Dataset Information

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 (n?=?116), CDGP (n?=?72) and control cohorts (n?=?36 874 ExAC and n?=?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%, P?=?7.6?×?10-11) or controls (18%, P?=?5.5?×?10-12). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%, P?=?0.002) and controls (2%, P?=?6.4?×?10-7). 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.

SUBMITTER: Cassatella D

PROVIDER: S-EPMC5863472 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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

Cassatella Daniele D Howard Sasha R SR Acierno James S JS Xu Cheng C Papadakis Georgios E GE Santoni Federico A FA Dwyer Andrew A AA Santini Sara S Sykiotis Gerasimos P GP Chambion Caroline C Meylan Jenny J Marino Laura L Favre Lucie L Li Jiankang J Liu Xuanzhu X Zhang Jianguo J Bouloux Pierre-Marc PM Geyter Christian De C Paepe Anne De A Dhillo Waljit S WS Ferrara Jean-Marc JM Hauschild Michael M Lang-Muritano Mariarosaria M Lemke Johannes R JR Flück Christa C Nemeth Attila A Phan-Hug Franziska F Pignatelli Duarte D Popovic Vera V Pekic Sandra S Quinton Richard R Szinnai Gabor G l'Allemand Dagmar D Konrad Daniel D Sharif Saba S Iyidir Özlem Turhan ÖT Stevenson Brian J BJ Yang Huanming H Dunkel Leo L Pitteloud Nelly N

European journal of endocrinology 20180201 4

<h4>Objective</h4>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.<h4>Design</h4>We characterized and compared the genetic architectures of CHH ...[more]

PMID: 29419413

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Project description:Constitutional delay of growth and puberty (CDGP) is the most common cause of pubertal delay. CDGP is defined as the proportion of the normal population who experience pubertal onset at least 2 SD later than the population mean, representing 2.3% of all adolescents. While adolescents with CDGP spontaneously enter puberty, they are at risk for short stature, decreased bone mineral density, and psychosocial problems. Genetic factors contribute heavily to the timing of puberty, but the vast majority of CDGP cases remain biologically unexplained, and there is no definitive test to distinguish CDGP from pathological absence of puberty during adolescence. Recently, we published a study identifying significant linkage between a locus at the pericentromeric region of chromosome 2 (chr 2) and CDGP in Finnish families. To investigate this region for causal variation, we sequenced chr 2 between the genomic coordinates of 79-124 Mb (genome build GRCh37) in the proband and affected parent of the 13 families contributing most to this linkage signal. One gene, DNAH6, harbored 6 protein-altering low-frequency variants (< 6% in the Finnish population) in 10 of the CDGP probands. We sequenced an additional 135 unrelated Finnish CDGP subjects and utilized the unique Sequencing Initiative Suomi (SISu) population reference exome set to show that while 5 of these variants were present in the CDGP set, they were also present in the Finnish population at similar frequencies. Additional variants in the targeted region could not be prioritized for follow-up, possibly due to gaps in sequencing coverage or lack of functional knowledge of non-genic genomic regions. Thus, despite having a well-characterized sample collection from a genetically homogeneous population with a large population-based reference sequence dataset, we were unable to pinpoint variation in the linked region predisposing delayed puberty. This study highlights the difficulties of detecting genetic variants under linkage regions for complex traits and suggests that advancements in annotation of gene function and regulatory regions of the genome will be critical for solving the genetic background of complex phenotypes like CDGP.

Dataset Information

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

Publications

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

Similar Datasets

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