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Type: Journal article
Title: Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID
Author: 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, F.
Peeters, H.
Haan, E.
Romano, C.
Mefford, H.C.
Scheffer, I.
Gecz, J.
et al.
Citation: Molecular Psychiatry, 2016; 21(1):126-132
Publisher: Nature Publishing Group
Issue Date: 2016
ISSN: 1359-4184
Statement of
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 Gecz, B B A de Vries and E E Eichler
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.
Keywords: Humans
Seizures, Febrile
Speech Disorders
Fetal Growth Retardation
Cohort Studies
Autistic Disorder
Stereotypic Movement Disorder
Middle Aged
Child, Preschool
Protein-Tyrosine Kinases
Young Adult
Intellectual Disability
Protein Serine-Threonine Kinases
Description: Molecular Psychiatry advance online publication 24 February 2015
Rights: © 2015 Macmillan Publishers Limited
DOI: 10.1038/mp.2015.5
Published version:
Appears in Collections:Aurora harvest 2
Paediatrics publications

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