Pathogenic mosaic variants in congenital hypogonadotropic hypogonadism

James S Acierno,Cheng Xu,Georgios E Papadakis,Nicolas J Niederländer,Jesse D Rademaker,Jenny Meylan,Andrea Messina,Zofia Kolesinska,Richard Quinton,Mariarosaria Lang-Muritano,Deborah Bartholdi,Irene Halperin,Christian De Geyter,Jérôme Bouligand,Lucia Bartoloni,Jacques Young,Federico A Santoni,Nelly Pitteloud

doi:10.1038/s41436-020-0896-0

Abstract

PurposeCongenital hypogonadotropic hypogonadism (CHH) is a rare disorder resulting in absent puberty and infertility. The genetic architecture is complex with multiple loci involved, variable expressivity, and incomplete penetrance. The majority of cases are sporadic, consistent with a disease affecting fertility. The current study aims to investigate mosaicism as a genetic mechanism for CHH, focusing on de novo rare variants in CHH genes. MethodsWe evaluated 60 trios for de novo rare sequencing variants (RSV) in known CHH genes using exome sequencing. Potential mosaicism was suspected among RSVs with altered allelic ratios and confirmed using customized ultradeep sequencing (UDS) in multiple tissues. ResultsAmong the 60 trios, 10 probands harbored de novo pathogenic variants in CHH genes. Custom UDS demonstrated that three of these de novo variants were in fact postzygotic mosaicism—two in FGFR1 (p.Leu630Pro and p.Gly348Arg), and one in CHD7 (p.Arg2428*). Statistically significant variation across multiple tissues (DNA from blood, buccal, hair follicle, urine) confirmed their mosaic nature. ConclusionsWe identified a significant number of de novo pathogenic variants in CHH of which a notable number (3/10) exhibited mosaicism. This report of postzygotic mosaicism in CHH patients provides valuable information for accurate genetic counseling.

Highlights

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic endocrine disorder resulting from a defect in gonadotropin-releasing hormone (GnRH) secretion or action, which leads to absent puberty and infertility
De novo analysis for CHH genes Exome sequencing for 60 trios shows 28 probands with rare sequence variants (RSVs) in the known CHH genes classified as either P, likely pathogenic (LP), or variation of unknown significance (VUS) and a minor allele frequencies (MAF) of
In this study of 60 CHH trios, we identified de novo pathogenic variants in the known CHH genes in 10 probands

Summary

Introduction

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic endocrine disorder resulting from a defect in gonadotropin-releasing hormone (GnRH) secretion or action, which leads to absent puberty and infertility (see Supplementary Table S1 for complete list of associated OMIM numbers). CHH is diagnosed in patients with (1) absent or partial puberty at age 17 years, (2) low or normal gonadotropin levels in the context of low serum sex steroids, (3) a normal hypothalamus and pituitary on imaging, and (4) otherwise normal anterior pituitary function. There is growing evidence that male patients with micropenis and/or cryptorchidism can be diagnosed with neonatal CHH by evidence of hypogonadotropic hypogonadism during minipuberty (ages 2 weeks to 6 months).[1,2,3].

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Conclusion