A novel hemizygous missense variant in the BEND2 gene is associated with nonobstructive azoospermia

Nonobstructive azoospermia (NOA), the most severe form of male infertility, frequently arises from genetic defects that disrupt spermatogenesis. In this study, a novel hemizygous missense variant (NM_001184767.2 [c.G1069A; p.V357I]) is identified in the X-linked BEN domain-containing 2 (BEND2) gene of a patient with NOA characterized by spermatocyte maturation arrest. Whole-exome sequencing and Sanger validation confirmed that this rare variant is absent in fertile controls and that no pathogenic variants were detected in established NOA genes. Computational analysis predicted potential structural alterations via AlphaFold modeling, leading to the hypothesis that the ability of BEND2 to recognize genomic targets may be compromised. The patient's phenotype phenocopies the meiotic arrest observed in Bend2-knockout mice. Expression profiling confirmed predominant BEND2 transcription in human and mouse testes, peaking in early spermatocytes and coinciding with meiotic initiation, with reduced transcript levels detected in the proband's peripheral blood compared with those in an obstructive azoospermia control. This study reports a pathogenic BEND2 variant associated with NOA with spermatocyte arrest, highlighting its critical role in human meiosis and expanding the genetic etiology of male infertility.