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Bramswig, N.C.* ; Bertoli-Avella, A.M.* ; Albrecht, B.* ; Al Aqeel, A.I.* ; Alhashem, A.* ; Al-Sannaa, N.* ; Bah, M.* ; Bröhl, K.* ; Depienne, C.* ; Dorison, N.* ; Doummar, D.* ; Ehmke, N.* ; Elbendary, H.M.* ; Gorokhova, S.* ; Héron, D.* ; Horn, D.* ; James, K.* ; Keren, B.* ; Kuechler, A.* ; Ismail, S.* ; Issa, M.Y.* ; Marey, I.* ; Mayer, M.* ; McEvoy-Venneri, J.* ; Megarbane, A.* ; Mignot, C.* ; Mohamed, S.* ; Nava, C.* ; Philip, N.* ; Ravix, C.* ; Rolfs, A.* ; Sadek, A.A.* ; Segebrecht, L.* ; Stanley, V.* ; Trautman, C.* ; Valence, S.* ; Villard, L.* ; Wieland, T. ; Engels, H.* ; Strom, T.M. ; Zaki, M.S.* ; Gleeson, J.G.* ; Lüdecke, H.J.* ; Bauer, P.* ; Wieczorek, D.*

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

Hum. Genet. 137, 753-768 (2018)
DOI PMC Verlagsversion bestellen
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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 variantlocated 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Severe Intellectual Disability; Biallelic Mutations; Respiratory Rhythm; Sequencing Data; Hypotonia; Unc80; Arthrogryposis; Npas4; Encephalopathy; Dysmorphism
ISSN (print) / ISBN 0340-6717
e-ISSN 1432-1203
Zeitschrift Human Genetics
Quellenangaben Band: 137, Heft: 9, Seiten: 753-768 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort 233 Spring St, New York, Ny 10013 Usa