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Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures


Abstract

OBJECTIVE
Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood.

DESIGN
We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders.

METHODS
Exome sequencing data were used to identify rare variants in known genes in CHH ( = 116), CDGP ( = 72) and control cohorts ( = 36 874 ExAC and  = 405 CoLaus).

RESULTS
Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%,  = 7.6 × 10) or controls (18%,  = 5.5 × 10). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%,  = 0.002) and controls (2%,  = 6.4 × 10).

CONCLUSIONS
Our data suggest that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty.

Abstract

OBJECTIVE
Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood.

DESIGN
We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders.

METHODS
Exome sequencing data were used to identify rare variants in known genes in CHH ( = 116), CDGP ( = 72) and control cohorts ( = 36 874 ExAC and  = 405 CoLaus).

RESULTS
Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%,  = 7.6 × 10) or controls (18%,  = 5.5 × 10). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%,  = 0.002) and controls (2%,  = 6.4 × 10).

CONCLUSIONS
Our data suggest that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Endocrinology, Diabetes and Metabolism
Life Sciences > Endocrinology
Language:English
Date:April 2018
Deposited On:29 Jan 2019 13:07
Last Modified:21 Dec 2020 08:06
Publisher:BioScientifica Ltd.
ISSN:0804-4643
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1530/EJE-17-0568
PubMed ID:29419413

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