ZSWIM7 Is Associated with Human Female Meiosis and Familial Primary Ovarian Insufficiency

Abstract

Background: Primary ovarian insufficiency (POI) affects 1% of women and is associated with significant medical consequences. A genetic cause for POI can be found in up to 30% of women, elucidating key roles for these genes in human ovary development. Objective: We aimed to identify the genetic mechanism underlying early-onset POI in 2 sisters from a consanguineous pedigree. Methods: Genome sequencing and variant filtering using an autosomal recessive model was performed in the 2 affected sisters and their unaffected family members. Quantitative reverse transcriptase PCR (qRT-PCR) and RNA sequencing were used to study the expression of key genes at critical stages of human fetal gonad development (Carnegie Stage 22/23, 9 weeks post conception (wpc), 11 wpc, 15/16 wpc, 19/20 wpc) and in adult tissue. Results: Only 1 homozygous variant cosegregating with the POI phenotype was found: A single nucleotide substitution in zinc finger SWIM-Type containing 7 (ZSWIM7), NM-001042697.2: c.173C>G; resulting in predicted loss-of-function p.(Ser58∗). qRT-PCR demonstrated higher expression of ZSWIM7 in the 15/16 wpc ovary compared with testis, corresponding to peak meiosis in the fetal ovary. RNA sequencing of fetal gonad samples showed that ZSWIM7 has a similar temporal expression profile in the developing ovary to other homologous recombination genes. Main conclusions: Disruption of ZSWIM7 is associated with POI in humans. ZSWIM7 is likely to be important for human homologous recombination; these findings expand the range of genes associated with POI in women.