De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum

Alma Kuechler*, Marjolein H. Willemsen, Beate Albrecht, Carlos A. Bacino, Dennis W. Bartholomew, Hans van Bokhoven, Marie Jose H. van den Boogaard, Nuria Bramswig, Christian Buettner, Kirsten Cremer, Johanna Christina Czeschik, Hartmut Engels, Koen van Gassen, Elisabeth Graf, Mieke van Haelst, Weimin He, Jacob S. Hogue, Marlies Kempers, David Koolen, Glen MonroeSonja de Munnik, Matthew Pastore, Andre Reis, Miriam S. Reuter, David H. Tegay, Joris Veltman, Gepke Visser, Peter van Hasselt, Eric E. J. Smeets, Lisenka Vissers, Thomas Wieland, Willemijn Wissink, Helger Yntema, Alexander Michael Zink, Tim M. Strom, Hermann-Josef Luedecke, Tjitske Kleefstra, Dagmar Wieczorek

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

53 Citations (Web of Science)

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.
Original languageEnglish
Pages (from-to)97-109
JournalHuman Genetics
Volume134
Issue number1
DOIs
Publication statusPublished - Jan 2015

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