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A framework for an evidence-based gene list relevant to autism spectrum disorder

Nature Reviews Genetics volume 21, pages 367–376 (2020)Cite this article

Abstract

Autism spectrum disorder (ASD) is often grouped with other brain-related phenotypes into a broader category of neurodevelopmental disorders (NDDs). In clinical practice, providers need to decide which genes to test in individuals with ASD phenotypes, which requires an understanding of the level of evidence for individual NDD genes that supports an association with ASD. Consensus is currently lacking about which NDD genes have sufficient evidence to support a relationship to ASD. Estimates of the number of genes relevant to ASD differ greatly among research groups and clinical sequencing panels, varying from a few to several hundred. This Roadmap discusses important considerations necessary to provide an evidence-based framework for the curation of NDD genes based on the level of information supporting a clinically relevant relationship between a given gene and ASD.

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Fig. 1: Overlap between three sets of genes considered to be associated with ASD susceptibility.
Fig. 2: Proposed pipeline.
Fig. 3: Systematic evaluation of quality of the ASD phenotype report.

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Acknowledgements

C.P.S. is supported by CDMRP Grant AR160154, the Foundation for Prader-Willi Research, the NR2F1 Foundation and the USP7 Foundation. K.A.D. is supported by the Boston Children’s Hospital Neuroscience Clinical Cluster grant. E.H.C. is supported by National Institute of Mental Health (NIMH) grant R01MH110920. P.S. is supported by Canadian Institutes of Health Research (CIHR) funding. S.W.S. is supported by the GlaxoSmithKline–CIHR Endowed Chair in Genome Sciences at the Hospital for Sick Children and University of Toronto. J.A.S.V. is funded by NIMH grant 1U01MH119741–01 and CIHR.

Author information

Authors and Affiliations

  1. Institute of Human Genetics, Heidelberg University, Heidelberg, Germany

    Christian P. Schaaf

  2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Christian P. Schaaf & Chun-An Chen

  3. Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA

    Christian P. Schaaf

  4. Neuroscience Paris Seine, Institut de Biologie Paris Seine, Sorbonne Université, INSERM, CNRS, Paris, France

    Catalina Betancur

  5. The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada

    Ryan K. C. Yuen, Janet A. Buchanan, Ny Hoang, Jennifer Howe, Christian R. Marshall, Olivia Rennie, Stephen W. Scherer & Jacob A. S. Vorstman

  6. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

    Ryan K. C. Yuen & Stephen W. Scherer

  7. Population Health Science Institute, Sir James Spence Institute, Newcastle University, Royal Victoria Infirmary, Newcastle, UK

    Jeremy R. Parr

  8. Institute of Child Health, University College London, London, UK

    David H. Skuse

  9. Department of Psychiatry & Neuropsychiatric Genetics Research Group, School of Medicine, The Trinity Centre for Health Sciences, Trinity College Dublin, Dublin, Ireland

    Louise Gallagher

  10. Department of Psychiatry and Behavioral Sciences, University of Washington, Center for Child Health, Behavior, and Disabilities, Seattle, WA, USA

    Raphael A. Bernier

  11. Children’s Autism Center, Seattle, WA, USA

    Raphael A. Bernier

  12. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Joseph D. Buxbaum

  13. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Joseph D. Buxbaum

  14. Translational Neuroscience Center, Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Kira A. Dies

  15. Montreal Neurological Institute, Azrieli Centre for Autism Research, McGill University, Montreal, QC, Canada

    Mayada Elsabbagh

  16. Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust & Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK

    Helen V. Firth

  17. Autism Speaks, Cleveland, OH, USA

    Thomas Frazier

  18. CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC, Canada

    Jacques L. Michaud

  19. Department of Psychiatry, Hospital for Sick Children, Toronto, ON, Canada

    Peter Szatmari & Jacob A. S. Vorstman

  20. Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada

    Peter Szatmari

  21. Department of Pediatrics (in Medicine), Columbia University Medical Center, New York, NY, USA

    Wendy K. Chung

  22. Institute of Psychiatry, King’s College London, London, UK

    Patrick F. Bolton

  23. Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA

    Edwin H. Cook

  24. McLaughlin Centre, University of Toronto, Toronto, ON, Canada

    Stephen W. Scherer

  25. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Jacob A. S. Vorstman

Authors
  1. Christian P. Schaaf
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  2. Catalina Betancur
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  3. Ryan K. C. Yuen
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  4. Jeremy R. Parr
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  5. David H. Skuse
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  6. Louise Gallagher
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  7. Raphael A. Bernier
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  8. Janet A. Buchanan
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  9. Joseph D. Buxbaum
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  10. Chun-An Chen
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  11. Kira A. Dies
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  12. Mayada Elsabbagh
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  13. Helen V. Firth
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  14. Thomas Frazier
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  15. Ny Hoang
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  16. Jennifer Howe
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  17. Christian R. Marshall
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  18. Jacques L. Michaud
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  19. Olivia Rennie
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  20. Peter Szatmari
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  21. Wendy K. Chung
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  22. Patrick F. Bolton
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  23. Edwin H. Cook
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  24. Stephen W. Scherer
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  25. Jacob A. S. Vorstman
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Contributions

C.P.S., C.B., N.H., J.H., O.R. and J.A.S.V. researched the literature. C.P.S., C.B., R.K.C.Y., J.R.P., D.H.S., L.G., R.A.B., J.A.B., J.D.B., C.-A.C., K.A.D., M.E., H.V.F., T.F., N.H., J.H., C.M., J.L.M., P.S., W.K.C., P.F.B., E.H.C., S.W.S. and J.A.S.V. provided substantial contributions to discussions of the content. C.P.S., C.B., N.H., S.W.S. and J.A.S.V. wrote the article. C.P.S., C.B., R.K.C.Y., J.R.P., D.H.S., L.G., R.A.B., J.A.B., J.D.B., K.A.D., M.E., H.V.F., T.F., N.H., J.H., C.M., J.L.M., P.S., W.K.C., P.F.B., E.H.C., S.W.S. and J.A.S.V. reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Stephen W. Scherer or Jacob A. S. Vorstman.

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Competing interests

H.V.F. is a section editor for Genetics for UpToDate. W.K.C. declares that she is part of the Regeneron Genetics Center Scientific Advisory Board. S.W.S. declares that he is part of scientific advisory committees and/or has intellectual property licensed to Deep Genomics, Population Bio, Lineagen and Athena Diagnostics.

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Nature Reviews Genetics thanks D. Amaral and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Schaaf, C.P., Betancur, C., Yuen, R.K.C. et al. A framework for an evidence-based gene list relevant to autism spectrum disorder. Nat Rev Genet 21, 367–376 (2020). https://doi.org/10.1038/s41576-020-0231-2

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