Journal article
Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP
Biological psychiatry (1969), Vol.85(4), pp.287-297
02/15/2019
DOI: 10.1016/j.biopsych.2018.02.1173
PMCID: PMC6139063
PMID: 29724491
Abstract
In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking.
We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires.
We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected.
This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.
Details
- Title: Subtitle
- Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP
- Creators
- Anke Van Dijck - University of AntwerpAnneke T. Vulto-van Silfhout - Department of Human Genetics, Radboud University Medical Center, Nijmegen, the NetherlandsElisa Cappuyns - University of AntwerpIlse M. van der Werf - University of AntwerpGrazia M. Mancini - Erasmus MCAndreas Tzschach - Technische Universität DresdenRaphael Bernier - University of WashingtonIllana Gozes - Tel Aviv UniversityEvan E. Eichler - University of WashingtonCorrado Romano - Oasi Maria SSAnna Lindstrand - Karolinska InstitutetAnn Nordgren - Karolinska InstitutetMadhura BakshiMeredith WilsonYemina BermanRebecca DicksonErik FransenCéline HelsmoortelJenneke Van den EndeNathalie Van der AaMarina J. van de WijdevenJessica RosenblumFabíola MonteiroFernando KokNada QuerciaSarah BowdinDavid DymentDavid ChitayatEbba AlkhunaiziSusanne E. BoonenBoris KerenAurelia JacquetteLaurence FaivreStephane BezieauBertrand IsidorAngelika RießUte MoogSally Ann LynchTerri McVeighOrly ElpelegMarie Falkenberg SmelandMadeleine FannemelArie van HaeringenSaskia M. MaasH.E. Veenstra-KnolMeyke SchoutenMarjolein H. WillemsenCarlo L. MarcelisCharlotte OckeloenIneke van der BurgtIlse FeenstraJasper van der SmagtAleksandra Jezela-StanekMalgorzata Krajewska-WalasekDomingo González-LamuñoBritt-Marie AnderlidHelena MalmgrenMagnus NordenskjöldEmma ClementJane HurstKay MetcalfeSahar MansourKatherine LachlanJill Clayton-SmithLaura G. HendonOmar A. AbdulrahmanEric MorrowClare McMillanJennifer GerdtsJoseph PeedenSamantha A. Schrier VerganoCaitlin ValentinoWendy K. ChungJillian R. OzmoreSandra Bedrosian-SermoneAnna DennisKayla TreatSusan Starling HughesNicole SafinaJean-Baptiste Le PichonMarianne McGuireElena InfanteSuneeta Madan-KhetarpalSonal DesaiPaul BenkeAlyson KrokoskyIngrid CristianLaura BakerKaren GrippHolly A. StessmanJacob EichenbergerParul JayakarAmy PizzinoMelanie Ann ManningLeah SlatteryMalin Kvarnung - Karolinska InstitutetTjitske Kleefstra - Radboud University NijmegenBert B.A. de Vries - Radboud University NijmegenSébastien Küry - Centre Hospitalier Universitaire de NantesJill A. Rosenfeld - Baylor College of MedicineMarije E. Meuwissen - University of AntwerpGeert Vandeweyer - University of AntwerpR. Frank Kooy - University of AntwerpADNP Consortium
- Resource Type
- Journal article
- Publication Details
- Biological psychiatry (1969), Vol.85(4), pp.287-297
- DOI
- 10.1016/j.biopsych.2018.02.1173
- PMID
- 29724491
- PMCID
- PMC6139063
- NLM abbreviation
- Biol Psychiatry
- ISSN
- 0006-3223
- eISSN
- 1873-2402
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100014370, name: Simons Foundation Autism Research Initiative, award: SFARI 303241; DOI: 10.13039/100000002, name: National Institutes of Health, award: R01MH101221; name: Health Innovation Challenge, award: HICF-1009–003; name: Wellcome Trust Sanger Institute, award: WT098051; name: UK Research Ethics Committee, award: 10/H0305/83; name: Republic of Ireland Research Ethics Committee, award: GEN/284/12
- Language
- English
- Date published
- 02/15/2019
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984354147402771
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