Compound heterozygous REC114 variants in dizygotic twins causes meiotic arrest and non-obstructive azoospermia.

Abstract

BACKGROUND: Meiosis is essential for gametogenesis and the maintenance of fertility. Central to this process is meiotic recombination, a mechanism that ensures accurate chromosome segregation and drives genetic diversity. Non-obstructive azoospermia (NOA), a severe form of male infertility, often results from meiotic arrest. Although monogenic variants in genes critical for meiosis have been identified as a cause, the etiology of approximately 60–70% of NOA cases remains unresolved, highlighting a significant gap in our understanding of its genetic basis. CASE PRESENTATION: We utilized whole-exome sequencing (WES) to identify novel compound heterozygous variants in REC114 (c.523_524del: p.Lys175GlufsTer50 and c.640_641del: p.Leu214SerfsTer11) in a pair of Chinese dizygotic twin brothers with NOA. These variants are predicted to generate a truncated REC114 protein and disrupt its interaction with MEI4, which is essential for the formation of double-strand breaks (DSBs) during meiosis. Testicular histopathology and meiotic chromosome spread analyses indicated meiotic arrest at the zygotene stage, consistent with a DSB formation defect. CONCLUSION: Our findings expand the spectrum of genetic factors contributing to NOA and suggest that the maintenance of DSB homeostasis is critical to the pathophysiology of meiotic arrest. This research offers new insights into the genetic basis of male infertility and holds potential for the development of improved genetic diagnostic tools.