Abstract
NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane
potential and neuronal excitability. It is part of a large ion channel complex, the “NALCN channelosome”, consisting of
multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an
important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small
number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM
615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 poreforming
segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD,
OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals
with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical
phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense
NALCN variant located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild
IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences
between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2
phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes
of these neurodevelopmental diseases to help improve counseling of affected families.