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

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 disa...

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Autores: Van Dijck, Anke, Vulto-van Silfhout, Anneke T., Cappuyns, Elisa, van der Werf, Ilse M., Mancini, Grazia M., Tzschach, Andreas, Bernier, Raphael, Gozes, Illana, Eichler, Evan E., Romano, Corrado, Lindstrand, Anna, Nordgren, Ann, ADNP Consortium, González-Lamuño Leguina, Domingo|||0000-0002-7578-241X
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Universidad de Cantabria (UC)
Repositorio:UCrea Repositorio Abierto de la Universidad de Cantabria
Idioma:inglés
OAI Identifier:oai:repositorio.unican.es:10902/16322
Acceso en línea:http://hdl.handle.net/10902/16322
Access Level:acceso abierto
Palabra clave:ADNP
Autism
Genetics
Helsmoortel-Van der Aa Síndrome
Intellectual Disability
Neurodevelopmental Disorder
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network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP
title Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP
spellingShingle Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP
Van Dijck, Anke
ADNP
Autism
Genetics
Helsmoortel-Van der Aa Síndrome
Intellectual Disability
Neurodevelopmental Disorder
title_short Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP
title_full Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP
title_fullStr Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP
title_full_unstemmed Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP
title_sort Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP
dc.creator.none.fl_str_mv Van Dijck, Anke
Vulto-van Silfhout, Anneke T.
Cappuyns, Elisa
van der Werf, Ilse M.
Mancini, Grazia M.
Tzschach, Andreas
Bernier, Raphael
Gozes, Illana
Eichler, Evan E.
Romano, Corrado
Lindstrand, Anna
Nordgren, Ann
ADNP Consortium
González-Lamuño Leguina, Domingo|||0000-0002-7578-241X
author Van Dijck, Anke
author_facet Van Dijck, Anke
Vulto-van Silfhout, Anneke T.
Cappuyns, Elisa
van der Werf, Ilse M.
Mancini, Grazia M.
Tzschach, Andreas
Bernier, Raphael
Gozes, Illana
Eichler, Evan E.
Romano, Corrado
Lindstrand, Anna
Nordgren, Ann
ADNP Consortium
González-Lamuño Leguina, Domingo|||0000-0002-7578-241X
author_role author
author2 Vulto-van Silfhout, Anneke T.
Cappuyns, Elisa
van der Werf, Ilse M.
Mancini, Grazia M.
Tzschach, Andreas
Bernier, Raphael
Gozes, Illana
Eichler, Evan E.
Romano, Corrado
Lindstrand, Anna
Nordgren, Ann
ADNP Consortium
González-Lamuño Leguina, Domingo|||0000-0002-7578-241X
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidad de Cantabria
dc.subject.none.fl_str_mv ADNP
Autism
Genetics
Helsmoortel-Van der Aa Síndrome
Intellectual Disability
Neurodevelopmental Disorder
topic ADNP
Autism
Genetics
Helsmoortel-Van der Aa Síndrome
Intellectual Disability
Neurodevelopmental Disorder
description 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.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019-02-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10902/16322
url http://hdl.handle.net/10902/16322
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv Biological Psychiatry Volume 85, Issue 4, 15 February 2019, Pages 287-297
reponame:UCrea Repositorio Abierto de la Universidad de Cantabria
instname:Universidad de Cantabria (UC)
instname_str Universidad de Cantabria (UC)
reponame_str UCrea Repositorio Abierto de la Universidad de Cantabria
collection UCrea Repositorio Abierto de la Universidad de Cantabria
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869416498316967936
spelling Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNPVan Dijck, AnkeVulto-van Silfhout, Anneke T.Cappuyns, Elisavan der Werf, Ilse M.Mancini, Grazia M.Tzschach, AndreasBernier, RaphaelGozes, IllanaEichler, Evan E.Romano, CorradoLindstrand, AnnaNordgren, AnnADNP ConsortiumGonzález-Lamuño Leguina, Domingo|||0000-0002-7578-241XADNPAutismGeneticsHelsmoortel-Van der Aa SíndromeIntellectual DisabilityNeurodevelopmental DisorderBackground 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.This work was supported by grants from the European Research Area Networks Network of European Funding for Neuroscience Research through the Research Foundation–Flanders and the Chief Scientist Office–Ministry of Health (to RFK, GV, IG). This research was supported, in part, by grants from the Simons Foundation Autism Research Initiative (Grant No. SFARI 303241 to EEE) and National Institutes of Health (Grant No. R01MH101221 to EEE). This work was also supported by the Italian Ministry of Health and ‘5 per mille’ funding (to CR). For many individuals, sequencing was provided by research initiatives like the Care4Rare Research Consortium in Canada or the Deciphering Developmental Disorders (DDD) study in the UK. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (Grant No. HICF-1009–003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (Grant No. WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South Research Ethics Committee, and GEN/284/12 granted by the Republic of Ireland Research Ethics Committee). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.ElsevierUniversidad de Cantabria20192019-02-01journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articlehttp://hdl.handle.net/10902/16322Biological Psychiatry Volume 85, Issue 4, 15 February 2019, Pages 287-297reponame:UCrea Repositorio Abierto de la Universidad de Cantabriainstname:Universidad de Cantabria (UC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repositorio.unican.es:10902/163222026-06-02T12:39:31Z
score 15,300724

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