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

2018; Oxford University Press; Volume: 178; Issue: 4 Linguagem: Inglês

10.1530/eje-17-0568

1479-683X

Daniele Cassatella, Sasha Howard, James S. Acierno, Cheng Xu, Georgios Papadakis, Federico Santoni, Andrew Dwyer, Sara Santini, Gerasimos P. Sykiotis, Caroline Chambion, J Meylan, Laura Marino, Lucie Favre, Jiankang Li, Xuanzhu Liu, Jianguo Zhang, Pierre‐Marc Bouloux, Christian De Geyter, Anne De Paepe, Waljit S. Dhillo, Jean-Marc Ferrara, Michael Hauschild, Mariarosaria Lang‐Muritano, Johannes R. Lemke, Christa E. Flück, Attila Németh, Franziska Phan-Hug, Duarte Pignatelli, Vera Popović, Sandra Pekić, Richard Quinton, Gabor Szinnai, Dagmar l’Allemand, Daniel Konrad, Saba Sharif, Özlem Turhan İyidir, Brian J. Stevenson, Huanming Yang, Leo Dunkel, Nelly Pitteloud,

Genomics and Chromatin Dynamics

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.