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

GEMINI Consortium

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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.Gln498Thrfs7 (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.

Original languageEnglish (US)
Pages (from-to)200-212
Number of pages13
JournalAmerican Journal of Human Genetics
Volume103
Issue number2
DOIs
StatePublished - Aug 2 2018
Externally publishedYes

Fingerprint

Fanconi Anemia
Azoospermia
Loss of Heterozygosity
Sertoli Cell-Only Syndrome
Sertoli Cells
Infertility
Estonia
Exome
Seminiferous Tubules
Portugal
Genomic Instability
Meiosis
Spermatogenesis
Mitosis
Germ Cells
Codon
Fathers
Ovarian Neoplasms
Spermatozoa
Siblings

Keywords

  • bi-allelic loss-of-function variants
  • FANCM
  • genetic cause of male infertility
  • immunohistochemistry
  • non-obstructive azoospermia
  • prostate
  • SCOS
  • Sertoli cell-only syndrome
  • spermatogenesis
  • testicular biopsy
  • whole-exome sequencing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Bi-allelic Recessive Loss-of-Function Variants in FANCM Cause Non-obstructive Azoospermia. / GEMINI Consortium.

In: American Journal of Human Genetics, Vol. 103, No. 2, 02.08.2018, p. 200-212.

Research output: Contribution to journalArticle

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abstract = "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.",
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