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

doi:10.1038/ng.2899

. 2014 Apr;46(4):380-4.

doi: 10.1038/ng.2899. Epub 2014 Feb 16.

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

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

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

Céline Helsmoortel et al. Nat Genet. 2014 Apr.

. 2014 Apr;46(4):380-4.

doi: 10.1038/ng.2899. Epub 2014 Feb 16.

Authors

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.

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Conflict of interest statement

Competing financial interests

EEE is on the scientific advisory boards for Pacific Biosciences, Inc., SynapDx Corp., and DNAnexus, Inc.

Figures

**Figure 1**
Frontal facial photographs of patient 1 (a),2 (b), 4 (c), 5 (d), 6 (e) and 8 (f) at young age. Note the clinical similarities, including a prominent forehead, a thin upper lip and a broad nasal bridge. Consent for the publication of photographs was obtained for these patients (1, 2, 4, 5, 6 and 8).

**Figure 2**
Schematic overview of the *ADNP* gene structure and functional domains. Identified mutations and corresponding patients are indicated by black arrows.

See this image and copyright information in PMC

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References

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1. O’Roak BJ, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012;485:246–50. - PMC - PubMed
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[1] Network, A.a.D.D.M. Prevalence of autism spectrum disorders--Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. Morbidity and mortality weekly report. Surveillance summaries. 2012;61:1–19. - PubMed

[2] Network, A.a.D.D.M. Prevalence of autism spectrum disorders--Autism and Developmental Disabilities Monitoring Network, 14 sites, United States, 2008. Morbidity and mortality weekly report. Surveillance summaries. 2012;61:1–19. - PubMed

[3] O’Roak BJ, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012;485:246–50. - PMC - PubMed

[4] O’Roak BJ, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012;485:246–50. - PMC - PubMed

[5] Neale BM, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012;485:242–5. - PMC - PubMed

[6] Neale BM, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012;485:242–5. - PMC - PubMed

[7] Yu TW, et al. Using whole-exome sequencing to identify inherited causes of autism. Neuron. 2013;77:259–73. - PMC - PubMed

[8] Yu TW, et al. Using whole-exome sequencing to identify inherited causes of autism. Neuron. 2013;77:259–73. - PMC - PubMed

[9] Sanders SJ, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012;485:237–41. - PMC - PubMed

[10] Sanders SJ, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012;485:237–41. - PMC - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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