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.
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Acknowledgments
We are grateful to the patients and their families for participating in this study and for giving consent to publish data and photographs. We thank Sabine Kaya and Daniela Falkenstein for excellent technical assistance. This work was supported by grants of The Netherlands Organization for Health Research and Development (ZonMw grant 907-00-365 to TK) and the European Union under the 7th framework program (Gencodys HEALTH-F4-2010-241995 to HvB and TK).
Conflict of interest
The authors declare that they have no competing interests. The views expressed are those of the author and do not reflect the official policy of the Department of the Army, the Department of Defense or the U. S. Government.
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T. Kleefstra and D. Wieczorek contributed equally.
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Supplementary figure S1: Cranial MRI scan of patient 8 indicating (A) dysgenesis of the corpus callosum (arrow), hypoplastic brainstem, and (B) enlarged lateral ventricles.(TIFF 520 kb)
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Supplementary Table S1: Detailed clinical data of all patients with CTNNB1 mutations known so far. n.e. not examined, n.r. not recorded, nl normal, PDA persistent ductus arteriosus, SD standard deviations, (l) left, (r) right, (*L published by de Ligt et al, 2012), (*T published by Tucci et al, 2014), (*D published by Dubruc et al, 2014), (** microcephaly of –2.1 SD at age 32 months), (***enlarged lateral ventricles, dysgenesis of the corpus callosum, abnormal gyration of the temporal lobe, absence of the right fornix, hypoplastic brainstem).(PDF 245 kb)
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Kuechler, A., Willemsen, M.H., Albrecht, B. et al. De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum. Hum Genet 134, 97–109 (2015). https://doi.org/10.1007/s00439-014-1498-1
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DOI: https://doi.org/10.1007/s00439-014-1498-1