Pathogenic mosaic variants in congenital hypogonadotropic hypogonadism.

Details

Serval ID
serval:BIB_DD363A0A5D79
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Pathogenic mosaic variants in congenital hypogonadotropic hypogonadism.
Journal
Genetics in medicine
Author(s)
Acierno J.S., Xu C., Papadakis G.E., Niederländer N.J., Rademaker J.D., 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 F.A., Pitteloud N.
ISSN
1530-0366 (Electronic)
ISSN-L
1098-3600
Publication state
Published
Issued date
11/2020
Peer-reviewed
Oui
Volume
22
Number
11
Pages
1759-1767
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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.
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.
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.
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.
Keywords
Genetic Counseling, Humans, Hypogonadism/genetics, Infertility, Mosaicism, Whole Exome Sequencing, CHD7, FGFR1, copy-number variation, hypogonadotropic hypogonadism, postzygotic mosaicism
Pubmed
Web of science
Create date
13/08/2020 9:28
Last modification date
12/05/2021 6:34
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