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.2015-06-092015-06-092016Molecular Psychiatry, 2016; 21(1):126-1321359-41841476-5578http://hdl.handle.net/2440/92018Molecular Psychiatry advance online publication 24 February 2015Dual-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.en© 2015 Macmillan Publishers LimitedHumansMicrocephalySeizures, FebrileSpeech DisordersFetal Growth RetardationSyndromeCohort StudiesSiblingsAutistic DisorderStereotypic Movement DisorderPhenotypeMutationAdolescentAdultMiddle AgedChildChild, PreschoolFemaleMaleProtein-Tyrosine KinasesYoung AdultIntellectual DisabilityProtein Serine-Threonine KinasesDyrk KinasesJournal article003002318010.1038/mp.2015.50003670969000162-s2.0-849519080302-s2.0-84923357246173883Kumar, R. [0000-0001-7976-8386]Haan, E. [0000-0002-7310-5124]Gecz, J. [0000-0002-7884-6861]