Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/12654
Title: Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID
Authors: van Bon, B W M;Coe, B P;Bernier, R;Green, C;Gerdts, J;Witherspoon, K;Kleefstra, T;Willemsen, M H;Kumar, R;Bosco, P;Fichera, M;Li, D;Amaral, D;Cristofoli, F;Peeters, H;Haan, E;Romano, C;Mefford, Heather C;Scheffer, Ingrid E;Gecz, Jozef;de Vries, B B A;Eichler, E E
Affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
Department of Psychiatry, University of Washington, Seattle, WA, USA
Florey Institute, University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, Victoria, Australia
I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy
Medical Genetics, University of Catania, Catania, Italy
Representing the Autism Phenome Project, MIND Institute, University of California-Davis, Sacramento, CA, USA
Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
Leuven Autism Research (LAuRes), Leuven, Belgium
South Australian Clinical Genetics Service, SA Pathology, Adelaide, South Australia, Australia
Robinson Institute, University of Adelaide, Adelaide, South Australia, Australia
Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands
Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
Issue Date: Jan-2016
EDate: 2015-02-24
Citation: Molecular Psychiatry 2015; 21(1): 126-132
Abstract: Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1A truncating mutations (P=0.00851) and an excess of de novo mutations (P=2.53 × 10(-10)) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n=5) and recontacted (n=3) cases with previous case reports, including larger CNV and translocation events (n=7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models.
Internal ID Number: 25707398
URI: http://ahro.austin.org.au/austinjspui/handle/1/12654
DOI: 10.1038/mp.2015.5
ORCID: 0000-0002-2311-2174
0000-0002-7884-6861
URL: http://www.ncbi.nlm.nih.gov/pubmed/25707398
Type: Journal Article
Appears in Collections:Journal articles

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