Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID Academic Article uri icon

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.

authors

  • van Bon, BWM
  • Coe, BP
  • Bernier, R
  • Green, Cherie C
  • Gerdts, J
  • Witherspoon, K
  • Kleefstra, T
  • Willemsen, MH
  • Kumar, R
  • Bosco, P
  • Fichera, M
  • Li, D
  • Amaral, D
  • Cristofoli, F
  • Peeters, H
  • Haan, E
  • Romano, C
  • Mefford, HC
  • Scheffer, I
  • Gecz, J
  • de Vries, BBA
  • Eichler, EE

publication date

  • 2016

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