Diverse genetic causes of amenorrhea in an ethnically homogeneous cohort and an evolving approach to diagnosis.

Autor: Bakhshalizadeh S; Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia., Afkhami F; Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran., Bell KM; Department of Bioinformatics, Murdoch Children's Research Institute, Melbourne, Australia., Robevska G; Murdoch Children's Research Institute, Melbourne, Australia., van den Bergen J; Murdoch Children's Research Institute, Melbourne, Australia., Cronin S; Cyto-Molecular Diagnostic Research Laboratory, Victorian Clinical Genetics Services and Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, 3052, Victoria, Australia., Jaillard S; Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de Recherche en Santé, Environnement et Travail), UMR_S 1085, F-35000, Rennes, France; CHU Rennes, Service de Cytogénétique et Biologie Cellulaire, F-35033, Rennes, France., Ayers KL; Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia., Kumar P; Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK., Siebold C; Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK., Xiao Z; Department of Chemistry, Imperial College London, 82 Wood Lane, London, W12 0BZ, UK., Tate EW; Department of Chemistry, Imperial College London, 82 Wood Lane, London, W12 0BZ, UK., Danaei S; Department of Obstetrics and Gynecology, Tabriz University of Medical Sciences, Tabriz, Iran., Farzadi L; Department of Obstetrics and Gynecology, Tabriz University of Medical Sciences, Tabriz, Iran., Shahbazi S; Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran., Sinclair AH; Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia., Tucker EJ; Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia. Electronic address: elena.tucker@mcri.edu.au.
Jazyk: angličtina
Zdroj: Molecular and cellular endocrinology [Mol Cell Endocrinol] 2024 Jun 01; Vol. 587, pp. 112212. Date of Electronic Publication: 2024 Mar 22.
DOI: 10.1016/j.mce.2024.112212
Abstrakt: Research Question: Premature ovarian insufficiency (POI) is characterised by amenorrhea associated with elevated follicle stimulating hormone (FSH) under the age of 40 years and affects 1-3.7% women. Genetic factors explain 20-30% of POI cases, but most causes remain unknown despite genomic advancements.
Design: We used whole exome sequencing (WES) in four Iranian families, validated variants via Sanger sequencing, and conducted the Acyl-cLIP assay to measure HHAT enzyme activity.
Results: Despite ethnic homogeneity, WES revealed diverse genetic causes, including a novel homozygous nonsense variant in SYCP2L, impacting synaptonemal complex (SC) assembly, in the first family. Interestingly, the second family had two independent causes for amenorrhea - the mother had POI due to a novel homozygous loss-of-function variant in FANCM (required for chromosomal stability) and her daughter had primary amenorrhea due to a novel homozygous GNRHR (required for gonadotropic signalling) frameshift variant. WES analysis also provided cytogenetic insights. WES revealed one individual was in fact 46, XY and had a novel homozygous missense variant of uncertain significance in HHAT, potentially responsible for complete sex reversal although functional assays did not support impaired HHAT activity. In the remaining individual, WES indicated likely mosaic Turners with the majority of X chromosome variants having an allelic balance of ∼85% or ∼15%. Microarray validated the individual had 90% 45,XO.
Conclusions: This study demonstrates the diverse causes of amenorrhea in a small, isolated ethnic cohort highlighting how a genetic cause in one individual may not clarify familial cases. We propose that, in time, genomic sequencing may become a single universal test required for the diagnosis of infertility conditions such as POI.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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