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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.

 Fuente: Biological Psychiatry Volume 85, Issue 4, 15 February 2019, Pages 287-297

Editorial: Elsevier

 Fecha de publicación: 01/02/2019

Nº de páginas: 10

Tipo de publicación: Artículo de Revista

DOI: 10.1016/j.biopsych.2018.02.1173

ISSN: 0006-3223,1873-2402

Url de la publicación: https://doi.org/10.1016/j.biopsych.2018.02.1173

Autores/as

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