Genetic variants in components of the NALCN–UNC80–UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies)
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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 pore-forming 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.
We are grateful to the families for participating in this study and giving their consent for publication. We thank Sabine Kaya for excellent technical assistance. NE is participant in the Clinician Scientist Program, funded by the Berlin Institute of Health (BIH) and the Charité. LS received a Medical Student Research Grant from the BIH. This work was in part supported by the German Ministry of Research and Education [grant numbers 01GS08164 (HE), 01GS08167 (DW), 01GS08163 (TMS), German Mental Retardation Network] as part of the National Genome Research Network, the Broad Institute (U54HG003067 to E. Lander and UM1HG008900 to D. MacArthur), the Yale Center for Mendelian Disorders (U54HG006504 to R. Lifton and M. Gunel), NIH grants R01NS048453, R01NS052455, the Simons Foundation for Autism Research Initiative and Howard Hughes Medical Institute (to JGG). We would like to thank Prince Abdullah Ben Khalid Celiac Disease Research Chair, Vice Deanship of Research Chairs, King Saud University, Riyadh, Kingdom of Saudi Arabia for their support.
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Conflict of interest
Arndt Rolfs is founder and shareholder of CENTOGENE AG, a commercial company offering genetic testing service. Aida Bertoli-Avella and Peter Bauer are employees of CENTOGENE AG.
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