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Title: | Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID | Austin 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, Bert B A;Eichler, E E | Affiliation: | Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA 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 |
Issue Date: | 2016 | Date: | 2015-02-24 | Publication information: | 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. | Gov't Doc #: | 25707398 | URI: | https://ahro.austin.org.au/austinjspui/handle/1/12654 | DOI: | 10.1038/mp.2015.5 | ORCID: | 0000-0002-2311-2174 0000-0002-7884-6861 |
Journal: | Molecular psychiatry | URL: | https://pubmed.ncbi.nlm.nih.gov/25707398 | Type: | Journal Article |
Appears in Collections: | Journal articles |
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