Delineating the Disease Boundaries: Homozygous Variants Underlying Nonsyndromic Hearing Loss and Hearing Impairment Infertile Male Syndrome.

BACKGROUND

Hereditary hearing loss is a genetically heterogeneous neurosensory disorder that affects many people. Deafness and infertility can coexist in some cases, creating the hearing impairment infertile male syndrome. There are several known molecular mechanisms that can cause deafness either on its own or in conjunction with infertility.

METHODS AND RESULTS

Here, we represent two consanguineous families (A, B), both families had clinical evidence of deafness, and family B also had infertility, so we referred to them as having nonsyndromic hearing loss (NSHL) and hearing impairment infertile male syndrome (HIIMS), respectively. These families' genetic makeup was examined using an Affymetrix GeneChip 250K Nsp array followed by Sanger sequencing. In family A, we identified a novel homozygous stop gain variant [NM_003672.4; c.1000C>T; p.(Gln334*)] and a homozygous missense variant [NM_003672.4; c.684C>A; p.(Asn228Lys)] in family B in gene (MIM#603504). In animal models, the gene causes both hearing loss and infertility; in addition, it also causes NSHL and HIIMS in humans.

CONCLUSIONS

Our study on the gene has identified two novel variants, crucial for delineating disease boundaries. Variants in exon 10 and upstream cause HIIMS, and those in exon 11 and downstream are linked exclusively to hearing impairment. This precision enhances diagnostics and offers potential for targeted interventions, marking a significant advancement in understanding the genetic basis of these conditions.