Pathogenic mosaic variants in congenital hypogonadotropic hypogonadism |
| |
| Institution: | 1. Service of Endocrinology, Diabetology and Metabolism Lausanne University Hospital Lausanne Switzerland;2. Faculty of Biology and Medicine University of Lausanne Lausanne Switzerland;3. Department of Reproductive Endocrinology Assistance Publique–Hôpitaux de Paris, Bicêtre Hôpital Le Kremlin-Bicêtre France;4. Department of Pediatric Endocrinology and Rheumatology Poznan University of Medical Sciences Poznan Poland;5. Translational & Clinical Research Institute University of Newcastle-upon-Tyne Newcastle-upon-Tyne UK;6. Division of Pediatric Endocrinology and Diabetology and Children’s Research Centre University Children’s Hospital Zurich Switzerland;7. Department of Human Genetics Inselspital, Bern University Hospital and University of Bern Bern Switzerland;8. Department of Endocrinology Hospital Clínic, Universitat de Barcelona Barcelona Spain;9. Reproductive Medicine and Gynecological Endocrinology (RME) University Hospital, University of Basel Basel Switzerland;10. Department of Molecular Genetics Pharmacogenomics, and Hormonology, Assistance Publique–Hôpitaux de Paris, Hôpital Bicêtre Le Kremlin-Bicêtre France;11. University of Paris-Saclay, Paris-Saclay Medical School Le Kremlin-Bicetre France;12. INSERM Unité 1185 Le Kremlin-Bicêtre France;1. Service of Endocrinology, Diabetology and Metabolism Lausanne University Hospital Lausanne Switzerland;2. Faculty of Biology and Medicine University of Lausanne Lausanne Switzerland;3. Department of Reproductive Endocrinology Assistance Publique–Hôpitaux de Paris, Bicêtre Hôpital Le Kremlin-Bicêtre France;4. Department of Pediatric Endocrinology and Rheumatology Poznan University of Medical Sciences Poznan Poland;5. Translational & Clinical Research Institute University of Newcastle-upon-Tyne Newcastle-upon-Tyne UK;6. Division of Pediatric Endocrinology and Diabetology and Children’s Research Centre University Children’s Hospital Zurich Switzerland;7. Department of Human Genetics Inselspital, Bern University Hospital and University of Bern Bern Switzerland;8. Department of Endocrinology Hospital Clínic, Universitat de Barcelona Barcelona Spain;9. Reproductive Medicine and Gynecological Endocrinology (RME) University Hospital, University of Basel Basel Switzerland;10. Department of Molecular Genetics Pharmacogenomics, and Hormonology, Assistance Publique–Hôpitaux de Paris, Hôpital Bicêtre Le Kremlin-Bicêtre France;11. University of Paris-Saclay, Paris-Saclay Medical School Le Kremlin-Bicetre France;12. INSERM Unité 1185 Le Kremlin-Bicêtre France |
| |
| 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. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
