Genet Med. 2023 May 11:100894. doi: 10.1016/j.gim.2023.100894. Online ahead of print.

ABSTRACT

PURPOSE: The “NALCN channelosome”, is an ion channel complex consisting of multiple proteins including NALCN, UNC79, UNC80, and FAM155A. NALCN and UNC80 variants are described in a small number of individuals leading to a neurodevelopmental syndrome. However, no pathogenic UNC79 variants have been reported and in vivo function of UNC79 in humans is largely unknown.

METHODS: We used international gene-matching efforts to identify patients harboring ultra-rare heterozygous loss-of-function UNC79 variants and no other putative responsible genes. We used genetic manipulations in Drosophila and mice to test potential causal relationships between UNC79 variants and the pathology.

RESULTS: We found six unrelated and affected patients with UNC79 variants. Five patients presented with overlapping neurodevelopmental features including mild to moderate intellectual disability and a mild developmental delay while a single patient reportedly had normal cognitive and motor development, but was diagnosed with epilepsy and autistic features. All displayed behavioral issues and four patients had epilepsy. Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a heterozygous loss-of-function variant have a developmental delay in body weight compared with wild-type. In addition, they have impaired ability in learning and memory.

CONCLUSION: Our results demonstrate that heterozygous loss-of-function UNC79 variants are associated with neurological pathologies.

PMID:37183800 | DOI:10.1016/j.gim.2023.100894