Novel bi-allelic variants in KASH5 are associated with meiotic arrest and non-obstructive azoospermia

KASH5 is an essential component of the LINC (linker of the nucleoskeleton and cytoskeleton) complex that regulates chromosome movements and nuclear envelope (NE) remodeling in mouse spermatocytes during meiosis prophase I, but its expression and function in human cells, as well as its association with male infertility are largely unknown. In this study, a novel heterozygous copy number variation (CNV) (seq [GRCh37] del(19) (19q13.33) chr19: g.49894043-49903011del) and a heterozygous loss of function variant (NM_144688: c.979_980del: p.R327Sfs*21) in human KASH5 were identified in a non-obstructive azoospermia (NOA)-affected patient and in his infertile sister by whole-exome sequencing and CNV array. Spermatogenesis in the proband was arrested at zygotene-like stage with a deficiency in homolog pairing and synapsis. KASH5 protein expression in human spermatocytes was evaluated and reported first in this study. Single-cell RNA sequencing demonstrated that the LINC complex and associated genes in human and mouse shared a similar expression pattern, indicating a conserved mechanism in the regulation of chromosome movements and NE remodeling. Kash5 knockout mouse displayed similar phenotypes, including a meiotic arrest at a zygotene-like stage and impaired pairing and synapsis. Collectively, we have identified novel rare variants within human KASH5 in patients with NOA and meiosis arrest. Our study expands the knowledge of KASH5 and associated proteins in regulating human meiosis prophase I progress and provides new insight into the genetic etiology of NOA.