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

• Type: Article in International Scientific Journal
• Date: 2018

Authors

Kasak, L (Author) Other; Punab, M (Author) Other; Nagirnaja, L (Author) Other; Grigorova, M (Author) Other; Minajeva, A (Author) Other; Lopes, AM (Author) Other; Punab, AM (Author) Other; Aston, KI (Author) Other; carvalho, f (Author) FMUP; Laasik, E (Author) Other; Smith, LB (Author) Other; Conrad, DF (Author) Other; Laan, M (Author) Other

Journal

Title: American Journal of Human Genetics

Vol. 103

Pages: 200-212

ISSN: 0002-9297

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 88 Citations

Scopus - 95 Citations

Other information

Authenticus ID: P-00P-20D

DOI: 10.1016/j.ajhg.2018.07.005

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13