A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP

Céline Helsmoortel; Anneke T Vulto-van Silfhout; Bradley P Coe; Geert Vandeweyer; Liesbeth Rooms; Jenneke van den Ende; Janneke H M Schuurs-Hoeijmakers; Carlo L Marcelis; Marjolein H Willemsen; Lisenka E L M Vissers; Helger G Yntema; Madhura Bakshi; Meredith Wilson; Kali T Witherspoon; Helena Malmgren; Ann Nordgren; Göran Annerén; Marco Fichera; Paolo Bosco; Corrado Romano; Bert B A de Vries; Tjitske Kleefstra; R Frank Kooy; Evan E Eichler; Nathalie Van der Aa

doi:10.1038/ng.2899

A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP

Nat Genet. 2014 Apr;46(4):380-4. doi: 10.1038/ng.2899. Epub 2014 Feb 16.

Authors

Céline Helsmoortel¹, Anneke T Vulto-van Silfhout², Bradley P Coe³, Geert Vandeweyer⁴, Liesbeth Rooms¹, Jenneke van den Ende⁵, Janneke H M Schuurs-Hoeijmakers⁶, Carlo L Marcelis⁶, Marjolein H Willemsen⁶, Lisenka E L M Vissers⁶, Helger G Yntema⁶, Madhura Bakshi⁷, Meredith Wilson⁸, Kali T Witherspoon⁹, Helena Malmgren¹⁰, Ann Nordgren¹⁰, Göran Annerén¹¹, Marco Fichera¹², Paolo Bosco¹³, Corrado Romano¹⁴, Bert B A de Vries¹⁵, Tjitske Kleefstra¹⁵, R Frank Kooy¹, Evan E Eichler⁹, Nathalie Van der Aa¹⁶

Affiliations

¹ Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
² 1] Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Institute for Genetic and Metabolic Disease, Radboud University Medical Center, Nijmegen, The Netherlands. [2].
³ 1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA. [2] Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA. [3].
⁴ 1] Department of Medical Genetics, University of Antwerp, Antwerp, Belgium. [2] Biomedical informatics research center Antwerpen (Biomina), Department of Mathematics and Computer Science, University of Antwerp, Edegem, Belgium.
⁵ University Hospital Antwerp, Antwerp, Belgium.
⁶ Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Institute for Genetic and Metabolic Disease, Radboud University Medical Center, Nijmegen, The Netherlands.
⁷ Department of Genetic Medicine, Westmead Hospital, Sydney, Australia.
⁸ Department of Clinical Genetics, Children's Hospital at Westmead, Westmead, Australia.
⁹ 1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA. [2] Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA.
¹⁰ Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
¹¹ Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
¹² 1] Unit of Neurology, I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy. [2] Medical Genetics, University of Catania, Catania, Italy.
¹³ Laboratory of Cytogenetics, I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy.
¹⁴ Unit of Pediatrics and Medical Genetics, I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy.
¹⁵ 1] Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Institute for Genetic and Metabolic Disease, Radboud University Medical Center, Nijmegen, The Netherlands. [2] Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁶ 1] Department of Medical Genetics, University of Antwerp, Antwerp, Belgium. [2] University Hospital Antwerp, Antwerp, Belgium.

PMID: 24531329
PMCID: PMC3990853
DOI: 10.1038/ng.2899

Abstract

Despite the high heritability of autism spectrum disorders (ASD), characterized by persistent deficits in social communication and interaction and restricted, repetitive patterns of behavior, interests or activities, a genetic diagnosis can be established in only a minority of patients. Known genetic causes include chromosomal aberrations, such as the duplication of the 15q11-13 region, and monogenic causes, as in Rett and fragile-X syndromes. The genetic heterogeneity within ASD is striking, with even the most frequent causes responsible for only 1% of cases at the most. Even with the recent developments in next-generation sequencing, for the large majority of cases no molecular diagnosis can be established. Here, we report ten patients with ASD and other shared clinical characteristics, including intellectual disability and facial dysmorphisms caused by a mutation in ADNP, a transcription factor involved in the SWI/SNF remodeling complex. We estimate this gene to be mutated in at least 0.17% of ASD cases, making it one of the most frequent ASD-associated genes known to date.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Abnormalities, Multiple / genetics*
Base Sequence
Child Development Disorders, Pervasive / genetics*
Chromosomal Proteins, Non-Histone / genetics*
Codon, Nonsense / genetics
Exome / genetics
Frameshift Mutation / genetics
Gene Components
Homeodomain Proteins / genetics*
Humans
Molecular Sequence Data
Nerve Tissue Proteins / genetics*
Real-Time Polymerase Chain Reaction
Sequence Analysis, DNA
Transcription Factors / genetics*

Substances

ADNP protein, human
Chromosomal Proteins, Non-Histone
Codon, Nonsense
Homeodomain Proteins
Nerve Tissue Proteins
SWI-SNF-B chromatin-remodeling complex
Transcription Factors

Grants and funding

R01 MH101221/MH/NIMH NIH HHS/United States