Genetic variants in components of the NALCN–UNC80–UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies)

• Published in: Human genetics Vol. 137; no. 9; pp. 753 - 768
• Main Authors: Bramswig, Nuria C., Bertoli-Avella, Aida M., Albrecht, Beate, Al Aqeel, Aida I., Alhashem, Amal, Al-Sannaa, Nouriya, Bah, Maissa, Bröhl, Katharina, Depienne, Christel, Dorison, Nathalie, Doummar, Diane, Ehmke, Nadja, Elbendary, Hasnaa M., Gorokhova, Svetlana, Héron, Delphine, Horn, Denise, James, Kiely, Keren, Boris, Kuechler, Alma, Ismail, Samira, Issa, Mahmoud Y., Marey, Isabelle, Mayer, Michèle, McEvoy-Venneri, Jennifer, Megarbane, Andre, Mignot, Cyril, Mohamed, Sarar, Nava, Caroline, Philip, Nicole, Ravix, Cecile, Rolfs, Arndt, Sadek, Abdelrahim Abdrabou, Segebrecht, Lara, Stanley, Valentina, Trautman, Camille, Valence, Stephanie, Villard, Laurent, Wieland, Thomas, Engels, Hartmut, Strom, Tim M., Zaki, Maha S., Gleeson, Joseph G., Lüdecke, Hermann-Josef, Bauer, Peter, Wieczorek, Dagmar
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-09-2018; Springer; Springer Nature B.V; Springer Verlag
• Subjects: Adolescent; Adult; Biomedical and Life Sciences; Biomedicine; Carrier Proteins - genetics; Channelopathies - genetics; Channelopathies - pathology; Child; Child, Preschool; Developmental Disabilities - genetics; Developmental Disabilities - pathology; Excitability; Female; Gene Function; Genetic aspects; Genetic diversity; Genetic Markers; Genetic Variation; Genetics; Human Genetics; Humans; Infant; Infant, Newborn; Intellectual disabilities; Ion Channels; Lamotrigine; Life Sciences; Male; Medical schools; Membrane potential; Membrane Proteins - genetics; Metabolic Diseases; Molecular Medicine; Neurodevelopmental disorders; Neurophysiology; Original Investigation; Phenotype; Phenotypes; Sodium; Sodium Channels - genetics; Young Adult
• ISSN: 0340-6717; 1432-1203; 1432-1203
• DOI: 10.1007/s00439-018-1929-5

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.