Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP

ADNP Consortium

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)287-297
Number of pages11
JournalBiological Psychiatry
Volume85
Issue number4
DOIs
StatePublished - Feb 15 2019

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Mutation
Autistic Disorder
Intellectual Disability
Genetic Association Studies
Parents
Language Development Disorders
Muscle Hypotonia
Congenital Heart Defects
Neurodevelopmental Disorders
Comorbidity
Epilepsy
Sleep
Genome
Brain
Genes
Surveys and Questionnaires

Keywords

  • ADNP
  • Autism
  • Genetics
  • Helsmoortel-Van der Aa syndrome
  • Intellectual disability
  • Neurodevelopmental disorder

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP. / ADNP Consortium.

In: Biological Psychiatry, Vol. 85, No. 4, 15.02.2019, p. 287-297.

Research output: Contribution to journalArticle

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title = "Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP",
abstract = "Background: 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. Methods: 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. Results: 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. Conclusions: 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.",
keywords = "ADNP, Autism, Genetics, Helsmoortel-Van der Aa syndrome, Intellectual disability, Neurodevelopmental disorder",
author = "{ADNP Consortium} and {Van Dijck}, Anke and {Vulto-van Silfhout}, {Anneke T.} and Elisa Cappuyns and {van der Werf}, {Ilse M.} and Mancini, {Grazia M.} and Andreas Tzschach and Raphael Bernier and Illana Gozes and Eichler, {Evan E.} and Corrado Romano and Anna Lindstrand and Ann Nordgren and Madhura Bakshi and Meredith Wilson and Yemina Berman and Rebecca Dickson and Erik Fransen and C{\'e}line Helsmoortel and {Van den Ende}, Jenneke and {Van der Aa}, Nathalie and {van de Wijdeven}, {Marina J.} and Jessica Rosenblum and Fab{\'i}ola Monteiro and Fernando Kok and Nada Quercia and Sarah Bowdin and David Dyment and David Chitayat and Ebba Alkhunaizi and Boonen, {Susanne E.} and Boris Keren and Aurelia Jacquette and Laurence Faivre and Stephane Bezieau and Bertrand Isidor and Angelika Rie{\ss} and Ute Moog and Lynch, {Sally Ann} and Terri McVeigh and Orly Elpeleg and Smeland, {Marie Falkenberg} and Madeleine Fannemel and {van Haeringen}, Arie and Maas, {Saskia M.} and Veenstra-Knol, {H. E.} and Meyke Schouten and Willemsen, {Marjolein H.} and Marcelis, {Carlo L.} and Charlotte Ockeloen and Jacob Eichenberger",
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T1 - Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP

AU - ADNP Consortium

AU - Van Dijck, Anke

AU - Vulto-van Silfhout, Anneke T.

AU - Cappuyns, Elisa

AU - van der Werf, Ilse M.

AU - Mancini, Grazia M.

AU - Tzschach, Andreas

AU - Bernier, Raphael

AU - Gozes, Illana

AU - Eichler, Evan E.

AU - Romano, Corrado

AU - Lindstrand, Anna

AU - Nordgren, Ann

AU - Bakshi, Madhura

AU - Wilson, Meredith

AU - Berman, Yemina

AU - Dickson, Rebecca

AU - Fransen, Erik

AU - Helsmoortel, Céline

AU - Van den Ende, Jenneke

AU - Van der Aa, Nathalie

AU - van de Wijdeven, Marina J.

AU - Rosenblum, Jessica

AU - Monteiro, Fabíola

AU - Kok, Fernando

AU - Quercia, Nada

AU - Bowdin, Sarah

AU - Dyment, David

AU - Chitayat, David

AU - Alkhunaizi, Ebba

AU - Boonen, Susanne E.

AU - Keren, Boris

AU - Jacquette, Aurelia

AU - Faivre, Laurence

AU - Bezieau, Stephane

AU - Isidor, Bertrand

AU - Rieß, Angelika

AU - Moog, Ute

AU - Lynch, Sally Ann

AU - McVeigh, Terri

AU - Elpeleg, Orly

AU - Smeland, Marie Falkenberg

AU - Fannemel, Madeleine

AU - van Haeringen, Arie

AU - Maas, Saskia M.

AU - Veenstra-Knol, H. E.

AU - Schouten, Meyke

AU - Willemsen, Marjolein H.

AU - Marcelis, Carlo L.

AU - Ockeloen, Charlotte

AU - Eichenberger, Jacob

PY - 2019/2/15

Y1 - 2019/2/15

N2 - Background: 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. Methods: 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. Results: 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. Conclusions: 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.

AB - Background: 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. Methods: 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. Results: 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. Conclusions: 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.

KW - ADNP

KW - Autism

KW - Genetics

KW - Helsmoortel-Van der Aa syndrome

KW - Intellectual disability

KW - Neurodevelopmental disorder

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JO - Biological Psychiatry

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