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|Title:||Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID|
|Author:||van Bon, B.|
|Citation:||Molecular Psychiatry, 2016; 21(1):126-132|
|Publisher:||Nature Publishing Group|
|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; Microcephaly; Seizures, Febrile; Speech Disorders; Fetal Growth Retardation; Syndrome; Protein-Serine-Threonine Kinases; Cohort Studies; Siblings; Autistic Disorder; Stereotypic Movement Disorder; Phenotype; Mutation; Adolescent; Adult; Middle Aged; Child; Child, Preschool; Female; Male; Protein-Tyrosine Kinases; Young Adult; Intellectual Disability|
|Description:||Molecular Psychiatry advance online publication 24 February 2015|
|Rights:||© 2015 Macmillan Publishers Limited|
|Appears in Collections:||Paediatrics publications|
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