Clinical Utility of Whole-Exome Sequencing in a Consanguineous Family with UNC80-related Neurodevelopmental Disorder: A Case Series and Review of the Literature

The <i>UNC79</i> and <i>UNC80</i> proteins form key regulatory subunits of the sodium leak channel, non-selective (NALCN), a channel fundamental to maintaining neuronal excitability. The <i>UNC80</i> gene, located on chromosome 2 at the 2q34 locus, encodes a critical component of this channel complex, contributing to its permeability to Na⁺, K⁺, and Ca²⁺ ions. Mutations in this gene are presumed to be linked to symptoms such as hypotonia, intellectual disability, seizures, and more. With fewer than 50 cases reported, the prevalence remains unknown. In this study, we present three novel cases. Two of the cases involve siblings: a seven-year-old girl and a two-year-old boy, both diagnosed through whole-exome sequencing with a homozygous mutation in the UNC80 gene. This mutation results in a clinical phenotype that includes seizure disorder, infantile hypotonia, global developmental delay, and failure to thrive. Additional manifestations in the girl included pulmonary stenosis and an atrial septal defect. The third case is their elder brother, diagnosed at the age of 17, although he initially received a diagnosis of spastic quadriplegic cerebral palsy earlier in his disease course. In this report, we highlight the diagnostic findings, previously published case reports, and management strategies for this rare genetic disorder.