• PMID: 30075111
• Gene Name: FANCM
• Condition: Non-obstructive azoospermia (NOA), Sertoli cell-only syndrome (SCOS)
• Association: Associated
• Mutation: p.Gln498Thr (rs761250416), (c.4387-10A>G), p.Arg1931?; rs144567652
• Population size: 4
• Population details: 4 (2 brothers with NOA and Sertoli cell-only syndrome (SCOS) )
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Non-obstructive azoospermia (NOA), Sertoli cell-only syndrome (SCOS)

Bi-allelic Recessive Loss-of-Function Variants in FANCM Cause Non-obstructive Azoospermia

Kasak L, Punab M, Nagirnaja L, Grigorova M, Minajeva A, Lopes AM, Punab AM, Aston KI, Carvalho F, Laasik E, Smith LB; GEMINI Consortium, Conrad DF, Laan M.

Infertility affects around 7% of men worldwide. Idiopathic non-obstructive azoospermia (NOA) is defined as the absence of spermatozoa in the ejaculate due to failed spermatogenesis. There is a high probability that NOA is caused by rare genetic defects. In this study, whole-exome sequencing (WES) was applied to two Estonian brothers diagnosed with NOA and Sertoli cell-only syndrome (SCOS). Compound heterozygous loss-of-function (LoF) variants in FANCM (Fanconi anemia complementation group M) were detected as the most likely cause for their condition. A rare maternally inherited frameshift variant p.Gln498Thrfs(∗)7 (rs761250416) and a previously undescribed splicing variant (c.4387-10A>G) derived from the father introduce a premature STOP codon leading to a truncated protein. FANCM exhibits enhanced testicular expression. In control subjects, immunohistochemical staining localized FANCM to the Sertoli and spermatogenic cells of seminiferous tubules with increasing intensity through germ cell development. This is consistent with its role in maintaining genomic stability in meiosis and mitosis. In the individual with SCOS carrying bi-allelic FANCM LoF variants, none or only faint expression was detected in the Sertoli cells. As further evidence, we detected two additional NOA-affected case subjects with independent FANCM homozygous nonsense variants, one from Estonia (p.Gln1701(∗); rs147021911) and another from Portugal (p.Arg1931(∗); rs144567652). The study convincingly demonstrates that bi-allelic recessive LoF variants in FANCM cause azoospermia. FANCM pathogenic variants have also been linked with doubled risk of familial breast and ovarian cancer, providing an example mechanism for the association between infertility and cancer risk, supported by published data on Fancm mutant mouse models. CI - Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. FAU - Kasak, Laura AU - Kasak L AD - Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu 50411, Estonia. FAU - Punab, Margus AU - Punab M AD - Andrology Centre, Tartu University Hospital, Tartu 50406, Estonia. FAU - Nagirnaja, Liina AU - Nagirnaja L AD - Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA. FAU - Grigorova, Marina AU - Grigorova M AD - Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu 50411, Estonia. FAU - Minajeva, Ave AU - Minajeva A AD - Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu 50411, Estonia. FAU - Lopes, Alexandra M AU - Lopes AM AD - IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Porto 4200-135, Portugal; i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal. FAU - Punab, Anna Maria AU - Punab AM AD - Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu 50411, Estonia. FAU - Aston, Kenneth I AU - Aston KI AD - Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT 84132, USA. FAU - Carvalho, Filipa AU - Carvalho F AD - i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal; Serviço de Genética, Departamento de Patologia, Faculdade de Medicina da Universidade do Porto, Porto 4200-319, Portugal. FAU - Laasik, Eve AU - Laasik E AD - Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu 50411, Estonia. FAU - Smith, Lee B AU - Smith LB AD - MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh EH16 4TJ, UK; School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW 2308, Australia. CN - GEMINI Consortium FAU - Conrad, Donald F AU - Conrad DF AD - Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.