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  • Original Article
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Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID

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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References

  1. Lai MC, Lombardo MV, Baron-Cohen S . Autism. Lancet 2014; 383: 896–910.

    Article  Google Scholar 

  2. Rosti RO, Sadek AA, Vaux KK, Gleeson JG . The genetic landscape of autism spectrum disorders. Dev Med Child Neurol 2014; 56: 12–18.

    Article  Google Scholar 

  3. Bernier R, Golzio C, Xiong B, Stessman HA, Coe BP, Penn O et al. Disruptive CHD8 mutations define a subtype of autism early in development. Cell 2014; 158: 263–276.

    Article  CAS  Google Scholar 

  4. Helsmoortel C, Vulto-van Silfhout AT, Coe BP, Vandeweyer G, Rooms L, van den Ende J et al. A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP. Nat Genet 2014; 46: 380–384.

    Article  CAS  Google Scholar 

  5. O'Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, Girirajan S et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet 2011; 43: 585–589.

    Article  CAS  Google Scholar 

  6. Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 2012; 485: 237–241.

    Article  CAS  Google Scholar 

  7. O'Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 2012; 338: 1619–1622.

    Article  CAS  Google Scholar 

  8. Brett M, McPherson J, Zang ZJ, Lai A, Tan ES, Ng I et al. Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel. PLoS One 2014; 9: e93409.

    Article  Google Scholar 

  9. Park J, Chung KC . New perspectives of Dyrk1A role in neurogenesis and neuropathologic features of Down syndrome. Exp Neurobiol 2013; 22: 244–248.

    Article  Google Scholar 

  10. Guimera J, Casas C, Pucharcos C, Solans A, Domenech A, Planas AM et al. A human homologue of Drosophila minibrain (MNB) is expressed in the neuronal regions affected in Down syndrome and maps to the critical region. Hum Mol Genet 1996; 5: 1305–1310.

    Article  CAS  Google Scholar 

  11. Moller RS, Kubart S, Hoeltzenbein M, Heye B, Vogel I, Hansen CP et al. Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly. Am J Hum Genet 2008; 82: 1165–1170.

    Article  Google Scholar 

  12. van Bon BW, Hoischen A, Hehir-Kwa J, de Brouwer AP, Ruivenkamp C, Gijsbers AC et al. Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly. Clin Genet 2011; 79: 296–299.

    Article  CAS  Google Scholar 

  13. Courcet JB, Faivre L, Malzac P, Masurel-Paulet A, Lopez E, Callier P et al. The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy. J Med Genet 2012; 49: 731–736.

    Article  CAS  Google Scholar 

  14. Redin C, Gerard B, Lauer J, Herenger Y, Muller J, Quartier A et al. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. J Med Genet 2014; 51: 724–736.

    Article  CAS  Google Scholar 

  15. Okamoto N, Miya F, Tsunoda T, Kato M, Saitoh S, Yamasaki M et al. Targeted next-generation sequencing in the diagnosis of neurodevelopmental disorders. Clin Genet, e-pub ahead of print 25 August 2014.doi:10.1111/cge.12492.

  16. Soundararajan M, Roos AK, Savitsky P, Filippakopoulos P, Kettenbach AN, Olsen JV et al. Structures of Down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition. Structure 2013; 21: 986–996.

    Article  CAS  Google Scholar 

  17. Parada GE, Munita R, Cerda CA, Gysling K . A comprehensive survey of non-canonical splice sites in the human transcriptome. Nucleic Acids Res 2014; 42: 10564–10578.

    Article  CAS  Google Scholar 

  18. Kervestin S, Jacobson A . NMD: a multifaceted response to premature translational termination. Nat Rev Mol Cell Biol 2012; 13: 700–712.

    Article  CAS  Google Scholar 

  19. Fotaki V, Dierssen M, Alcantara S, Martinez S, Marti E, Casas C et al. Dyrk1A haploinsufficiency affects viability and causes developmental delay and abnormal brain morphology in mice. Mol Cell Biol 2002; 22: 6636–6647.

    Article  CAS  Google Scholar 

  20. Dierssen M, de Lagran MM . DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A): a gene with dosage effect during development and neurogenesis. ScientificWorldJournal 2006; 6: 1911–1922.

    Article  CAS  Google Scholar 

  21. Arque G, de Lagran MM, Arbones ML, Dierssen M . Age-associated motor and visuo-spatial learning phenotype in Dyrk1A heterozygous mutant mice. Neurobiol Dis 2009; 36: 312–319.

    Article  CAS  Google Scholar 

  22. Marti E, Altafaj X, Dierssen M, de la LS, Fotaki V, Alvarez M et al. Dyrk1A expression pattern supports specific roles of this kinase in the adult central nervous system. Brain Res 2003; 964: 250–263.

    Article  CAS  Google Scholar 

  23. Arque G, Casanovas A, Dierssen M . Dyrk1A is dynamically expressed on subsets of motor neurons and in the neuromuscular junction: possible role in Down syndrome. PLoS One 2013; 8: e54285.

    Article  CAS  Google Scholar 

  24. Laguna A, Aranda S, Barallobre MJ, Barhoum R, Fernandez E, Fotaki V et al. The protein kinase DYRK1A regulates caspase-9-mediated apoptosis during retina development. Dev Cell 2008; 15: 841–853.

    Article  CAS  Google Scholar 

  25. Luebbering N, Charlton-Perkins M, Kumar JP, Lochead PA, Rollmann SM, Cook T et al. Drosophila Dyrk2 plays a role in the development of the visual system. PLoS One 2013; 8: e76775.

    Article  CAS  Google Scholar 

  26. Laguna A, Barallobre MJ, Marchena MA, Mateus C, Ramirez E, Martinez-Cue C et al. Triplication of DYRK1A causes retinal structural and functional alterations in Down syndrome. Hum Mol Genet 2013; 22: 2775–2784.

    Article  CAS  Google Scholar 

  27. Kurabayashi N, Hirota T, Sakai M, Sanada K, Fukada Y . DYRK1A and glycogen synthase kinase 3beta, a dual-kinase mechanism directing proteasomal degradation of CRY2 for circadian timekeeping. Mol Cell Biol 2010; 30: 1757–1768.

    Article  CAS  Google Scholar 

  28. Kinstrie R, Lochhead PA, Sibbet G, Morrice N, Cleghon V . dDYRK2 and Minibrain interact with the chromatin remodelling factors SNR1 and TRX. Biochem J 2006; 398: 45–54.

    Article  CAS  Google Scholar 

  29. Parrish JZ, Kim MD, Jan LY, Jan YN . Genome-wide analyses identify transcription factors required for proper morphogenesis of Drosophila sensory neuron dendrites. Genes Dev 2006; 20: 820–835.

    Article  CAS  Google Scholar 

  30. Lepagnol-Bestel AM, Zvara A, Maussion G, Quignon F, Ngimbous B, Ramoz N et al. DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin remodelling complex to deregulate gene clusters involved in the neuronal phenotypic traits of Down syndrome. Hum Mol Genet 2009; 18: 1405–1414.

    Article  CAS  Google Scholar 

  31. Hoyer J, Ekici AB, Endele S, Popp B, Zweier C, Wiesener A et al. Haploinsufficiency of ARID1B, a member of the SWI/SNF-a chromatin-remodeling complex, is a frequent cause of intellectual disability. Am J Hum Genet 2012; 90: 565–572.

    Article  CAS  Google Scholar 

  32. Kosho T, Okamoto N, Ohashi H, Tsurusaki Y, Imai Y, Hibi-Ko Y et al. Clinical correlations of mutations affecting six components of the SWI/SNF complex: detailed description of 21 patients and a review of the literature. Am J Med Genet A 2013; 161A: 1221–1237.

    Article  Google Scholar 

  33. Santen GW, Aten E, Vulto-van Silfhout AT, Pottinger C, van Bon BW, van Minderhout IJ et al. Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients. Hum Mutat 2013; 34: 1519–1528.

    Article  CAS  Google Scholar 

  34. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Ercument Cicek A et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 2014; 515: 209–215.

    Article  CAS  Google Scholar 

  35. Iossifov I, O'Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 2014; 515: 216–221.

    Article  CAS  Google Scholar 

  36. Carvill GL, Heavin SB, Yendle SC, McMahon JM, O'Roak BJ, Cook J et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet 2013; 45: 825–830.

    Article  CAS  Google Scholar 

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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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Correspondence to E E Eichler.

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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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