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

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.

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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.

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

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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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