutations and an additional mutation in another CHH/KS loci (i.e. potential oligogenic transmission -see below) (51,53,54).…”

Section: Chh/ks Is a Treatable Form Of Infertilitymentioning

confidence: 99%

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

Maione

Dwyer

Francou

et al. 2018

European Journal of Endocrinology

131

166

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Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) are rare, related diseases that prevent normal pubertal development and cause infertility in affected men and women.However, the infertility carries a good prognosis as increasing numbers of patients with CHH/KS are now able to have children through medically assisted procreation.These are genetic diseases that can be transmitted to patients' offspring. Importantly patients and their families should be informed of this risk and given genetic counseling. CHH and KS are phenotypically and genetically heterogeneous diseases in which the risk of transmission largely depends on the gene(s) responsible(s). Inheritance may be classically Mendelian yet more complex, oligogenic modes of transmission have also been described. The prevalence of oligogenicity has risen dramatically since the advent of massively parallel next-generation sequencing (NGS) in which tens, hundreds or thousands of genes are sequenced at the same time. NGS is medically and economically more efficient and more rapid than traditional Sanger sequencing, and is increasingly being used in medical practice. Thus it seems plausible that oligogenic forms of CHH/KS will be increasingly identified making genetic counseling even more complex. In this context, the main challenge will be to differentiate true oligogenism from situations when several rare variants that do not have a clear phenotypic effect are identified by chance. This review aims to summarize the genetics of CHH/KS and to discuss the challenges of oligogenic transmission but also its role in incomplete penetrance and variable expresivity in a perspective of genetic counseling.

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Complete Idiopathic Hypogonadotropic Hypogonadism due to Homozygous <b><i>GNRH1</i></b> Mutations in the Mutational Hot Spots in the Region Encoding the Decapeptide

Cited by 21 publications

References 24 publications

Update on the Genetics of Idiopathic Hypogonadotropic Hypogonadism

Update on the Genetics of Idiopathic Hypogonadotropic Hypogonadism

New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

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