title: De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum.
abstract: Recently, de novo heterozygous loss-of-function mutations in beta-catenin (CTNNB1) were described for the first time in four individuals with intellectual disability (ID), microcephaly, limited speech and (progressive) spasticity, and functional consequences of CTNNB1 deficiency were characterized in a mouse model. Beta-catenin is a key downstream component of the canonical Wnt signaling pathway. Somatic gain-of-function mutations have already been found in various tumor types, whereas germline loss-of-function mutations in animal models have been shown to influence neuronal development and maturation. We report on 16 additional individuals from 15 families in whom we newly identified de novo loss-of-function CTNNB1 mutations (six nonsense, five frameshift, one missense, two splice mutation, and one whole gene deletion). All patients have ID, motor delay and speech impairment (both mostly severe) and abnormal muscle tone (truncal hypotonia and distal hypertonia/spasticity). The craniofacial phenotype comprised microcephaly (typically -2 to -4 SD) in 12 of 16 and some overlapping facial features in all individuals (broad nasal tip, small alae nasi, long and/or flat philtrum, thin upper lip vermillion). With this detailed phenotypic characterization of 16 additional individuals, we expand and further establish the clinical and mutational spectrum of inactivating CTNNB1 mutations and thereby clinically delineate this new CTNNB1 haploinsufficiency syndrome.
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany, alma.kuechler@uni-due.de.
authors.forename: Alma
authors.initials: A
authors.lastname: Kuechler
authors.forename: Marjolein H
authors.initials: MH
authors.lastname: Willemsen
authors.forename: Beate
authors.initials: B
authors.lastname: Albrecht
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bacino
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Bartholomew
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Marie Jose H
authors.initials: MJ
authors.lastname: van den Boogaard
authors.forename: Nuria
authors.initials: N
authors.lastname: Bramswig
authors.forename: Christian
authors.initials: C
authors.lastname: Büttner
authors.forename: Kirsten
authors.initials: K
authors.lastname: Cremer
authors.forename: Johanna Christina
authors.initials: JC
authors.lastname: Czeschik
authors.forename: Hartmut
authors.initials: H
authors.lastname: Engels
authors.forename: Koen
authors.initials: K
authors.lastname: van Gassen
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Graf
authors.forename: Mieke
authors.initials: M
authors.lastname: van Haelst
authors.forename: Weimin
authors.initials: W
authors.lastname: He
authors.forename: Jacob S
authors.initials: JS
authors.lastname: Hogue
authors.forename: Marlies
authors.initials: M
authors.lastname: Kempers
authors.forename: David
authors.initials: D
authors.lastname: Koolen
authors.forename: Glen
authors.initials: G
authors.lastname: Monroe
authors.forename: Sonja
authors.initials: S
authors.lastname: de Munnik
authors.forename: Matthew
authors.initials: M
authors.lastname: Pastore
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Miriam S
authors.initials: MS
authors.lastname: Reuter
authors.forename: David H
authors.initials: DH
authors.lastname: Tegay
authors.forename: Joris
authors.initials: J
authors.lastname: Veltman
authors.forename: Gepke
authors.initials: G
authors.lastname: Visser
authors.forename: Peter
authors.initials: P
authors.lastname: van Hasselt
authors.forename: Eric E J
authors.initials: EE
authors.lastname: Smeets
authors.forename: Lisenka
authors.initials: L
authors.lastname: Vissers
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.forename: Willemijn
authors.initials: W
authors.lastname: Wissink
authors.forename: Helger
authors.initials: H
authors.lastname: Yntema
authors.forename: Alexander Michael
authors.initials: AM
authors.lastname: Zink
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Lüdecke
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
mesh_terms: D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D057895:Haploinsufficiency; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D013577:Syndrome; D051176:beta Catenin / Q000235:genetics*
chemical_list: C495270:CTNNB1 protein, human; D051176:beta Catenin