Abstract
Non-obstructive azoospermia (NOA) is the most severe disease in male infertility, but the genetic causes for the majority of NOA remain unknown. FANCM is a member of Fanconi Anemia (FA) core complex, whose defects are associated with cell hypersensitivity to DNA interstrand crosslink (ICL)-inducing agents. It was reported that variants in FANCM (MIM: 609644) might cause azoospermia or oligospermia. However, there is still a lack of evidence to explain the association between different FANCM variants and male infertility phenotypes. Herein, we identified compound heterozygous variants in FANCM in two NOA-affected brothers (c. 1778delG:p. R593Qfs*76 and c. 1663G > T:p. V555F), and a homozygous variant in FANCM (c. 1972C > T:p. R658X) in a sporadic case with NOA, respectively. H&E staining and immunohistochemistry showed Sertoli cell-only Syndrome (SCOS) in the three patients with NOA. Collectively, our study expands the knowledge of variants in FANCM, and provides a new insight to understand the genetic etiology of NOA.
Highlights
Infertility is a common reproductive disorder affecting about 8–12% of couples worldwide
Reproductive congenital diseases such as Klinefelter syndrome and genomic AZF deletions, or other azoospermia-associated factors including varicocele, radiation, chemotherapy, orchitis, cryptorchidism, and testicular cancer were excluded for these patients with non-obstructive azoospermia (NOA)
Written informed consent was obtained from the individual(s) and/or minor(s) legal guardian/ of kin for the publication of any potentially identifiable images or data included in this article
Summary
Infertility is a common reproductive disorder affecting about 8–12% of couples worldwide. Azoospermia, which is defined as the complete absence of spermatozoa in the ejaculate, and accounts for 10–15% of male infertility cases. 70% of cases represent non-obstructive azoospermia (NOA) with the absence or reduction of germ cells owing to testicular atrophy (Stephen and Chandra, 2006). Sertoli cell-only Syndrome (SCOS) is the most severe type of NOA with impairment of spermatogenesis, which is characterized as complete loss of male germ cells in the seminiferous tubules with only Sertoli cells retained (Ezeh et al, 1998). NOA is heterogeneous in etiology, including Y chromosome microdeletions, chromosomal abnormalities, hypogonadism, testicular tumor, cryptorchidism, varicocele, improper drug administration, and single gene mutations (Minhas et al, 2021). Several causative genes have been identified by whole-exome sequencing (WES) in NOA pedigrees, such as DNA Meiotic Recombinase 1 (DMC1 MIM: 602721), Stromal Antigen 3 (STAG3 MIM:608489), Testis Expressed 11 (TEX11 MIM: 300311), Shortage In Chiasmata 1 (SHOC1, MIM: 618038), Synaptonemal Complex Central Element Protein 1 (SYCE1 MIM: 611486), Meiosis Specific
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