Send to

Choose Destination
Biol Psychiatry. 2019 Feb 15;85(4):287-297. doi: 10.1016/j.biopsych.2018.02.1173. Epub 2018 Mar 15.

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

Author information

Department of Medical Genetics, University of Antwerp, Antwerp, Belgium; Department of Neurology, University Hospital Antwerp, Antwerp, Belgium. Electronic address:
Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
Institute für Klinische Genetik, Technische Universität Dresden, Dresden, Germany.
Department of Psychiatry, University of Washington, Seattle, Washington.
Elton Laboratory for Molecular Neuroendocrinology, Tel Aviv University, Tel Aviv, Israel; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel; Adams Super Center for Brain Studies, Tel Aviv University, Tel Aviv, Israel.
Department of Genome Sciences, University of Washington, Seattle, Washington; Howard Hughes Medical Institute, University of Washington, Seattle, Washington.
Unit of Pediatrics and Medical Genetics, Istituto di Ricovero e Cura a Carattere Scientifico Associazione Oasi Maria Santissima, Troina, Italy.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes, France.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.



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.


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

[Available on 2019-08-15]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center