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Pathogenic mosaic variants in congenital hypogonadotropic hypogonadism

Lookup NU author(s): Dr Richard Quinton

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Abstract

© 2020, American College of Medical Genetics and Genomics. Purpose: Congenital 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. Methods: We 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. Results: Among 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. Conclusions: We 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.

Publication metadata

Author(s): Acierno JS, Xu C, Papadakis GE, Niederlander NJ, Rademaker JD, Meylan J, Messina A, Kolesinska Z, Quinton R, Lang-Muritano M, Bartholdi D, Halperin I, De Geyter C, Bouligand J, Bartoloni L, Young J, Santoni FA, Pitteloud N

Publication type: Article

Publication status: Published

Journal: Genetics in Medicine

Year: 2020

Volume: 22

Pages: 1759-1767

Print publication date: 01/11/2020

Online publication date: 29/07/2020

Acceptance date: 25/06/2020

ISSN (print): 1098-3600

ISSN (electronic): 1530-0366

Publisher: Springer Nature

URL: https://doi.org/10.1038/s41436-020-0896-0

DOI: 10.1038/s41436-020-0896-0

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