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

• DOI: 10.1038/mp.2015.5
• Publication Date: 2015-02-24T08:56:58Z
• Authors: 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; E E Eichler
• Keywords: Adult; Male; 0301 basic medicine; Adolescent; Stereotypic Movement Disorder; Protein Serine-Threonine Kinases; Seizures, Febrile; Speech Disorders; Febrile; Cohort Studies; Young Adult; 03 medical and health sciences; Seizures; Intellectual Disability; 616; Humans; Autistic Disorder; Preschool; Child; Fetal Growth Retardation; Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical Neuroscience; Siblings; Radboudumc 9: Rare cancers RIHS: Radboud Institute for Health Sciences; Syndrome; Middle Aged; Protein-Tyrosine Kinases; Phenotype; Child, Preschool; Mutation; Microcephaly; Female

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.