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

Mol Psychiatry. 2016 Jan;21(1):126-32. doi: 10.1038/mp.2015.5. Epub 2015 Feb 24.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Autistic Disorder / genetics*
  • Child
  • Child, Preschool
  • Cohort Studies
  • Female
  • Fetal Growth Retardation / genetics
  • Humans
  • Intellectual Disability / genetics*
  • Male
  • Microcephaly / genetics
  • Middle Aged
  • Mutation*
  • Phenotype*
  • Protein Serine-Threonine Kinases / genetics*
  • Protein-Tyrosine Kinases / genetics*
  • Seizures, Febrile / genetics
  • Siblings
  • Speech Disorders / genetics
  • Stereotypic Movement Disorder / genetics
  • Syndrome
  • Young Adult

Substances

  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases