Identification and Characterization of a Novel Biallelic SLC12A2 Variant Associated With Kilquist Syndrome (OMIM #619080).

This study presents the case of a child with multiple congenital anomalies, severe hypotonia, and profound bilateral sensorineural hearing loss. Functional bioenergetic assessments showed no significant mitochondrial respiratory defects, and riboflavin (Rf) status evaluation excluded a deficiency in Rf transporters as a cause of hearing loss. Clinical findings were consistent with Kilquist syndrome (KILQS), and genetic investigations confirmed the diagnosis by identifying a novel homozygous splice-site variant, c.[3101-1G>C];[3101-1G>C], in the SLC12A2 gene, which encodes the Na+-K+-2Cl- Cotransporter 1 (NKCC1) protein. The effect of this mutation was further investigated using exon-walking PCR and Sanger sequencing, which confirmed exon 23 skipping in the patient's mRNA, resulting in a truncated NKCC1 protein. In silico structural modeling suggested compromised dimerization stability, which was supported by immunoblotting analysis, revealing the absence of the dimeric form of NKCC1 in patient-derived peripheral blood mononuclear cells. This study provides critical insights into the molecular and structural consequences of NKCC1 disruption, contributing to the understanding of its role in KILQS pathogenesis. Further studies are needed to elucidate the precise molecular mechanisms and explore potential therapeutic interventions.