Submission Details

Autosomal dominant

09/10/2019

The UNC80 gene is located on chromosome 2 at 2q34 and encodes unc-80 homolog, NALCN channel complex subunit, which is a component of a sodium channel complex that regulates channel activity. UNC80 was first reported in relation to autosomal recessive UNC80-related hypotonia, infantile, with psychomotor retardation and characteristic facies, in 2016 (26708753: Shamseldin et al., 2016; 26708751: Stray-Pedersen et al. 2016). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 11 unique variants reported in eight cases from four publications (26708753: Shamseldin et al. 2016; 26708751: Stray-Pedersen et al. 2016; 30167850: Bramswig et al. 2018; 30771478: Kuptanon et al. 2019) One variant was a missense with experimental evidence of a loss-of-function effect; the remainder were predicted null variants. No segregation evidence was scored, but variants in this gene co-segregated with disease in three additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. Homozygous loss of function is implicated as the mechanism of disease. This gene-disease relationship is supported by knockout/knockdown models in C. Elegans and Drosophila, including rescue, as well as demonstration of physical interaction with another gene product associated with a similar phenotype (18336069: Yeh et al. 2008; 24223770: Lear et al. 2013). In summary, UNC80 is definitively associated with autosomal recessive UNC80-related hypotonia, infantile, with psychomotor retardation and characteristic facies. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

26708753 26708751 30167850 30771478 24223770 18336069