Title: Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID
Authors: van Bon, B W M
Coe, B P
Bernier, R
Green, C
Gerdts, J
Witherspoon, K
Kleefstra, T
Willemsen, M H
Kumar, R
Bosco, P
Fichera, M
Li, D
Amaral, D
Cristofoli, Francesca
Peeters, Hilde
Haan, E
Romano, C
Mefford, H C
Scheffer, I
Gecz, J
de Vries, B B A
Eichler, E E # ×
Issue Date: Jan-2016
Publisher: Stockton Press
Series Title: Molecular Psychiatry vol:21 issue:1 pages:126-32
Article number: 10.1038/mp.2015.5
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.Molecular Psychiatry advance online publication, 24 February 2015; doi:10.1038/mp.2015.5.
ISSN: 1359-4184
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory for Cytogenetics and Genome Research
× corresponding author
# (joint) last author

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