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

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dc.contributor.authorvan Bon, B.W.M.
dc.contributor.authorCoe, B.P.
dc.contributor.authorBernier, R.
dc.contributor.authorGreen, C.
dc.contributor.authorGerdts, J.
dc.contributor.authorWitherspoon, K.
dc.contributor.authorKleefstra, T.
dc.contributor.authorWillemsen, M.H.
dc.contributor.authorKumar, R.
dc.contributor.authorBosco, P.
dc.contributor.authorFichera, M.
dc.contributor.authorLi, D.
dc.contributor.authorAmaral, D.
dc.contributor.authorCristofoli, F.
dc.contributor.authorPeeters, H.
dc.contributor.authorHaan, E.
dc.contributor.authorRomano, C.
dc.contributor.authorMefford, H.C.
dc.contributor.authorScheffer, I.
dc.contributor.authorGecz, J.
dc.contributor.authoret al.
dc.date.issued2016
dc.descriptionMolecular Psychiatry advance online publication 24 February 2015
dc.description.abstractDual-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.
dc.description.statementofresponsibilityB 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
dc.identifier.citationMolecular Psychiatry, 2016; 21(1):126-132
dc.identifier.doi10.1038/mp.2015.5
dc.identifier.issn1359-4184
dc.identifier.issn1476-5578
dc.identifier.orcidKumar, R. [0000-0001-7976-8386]
dc.identifier.orcidHaan, E. [0000-0002-7310-5124]
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]
dc.identifier.urihttp://hdl.handle.net/2440/92018
dc.language.isoen
dc.publisherNature Publishing Group
dc.rights© 2015 Macmillan Publishers Limited
dc.source.urihttps://doi.org/10.1038/mp.2015.5
dc.subjectHumans
dc.subjectMicrocephaly
dc.subjectSeizures, Febrile
dc.subjectSpeech Disorders
dc.subjectFetal Growth Retardation
dc.subjectSyndrome
dc.subjectCohort Studies
dc.subjectSiblings
dc.subjectAutistic Disorder
dc.subjectStereotypic Movement Disorder
dc.subjectPhenotype
dc.subjectMutation
dc.subjectAdolescent
dc.subjectAdult
dc.subjectMiddle Aged
dc.subjectChild
dc.subjectChild, Preschool
dc.subjectFemale
dc.subjectMale
dc.subjectProtein-Tyrosine Kinases
dc.subjectYoung Adult
dc.subjectIntellectual Disability
dc.subjectProtein Serine-Threonine Kinases
dc.subjectDyrk Kinases
dc.titleDisruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID
dc.typeJournal article
pubs.publication-statusPublished

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