title: Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID.
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.
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: B W M
authors.initials: BW
authors.lastname: van Bon
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: B P
authors.initials: BP
authors.lastname: Coe
authors.affiliation: Department of Psychiatry, University of Washington, Seattle, WA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Bernier
authors.affiliation: Florey Institute, University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Green
authors.affiliation: Department of Psychiatry, University of Washington, Seattle, WA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gerdts
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Witherspoon
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Kleefstra
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: M H
authors.initials: MH
authors.lastname: Willemsen
authors.affiliation: School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Kumar
authors.affiliation: I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Bosco
authors.affiliation: I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy.|Medical Genetics, University of Catania, Catania, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Fichera
authors.affiliation: Representing the Autism Phenome Project, MIND Institute, University of California-Davis, Sacramento, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Li
authors.affiliation: Representing the Autism Phenome Project, MIND Institute, University of California-Davis, Sacramento, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Amaral
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Cristofoli
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.|Leuven Autism Research (LAuRes), Leuven, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Peeters
authors.affiliation: School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.|South Australian Clinical Genetics Service, SA Pathology, Adelaide, South Australia, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Haan
authors.affiliation: I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Romano
authors.affiliation: Department of Psychiatry, University of Washington, Seattle, WA, USA.
authors.forename: H C
authors.initials: HC
authors.lastname: Mefford
authors.affiliation: Florey Institute, University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: I
authors.initials: I
authors.lastname: Scheffer
authors.affiliation: School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.|South Australian Clinical Genetics Service, SA Pathology, Adelaide, South Australia, Australia.|Robinson Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: J
authors.identifier: http://orcid.org/0000-0002-7884-6861
authors.initials: J
authors.lastname: Gecz
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands.
authors.forename: B B A
authors.initials: BB
authors.lastname: de Vries
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.|Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
authors.forename: E E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D003294:Seizures, Febrile / Q000235:genetics; D035781:Siblings; D013064:Speech Disorders / Q000235:genetics; D019956:Stereotypic Movement Disorder / Q000235:genetics; D013577:Syndrome; D055815:Young Adult; D000097603:Dyrk Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases