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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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2019
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| In: |
Biological psychiatry
Year: 2018, Volume: 85, Issue: 4, Pages: 287-297 |
| ISSN: | 1873-2402 |
| DOI: | 10.1016/j.biopsych.2018.02.1173 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1016/j.biopsych.2018.02.1173 Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S0006322318313039 
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| Author Notes: | Anke Van Dijck, Anneke T. Vulto-van Silfhout, Elisa Cappuyns, Ilse M. van der Werf, Grazia M. Mancini, Andreas Tzschach, Raphael Bernier, Illana Gozes, Evan E. Eichler, Corrado Romano, Anna Lindstrand, Ann Nordgren, Madhura Bakshi, Meredith Wilson, Yemina Berman, Rebecca Dickson, Erik Fransen, Céline Helsmoortel, Jenneke Van den Ende, Nathalie Van der Aa, Marina J. van de Wijdeven, Jessica Rosenblum, Fabíola Monteiro, Fernando Kok, Nada Quercia, Sarah Bowdin, David Dyment, David Chitayat, Ebba Alkhunaizi, Susanne E. Boonen, Boris Keren, Aurelia Jacquette, Laurence Faivre, Stephane Bezieau, Bertrand Isidor, Angelika Rieß, Ute Moog, Sally Ann Lynch, Terri McVeigh, Orly Elpeleg, Marie Falkenberg Smeland, Madeleine Fannemel, Arie van Haeringen, Saskia M. Maas, H. E. Veenstra-Knol, Meyke Schouten, Marjolein H. Willemsen, Carlo L. Marcelis, Charlotte Ockeloen, Ineke van der Burgt, Ilse Feenstra, Jasper van der Smagt, Aleksandra Jezela-Stanek, Malgorzata Krajewska-Walasek, Domingo González-Lamuño, Britt-Marie Anderlid, Helena Malmgren, Magnus Nordenskjöld, Emma Clement, Jane Hurst, Kay Metcalfe, Sahar Mansour, Katherine Lachlan, Jill Clayton-Smith, Laura G. Hendon, Omar A. Abdulrahman, Eric Morrow, Clare McMillan, Jennifer Gerdts, Joseph Peeden, Samantha A. Schrier Vergano, Caitlin Valentino, Wendy K. Chung, Jillian R. Ozmore, Sandra Bedrosian-Sermone, Anna Dennis, Kayla Treat, Susan Starling Hughes, Nicole Safina, Jean-Baptiste Le Pichon, Marianne McGuire, Elena Infante, Suneeta Madan-Khetarpal, Sonal Desai, Paul Benke, Alyson Krokosky, Ingrid Cristian, Laura Baker, Karen Gripp, Holly A. Stessman, Jacob Eichenberger, Parul Jayakar, Amy Pizzino, Melanie Ann Manning, Leah Slattery, Malin Kvarnung, Tjitske Kleefstra, Bert B. A. de Vries, Sébastien Küry, Jill A. Rosenfeld, Marije E. Meuwissen, Geert Vandeweyer and R. Frank Kooy |
| Summary: | 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. |
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| Item Description: | Available online 15 March 2018 Im Titel ist "ADNP" kursiv geschrieben Gesehen am 15.02.2019 |
| Physical Description: | Online Resource |
| ISSN: | 1873-2402 |
| DOI: | 10.1016/j.biopsych.2018.02.1173 |