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 activities1, 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 established2,3,4,5,6,7. 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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Acknowledgements

This work was funded by the Belgian National Fund for Scientific Research-Flanders (FWO) to G.V. and R.F.K., the Special Research Fund of the University of Antwerp (Bijzonder Onderzoeksfonds (BOF-IWT)) to C.H., by grants from the Dutch Organization for Health Research and Development (917-86-319 and 40-00812-98-12109 to B.B.A.d.V. and 907-00-365 to T.K.), the EU-funded GENCODYS project (EU-7th-2010-241995 to A.T.V.-v.S., B.B.A.d.V. and T.K.), Simons Foundation Autism Research Initiative award (SFARI191889EE to E.E.E.) and NIH (MH101221 to E.E.E.). We acknowledge R. Pettinato and M. Elia for the first enrolling of patients 8 and 9, respectively, and J. Shendure and B. O'Roak for details regarding ADNP molecular inversion probe design. E.E.E. is an investigator of the Howard Hughes Medical Institute.

Author information

Author notes

    • Anneke T Vulto-van Silfhout
    •  & Bradley P Coe

    These authors contributed equally to this work.

Affiliations

  1. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.

    • Céline Helsmoortel
    • , Geert Vandeweyer
    • , Liesbeth Rooms
    • , R Frank Kooy
    •  & Nathalie Van der Aa
  2. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Institute for Genetic and Metabolic Disease, Radboud University Medical Center, Nijmegen, The Netherlands.

    • Anneke T Vulto-van Silfhout
    • , Janneke H M Schuurs-Hoeijmakers
    • , Carlo L Marcelis
    • , Marjolein H Willemsen
    • , Lisenka E L M Vissers
    • , Helger G Yntema
    • , Bert B A de Vries
    •  & Tjitske Kleefstra
  3. Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.

    • Bradley P Coe
    • , Kali T Witherspoon
    •  & Evan E Eichler
  4. Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA.

    • Bradley P Coe
    • , Kali T Witherspoon
    •  & Evan E Eichler
  5. Biomedical informatics research center Antwerpen (Biomina), Department of Mathematics and Computer Science, University of Antwerp, Edegem, Belgium.

    • Geert Vandeweyer
  6. University Hospital Antwerp, Antwerp, Belgium.

    • Jenneke van den Ende
    •  & Nathalie Van der Aa
  7. Department of Genetic Medicine, Westmead Hospital, Sydney, Australia.

    • Madhura Bakshi
  8. Department of Clinical Genetics, Children's Hospital at Westmead, Westmead, Australia.

    • Meredith Wilson
  9. Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

    • Helena Malmgren
    •  & Ann Nordgren
  10. Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.

    • Göran Annerén
  11. Unit of Neurology, I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy.

    • Marco Fichera
  12. Medical Genetics, University of Catania, Catania, Italy.

    • Marco Fichera
  13. Laboratory of Cytogenetics, I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy.

    • Paolo Bosco
  14. Unit of Pediatrics and Medical Genetics, I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy.

    • Corrado Romano
  15. Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.

    • Bert B A de Vries
    •  & Tjitske Kleefstra

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Contributions

The study was designed and the results were interpreted by A.T.V.-v.S., B.B.A.d.V., T.K., B.P.C., E.E.E., C.H., G.V., N.V.d.A. and R.F.K. Subject ascertainment and recruitment were carried out by A.T.V.-v.S., J.H.M.S.-H., C.L.M., M.H.W., B.B.A.d.V., T.K., C.R., J.v.d.E., N.V.d.A., A.N., G.A., M.B. and M.W. Sequencing, validation and genotyping were carried out and interpreted by C.H., L.R., G.V., H.M., K.T.W., P.B., B.P.C., L.E.L.M.V., M.F., K.T.W. and H.G.Y. The manuscript was drafted by C.H., G.V., N.V.d.A. and R.F.K. All authors contributed to the final version of the paper.

Competing interests

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

Corresponding authors

Correspondence to R Frank Kooy or Nathalie Van der Aa.

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https://doi.org/10.1038/ng.2899

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