A scan for repeat-mediated genomic disorders in clinical cases of male infertility

Genomic disorders are diseases caused by recurrent genomic rearrangements arising from unstable genome architecture, most commonly through non-allelic homologous recombination (NAHR). While NAHR-mediated disorders are well established in neurodevelopmental disease, comparatively few have been described in male infertility beyond recurrent rearrangements of the Y chromosome azoospermia factor (AZF) region and deletions of DPY19L2 and SYCE1 . To identify additional genomic disorders of spermatogenic failure, we performed copy number variant (CNV) analysis on whole-exome sequencing data from 1,608 clinically diagnosed cases of infertility and 644 normozoospermic controls recruited through an international multicenter study. Candidate variants were evaluated using manual inspection, PCR, and Oxford Nanopore whole-genome sequencing. We observed an enrichment of rare deletions affecting infertility genes in cases and identified causal CNVs in 0.85% of patients, including rearrangements involving the AZF region, ADAD2 , DMRT1 , RBBP7 , STRA8 , and STX2 . We describe two candidate genomic disorder loci on the X chromosome. The first, at Xp22.31 involves recurrent NAHR-mediated deletions of testis-expressed genes VCX and PUDP . The other, on Xp22.13 involves recurrent deletions and duplications of the known male infertility gene BEND2 and the testis expressed gene RAI2 . These findings expand the spectrum of structural variation contributing to male infertility and support an underappreciated role for recurrent genomic rearrangements in spermatogenic failure.