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

B. W.M. Van Bon, B. P. Coe, R. Bernier, C. Green, J. Gerdts, K. Witherspoon, T. Kleefstra, M. H. Willemsen, R. Kumar, P. Bosco, M. Fichera, D. Li, D. Amaral, F. Cristofoli, H. Peeters, E. Haan, C. Romano, H. C. Mefford, I. Scheffer, J. GeczB. B.A. De Vries, E. E. Eichler

Research output: Contribution to journalArticle

67 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)126-132
Number of pages7
JournalMolecular Psychiatry
Volume21
Issue number1
DOIs
Publication statusPublished - 1 Jan 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this