Disruption of Meiotic Double-Strand Break Dynamics Provokes Germline Human Infertility in Both Sexes

Exome sequencing of three consanguineous families found homozygous loss-of-function variants in SPIDR, TOP6BL, or RAD51AP2 — all meiotic DNA repair genes — causing infertility in both sexes.

Journal: Journal of Assisted Reproduction and Genetics | Published: 2026-02-05 | Type: Journal Article | PMID: 41644825 Authors: Okutman O et al. — Hôpital Universitaire de Bruxelles (CUB Erasme), Novafertil IVF Centre (Turkey), Hôpitaux Universitaires de Strasbourg, Istanbul Genetik Grubu Funding/COI: Fondation Maladies Rares. No competing interests declared.

Summary

Three consanguineous families — meaning the parents in each are related — each carried a different homozygous loss-of-function variant in a gene involved in meiotic double-strand break (DSB) repair: SPIDR, TOP6BL, and RAD51AP2. In each family, the infertile index cases were homozygous for the variant while parents and fertile siblings were heterozygous carriers, supporting an autosomal recessive inheritance pattern. The paper adds new patients and variants to the evidence base for these three gene-disease relationships, and flags that DNA repair gene defects may also raise long-term cancer risk via chromosomal instability.

Claims

• Homozygous loss-of-function variant in SPIDR identified by exome sequencing in family 1 (index case sequenced alone); parents and fertile siblings confirmed as carriers by Sanger sequencing
• Homozygous loss-of-function variant in TOP6BL identified in family 2 via trio sequencing (index + both parents); segregation pattern consistent
• Homozygous loss-of-function variant in RAD51AP2 identified in family 3 via trio sequencing; all three genes participate in DSB formation or homologous recombination repair during meiosis
• Infertility phenotype affects both sexes within families, consistent with the sex-agnostic role of meiosis
• Authors assert identification of pathogenic variants "might help avoid unsuccessful fertility treatments" by redirecting patients away from procedures unlikely to succeed
• Authors recommend long-term oncology surveillance for carriers of DNA repair gene variants due to potential chromosomal instability

Study Quality

This is a case series of three families — the lowest tier of evidence above a single case report. Three families, three genes, and an unknown number of total affected individuals is not enough to estimate penetrance, phenotypic expressivity, or population-level prevalence of these variants. Trio exome sequencing in families 2 and 3 is methodologically sound for variant discovery; sequencing only the index case in family 1, without parental exomes, is weaker. Sanger sequencing for segregation confirmation is standard and appropriate. There is no functional validation: the authors infer pathogenicity from prior literature and the theoretical impact of loss-of-function in known meiotic pathway genes, but do not demonstrate mechanistically that these specific variants abolish DSB repair in these patients.

The full-text sections provided to review are identical to the abstract — if additional methods, variant-level data (genomic coordinates, predicted protein consequences, population allele frequencies from gnomAD), or histology/testicular biopsy data exist in the full paper, they are not available here for assessment.

Red Flags

• N=3 families total — far too small to draw generalizable conclusions; the paper is essentially a case series dressed in exome-sequencing language
• No functional validation — pathogenicity is inferred, not demonstrated
• Consanguineous families only — these are rare, high-inbreeding pedigrees; findings may not generalize to outbred infertile populations
• Family 1 index-only sequencing — weaker than trio design; parental variant confirmation by Sanger alone
• Full text unavailable for review — variant-level data (positions, allele frequencies, ACMG classifications) cannot be assessed
• Cancer surveillance recommendation issued in the conclusion without citing any supporting evidence that these specific gene variants elevate cancer risk in heterozygous or homozygous carriers
• Conclusion edges into clinical recommendation ("genetic screening could be recommended") — appropriate for a case report conclusion but unsupported by evidence presented

Strengths

• Multi-family, multi-gene design converging on a single biological pathway (meiotic DSB repair) adds coherent mechanistic logic
• Autosomal recessive segregation confirmed in each family: parents and fertile siblings heterozygous, affected cases homozygous
• Trio sequencing in two of three families is the appropriate design for de novo vs. inherited variant detection
• Affects both sexes, establishing that the meiotic DSB pathway is not sex-limited — clinically useful framing
• No industry funding; Fondation Maladies Rares is an independent rare-disease foundation
• No competing interests declared

Verdict

This paper is a competent case series that adds three families and three confirmed variants to the growing literature on meiotic gene defects as a cause of primary infertility. It will matter to clinical geneticists who see unexplained infertility in consanguineous families — it expands the variant catalog for SPIDR, TOP6BL, and RAD51AP2. For anyone else, the sample size of three families should flash a loud warning: there is no quantification here, no effect size, and no population-level claim that can be made. The cancer surveillance recommendation in the conclusion is the weakest part of the paper — it's clinically intuitive given what we know about DNA repair genes and genomic instability, but the authors cite no specific evidence that these variants elevate cancer risk and yet recommend "long-term follow-up by a multidisciplinary team." Read it as hypothesis-generating, not practice-changing.