Compound Heterozygous Variants in ZSWIM7 Gene Linked to Infertility and Its Role in Gonadal Development

This study aims to elucidate the role of the ZSWIM7 gene in the etiology of infertility, focusing on its potential association with premature ovarian insufficiency and azoospermia. We investigated an 18-year-old female patient who presented with primary amenorrhea, hypoplasia of the uterus and ovaries, Tanner stage II breast and pubic hair development, severe scoliosis (surgically repaired), recurrent urinary infections, and hypothyroidism. Genetic analysis revealed two heterozygous variants: a loss-of-function frameshift mutation in ZSWIM7 and a chromosomal deletion encompassing the same gene-a combination not previously described in the literature. Diagnostic techniques included G-banding karyotype analysis, evaluation of FMR1 premutation by PCR, and whole-genome sequencing to identify gene variants and copy number variations (CNVs). The patient carries a pathogenic single-nucleotide variant (SNV) and, in the other chromosome, a deletion encompassing the ZSWIM7 gene. In silico network analysis indicated that ZSWIM7 interacts with genes involved in DNA repair and gonadal development. A literature review identified previous cases of homozygosity for the same variant, but this is the first reported case of compound heterozygosity involving both a base deletion and a CNV. A review of five prior studies on ZSWIM7 variants and infertility supports the conclusion that ZSWIM7 is associated with infertility in both sexes. Our findings suggest that loss-of-function pathogenic variants in ZSWIM7 negatively affect the formation and maintenance of male and female gonads.