GNRHR biallelic and digenic mutations in patients with normosmic congenital hypogonadotropic hypogonadism

Gonçalves, Catarina I.; Aragüés, José Maria; Bastos, Maria de Lourdes; Barros, Luísa; Vicente, Nuno; Carvalho, Davide; Lemos, Manuel C.

doi:10.1530/ec-17-0104

Cited by 17 publications

(11 citation statements)

References 21 publications

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“…This is a high prevalence when compared to the contribution of other genes that have been historically considered as priorities in the genetic study of CHH, namely the ANOS1 ( KAL1 ), FGFR1 , and GNRHR genes 26 . Indeed, previous studies in the Portuguese population have shown that the ANOS1 ( KAL1 ), FGFR1 , and GNRHR genes are mutated in only 7.1%, 12.0%, and 12.5% of cases, respectively 14–16 . Studies in other populations have also shown an important contribution of CHD7 mutations in the aetiology of CHH, with frequencies ranging from 5.2% to 19.0%, of cases 6–11 .…”

Section: Discussionmentioning

confidence: 99%

“…Genomic deoxyribonucleic acid (DNA) was extracted from peripheral blood leucocytes using previously described methods 13 . Patients had already been screened for mutations in the ANOS1 , FGFR1 and GNRHR genes, resulting in the discovery of three mutations in ANOS1 14 , six mutations in FGFR1 15 and six mutations in GNRHR 16 . All 50 patients were subsequently screened for mutations in the CHD7 gene by polymerase chain reaction (PCR) amplification of the coding exons and exon-intron boundaries, and bi-directional sequencing using CEQ DTCS sequencing kit (Beckman Coulter, Fullerton, CA, USA) and an automated capillary DNA sequencer (GenomeLab TM GeXP, Genetic Analysis System, Beckman Coulter).…”

Section: Methodsmentioning

confidence: 99%

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High frequency of CHD7 mutations in congenital hypogonadotropic hypogonadism

Gonçalves

Patriarca

Aragüés

et al. 2019

Sci Rep

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Congenital hypogonadotropic hypogonadism (CHH) is characterized by lack of normal pubertal development due to deficient gonadotropin-releasing hormone (GnRH) secretion or action, and is caused by genetic defects in several genes. Mutations in the CHD7 gene cause CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and development, Genital hypoplasia and Ear abnormalities), but have also been found in patients with isolated CHH. The aim of this study was to identify CHD7 mutations in patients with CHH. Fifty Portuguese patients with CHH were screened for mutations in the CHD7 gene by DNA sequencing. Eight (16%) patients had CHD7 rare sequence variants that consisted of six missense (p.Gly388Glu, p.His903Pro, p.Thr1082Ile, p.Val1452Leu, p.Asp1854Gly, and p.Arg2065His) and two synonymous (p.Ser559Ser, and p.Ala2785Ala) mutations. Five of these mutations have never been reported before. Three CHD7 mutations occurred in patients that had mutations in additional CHH-genes. This study uncovered novel genetic variants that expand the known spectrum of mutations associated with CHH. The frequency of CHD7 mutations in this cohort was higher than that of other major CHH-genes and confirms the importance of including CHD7 in the genetic testing of CHH, even in the absence of additional CHARGE features.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

High frequency of CHD7 mutations in congenital hypogonadotropic hypogonadism

Gonçalves

Patriarca

Aragüés

et al. 2019

Sci Rep

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“…Pathological changes in any of these processes can lead to CHH. To date, over 30 genes have been found to be associated with CHH and many encode receptor-ligand pairs, such as FGFR1 (OMIM 136350) and FGF8 (OMIM 600483), GNRHR (OMIM 138850) and GNRH1 (OMIM 152760), TACR3 (OMIM 162332) and TAC3 (OMIM 162330), KISS1R (OMIM 604161) and KISS1 (OMIM 603286), as well as PROKR2 (OMIM 607123) and PROK2 (OMIM 607002) (7,8,9,10,11,12,13). Furthermore, disruption in the dynamic remodelling of the cell's cytoskeleton during migration of GnRH neurons may also result in CHH (14,15,16).…”

Section: Introductionmentioning

confidence: 99%

Genotypic and phenotypic spectrum of CCDC141 variants in a Chinese cohort with congenital hypogonadotropic hypogonadism

Qiao

Zhao

et al. 2020

European Journal of Endocrinology

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Objective: To identify CCDC141 variants in a large Chinese cohort with congenital hypogonadotropic hypogonadism (CHH), and to assess the contribution of CCDC141 to CHH. Design: Detailed phenotyping was conducted in CHH patients with CCDC141 variants and co-segregation analysis was performed, when possible. Methods: Whole-exome sequencing was performed in 177 CHH patients and 450 unrelated, ethnically controls from China. Results: Seven novel CCDC141 rare sequencing variants (RSVs) were identified in 12 CHH pedigrees. Four of the variants were private mutations; however, p.Q409X, p.Q871X and p.G1488S were identified in more than one patient. Up to 75% (9/12) of patients had mutations in other CHH-associated genes, which is significantly higher than CHH patients without CCDC141 RSVs. The co-segregation analysis for eight CHH families showed that 75% (6/8) CCDC141 RSVs were inherited from their fertile parents. Over half (58.3%, 8/18) of patients exhibited other clinical deformities in addition to hypogonadism. One patient harbouring a CCDC141 RSV showed a reversal of CHH after sex steroid replacement. Conclusions: Our results broaden the genotypic spectrum of CCDC141 in CHH, as CCDC141 RSVs alone do not appear sufficient to cause CHH. The phenotypic spectrum in patients with CCDC141 RSVs is much wider than originally believed.

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“…Most cases of HH that are caused by GNRHR variants, are biallelic, consistent with an autosomal recessive mode of inheritance. However, digenic inheritance of HH has also been reported due to a monoallelic GNRHR variant together with monoallelic variants in other genes causing HH including PROKR2, FGFR1 , and WDR11 ( 26 – 28 ). Basal plasma concentrations of LH and FSH were low and did not increase after GnRH test, while the plasma estradiol concentration was prepubertal.…”

Section: Resultsmentioning

confidence: 99%

Peripheral Precocious Puberty of Ovarian Origin in a Series of 18 Girls: Exome Study Finds Variants in Genes Responsible for Hypogonadotropic Hypogonadism

2021

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Background: Peripheral precocious puberty of ovarian origin is a very rare condition compared to central form. It may be associated with an isolated ovarian cyst (OC). The causes of OC in otherwise healthy prepubertal girls is currently unknown.Methods: Exome sequencing was performed on a cohort of 18 unrelated girls presenting with prenatal and/or prepubertal OC at pelvic ultrasonography. The presenting symptom was prenatal OC in 5, breast development in 7 (with vaginal bleeding in 3) and isolated vaginal bleeding in 6. All had OC ≥ 10 mm. The girls had no other anomalies. Four patients had a familial history of ovarian anomalies and/or infertility.Results: In 9 girls (50%), candidate or known pathogenic variants were identified in genes associated with syndromic and non-syndromic forms of hypogonadotropic hypogonadism including PNPLA6, SEMA3A, TACR3, PROK2, KDM6A, KMT2D, OFD1, GNRH1, GNRHR, GLI3, INSR, CHD7, CDON, RNF216, PROKR2, GLI3, LEPR. Basal plasma concentrations of gonadotropins were undetectable and did not increase after gonadotropin-releasing hormone test in 3 of them whilst 5 had prepubertal values. The plasma estradiol concentrations were prepubertal in 6 girls, high (576 pmol/L) in one and not evaluated in 2 of them.Conclusions: In the first study reporting exome sequencing in prepubertal OC, half of the patients with OC carry either previously reported pathogenic variants or potentially pathogenic variants in genes known to be associated with isolated or syndromic forms of congenital hypogonadotropic hypogonadism. Functional studies and studies of other cohorts are recommended to establish the causality of these variants.

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GNRHR biallelic and digenic mutations in patients with normosmic congenital hypogonadotropic hypogonadism

Cited by 17 publications

References 21 publications

High frequency of CHD7 mutations in congenital hypogonadotropic hypogonadism

High frequency of CHD7 mutations in congenital hypogonadotropic hypogonadism

Genotypic and phenotypic spectrum of CCDC141 variants in a Chinese cohort with congenital hypogonadotropic hypogonadism

Peripheral Precocious Puberty of Ovarian Origin in a Series of 18 Girls: Exome Study Finds Variants in Genes Responsible for Hypogonadotropic Hypogonadism

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