De novo variants of NALCN differentially impact both the phenotypic spectrum of patients and the biophysical properties of the NALCN current

The Na+ leak channel NALCN regulates the resting membrane potential and consequently cell excitability of several cell types, including neurons. Studies of animal models demonstrated that NALCN is involved in fundamental physiological functions such as respiratory rhythm, circadian rhythm, sleep, locomotor behavior and pain perception. Pathogenic variants of NALCN have been associated with ultra-rare developmental disorders characterized by a wide range of symptoms with variable severity. We and others previously showed that pathogenic variants of NALCN can be categorized in 2 groups. The first group corresponds to inherited biallelic loss-of-function variants with patients suffering from the IHPRF1 syndrome (OMIM #615419). The second one corresponds to de novo gain-of-function variants that cause the CLIFAHDD syndrome (OMIM #616266). In this study, we provide a standardized phenotypic description of a large group of 35 individuals with de novo pathogenic variants of NALCN. In addition, we performed functional studies of several of these variants using the patch clamp technique in a recombinant system. We highlight a large heterogeneity in terms of both expressed symptoms and their severity. By contrast with previous reports only showing a pure gain-of-function effect of de novo pathogenic variants, we found that de novo variants of NALCN differentially impact the biophysical properties of the NALCN current and likely influence cell excitability. To conclude, de novo variants of NALCN differentially impact the biophysical properties of the NALCN current. We hypothesize that this may at least partly explain the phenotypic diversity observed in patients.