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Purpose <p>To explore genetic basis leading to&#xa0;meiotic disruption in human gametogenesis via exome sequencing.</p> Methods <p>This study included three consanguineous families with well-defined infertility phenotypes. Exome sequencing was performed for the index case in family 1 and for the trio (index with parents) in the other two families. Sanger sequencing was used for confirmation and family segregation analysis.</p> Results <p>Exome sequencing revealed homozygous loss-of-function variations in <i>SPIDR</i>, <i>TOP6BL</i>, and <i>RAD51AP2</i> in families 1, 2, and 3, respectively. Segregation in individual families revealed that the parents were carriers, as were the fertile siblings in families 1 and 2. All three genes function in double-strand break formation or repair, identified variants may therefore impair, potentially preventing its completion and contributing to infertility in the index cases. Gene-disease relationships (GDR) were re-evaluated due to the addition of new patients and/or variants in the literature.</p> Conclusion <p>Our findings provide additional evidence for the role of <i>SPIDR</i>, <i>TOP6BL</i>, and <i>RAD51AP2</i> as genetic contributors to human infertility due to meiotic errors. For patients with a similar phenotype, genetic screening could be recommended, and the identification of pathogenic variations might help avoid unsuccessful fertility treatments. Additionally, in patients with molecular defects in DNA repair genes, chromosomal instability may increase the risk of cancer; therefore, long-term follow-up by a multidisciplinary team is recommended.</p>

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Disruption of meiotic double-strand break dynamics provokes germline human infertility in both sexes

  • 期刊论文

  • 发表日期：

    2026年2月5日

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  • Ozlem Okutman,
  • Asma Sassi,
  • Ahmet Salvarci,
  • Sophie Lambert,
  • Cécile Brachet,
  • Xavier Peyrassol,
  • Cécile Lang,
  • Didem Savas Alptekin,
  • Ridvan Seçkin Ozen,
  • Jean Muller,
  • Guillaume Smits,
  • Necati Findikli,
  • Anne Delbaere,
  • Stéphane Viville

摘要

Purpose

To explore genetic basis leading to meiotic disruption in human gametogenesis via exome sequencing.

Methods

This study included three consanguineous families with well-defined infertility phenotypes. Exome sequencing was performed for the index case in family 1 and for the trio (index with parents) in the other two families. Sanger sequencing was used for confirmation and family segregation analysis.

Results

Exome sequencing revealed homozygous loss-of-function variations in SPIDR, TOP6BL, and RAD51AP2 in families 1, 2, and 3, respectively. Segregation in individual families revealed that the parents were carriers, as were the fertile siblings in families 1 and 2. All three genes function in double-strand break formation or repair, identified variants may therefore impair, potentially preventing its completion and contributing to infertility in the index cases. Gene-disease relationships (GDR) were re-evaluated due to the addition of new patients and/or variants in the literature.

Conclusion

Our findings provide additional evidence for the role of SPIDR, TOP6BL, and RAD51AP2 as genetic contributors to human infertility due to meiotic errors. For patients with a similar phenotype, genetic screening could be recommended, and the identification of pathogenic variations might help avoid unsuccessful fertility treatments. Additionally, in patients with molecular defects in DNA repair genes, chromosomal instability may increase the risk of cancer; therefore, long-term follow-up by a multidisciplinary team is recommended.