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Molecular Psychiatry
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Disruptivede novo mutations ofDYRK1A lead to a syndromic form of autism and ID

Molecular Psychiatryvolume 21, pages126–132 (2016)Cite this article

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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 ofDYRK1A 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 withDYRK1A 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 ofDYRK1A truncating mutations (P=0.00851) and an excess ofde 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 inDYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine andDrosophila 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 athttps://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 portalhttp://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.

Author information

Author notes

  1. B W M van Bon and B P Coe: Shared first authors.

  2. B B A de Vries and E E Eichler: Shared last authors.

Authors and Affiliations

  1. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands

    B W M van Bon, T Kleefstra, M H Willemsen & B B A de Vries

  2. School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia

    B W M van Bon, R Kumar, E Haan & J Gecz

  3. Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA

    B P Coe, K Witherspoon & E E Eichler

  4. Department of Psychiatry, University of Washington, Seattle, WA, USA

    R Bernier, J Gerdts & H C Mefford

  5. Florey Institute, University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, Victoria, Australia

    C Green & I Scheffer

  6. I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy

    P Bosco, M Fichera & C Romano

  7. Medical Genetics, University of Catania, Catania, Italy

    M Fichera

  8. Representing the Autism Phenome Project, MIND Institute, University of California-Davis, Sacramento, CA, USA

    D Li & D Amaral

  9. Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium

    F Cristofoli & H Peeters

  10. Leuven Autism Research (LAuRes), Leuven, Belgium

    H Peeters

  11. South Australian Clinical Genetics Service, SA Pathology, Adelaide, South Australia, Australia

    E Haan & J Gecz

  12. Robinson Institute, University of Adelaide, Adelaide, South Australia, Australia

    J Gecz

  13. Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands

    B B A de Vries

  14. Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA

    E E Eichler

Authors
  1. B W M van Bon

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  2. B P Coe

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  3. R Bernier

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  4. C Green

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  5. J Gerdts

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  6. K Witherspoon

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  7. T Kleefstra

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  8. M H Willemsen

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  9. R Kumar

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  10. P Bosco

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  11. M Fichera

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  12. D Li

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  13. D Amaral

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  14. F Cristofoli

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  15. H Peeters

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  16. E Haan

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  17. C Romano

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  18. H C Mefford

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  19. I Scheffer

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  20. J Gecz

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  21. B B A de Vries

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  22. E E Eichler

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Corresponding author

Correspondence toE E Eichler.

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Competing interests

EEE is on the scientific advisory board (SAB) of DNAnexus. The remaining authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

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van Bon, B., Coe, B., Bernier, R.et al. Disruptivede novo mutations ofDYRK1A lead to a syndromic form of autism and ID.Mol Psychiatry21, 126–132 (2016). https://doi.org/10.1038/mp.2015.5

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