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.
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Acknowledgements
We thank the patients and their parents for participation. We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A Beaudet, R Bernier, J Constantino, E Cook, E Fombonne, D Geschwind, R Goin-Kochel, E Hanson, D Grice, A Klin, D Ledbetter, C Lord, C Martin, D Martin, R Maxim, J Miles, O Ousley, K Pelphrey, B Peterson, J Piggot, C Saulnier, M State, W Stone, J Sutcliffe, C Walsh, Z Warren, E Wijsman). We appreciate obtaining access to phenotypic data on the Simons Foundation Autism Research Initiative (SFARI) Base. Approved researchers can obtain the SSC population dataset described in this study (https://ordering.base.sfari.org/~browse_collection/archive[ssc_v13]/ui:view) by applying at https://base.sfari.org. This study was financially supported by (1) the Ter Meulen Fonds (stipendium to BvB), (2) the Dutch Organisation for Health Research and Development: ZON-MW grants 917-86-319 (BBAdV) and 912-12-109 (BBAdV), and (3) the Simons Foundation Autism Research Initiative (SFARI 303241) and National Institutes of Health (NIH) grant R01MH101221 to EEE. EEE is an Investigator of the Howard Hughes Medical Institute. FC is a PhD aspirant of the Research Foundation Flanders (FWO).
Web resources
The URLs for data presented herein are as follows (accessed September 2014): Database of Genomic Variants, http://projects.tcag.ca/variation/; Exome Variant Server, NHLBI Exome Sequencing Project (ESP), Seattle WA: http://evs.gs.washington.edu/EVS/); The Genotype-Tissue Expression project portal http://www.gtexportal.org/home/; Human protein reference database: http://www.hprd.org; Online Mendelian Inheritance in Man (OMIM), http://www.omim.org; UCSC genome browser: http://genome.ucsc.edu/; Universal Protein Resource: http://www.uniprot.org.
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EEE is on the scientific advisory board (SAB) of DNAnexus. The remaining authors declare no conflict of interest.
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van Bon, B., Coe, B., Bernier, R. et al. Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID. Mol Psychiatry 21, 126–132 (2016). https://doi.org/10.1038/mp.2015.5
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DOI: https://doi.org/10.1038/mp.2015.5
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