Insufficient Evidence for "Autism-Specific" Genes

Scott M Myers; Thomas D Challman; Raphael Bernier; Thomas Bourgeron; Wendy K Chung; John N Constantino; Evan E Eichler; Sebastien Jacquemont; David T Miller; Kevin J Mitchell; Huda Y Zoghbi; Christa Lese Martin; David H Ledbetter

doi:10.1016/j.ajhg.2020.04.004

Insufficient Evidence for "Autism-Specific" Genes

Am J Hum Genet. 2020 May 7;106(5):587-595. doi: 10.1016/j.ajhg.2020.04.004. Epub 2020 Apr 30.

Authors

Affiliations

¹ Geisinger Autism and Developmental Medicine Institute, Danville, PA 17822, USA. Electronic address: smyers1@geisinger.edu.
² Geisinger Autism and Developmental Medicine Institute, Danville, PA 17822, USA.
³ Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
⁴ Human Genetics and Cognitive Functions Unit, Institut Pasteur, UMR 3571 CNRS, Université de Paris, Paris, 75015, France.
⁵ Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁶ Department of Psychiatry, Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St Louis, MO 63120, USA; Department of Pediatrics, Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St Louis, MO 63120, USA.
⁷ Department of Genome Sciences, University of Washington School of Medicine and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
⁸ Sainte Justine Hospital Research Center, Department of Pediatrics, University of Montreal, Montreal, Quebec, H4A3J1, Canada.
⁹ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
¹⁰ Smurfit Institute of Genetics, Trinity College Dublin, Dublin, D02PN40, Ireland; Institute of Neuroscience, Trinity College Dublin, Dublin, D02PN40, Ireland.
¹¹ Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
¹² Geisinger Autism and Developmental Medicine Institute, Danville, PA 17822, USA. Electronic address: dhledbetter@geisinger.edu.

Abstract

Despite evidence that deleterious variants in the same genes are implicated across multiple neurodevelopmental and neuropsychiatric disorders, there has been considerable interest in identifying genes that, when mutated, confer risk that is largely specific for autism spectrum disorder (ASD). Here, we review the findings and limitations of recent efforts to identify relatively "autism-specific" genes, efforts which focus on rare variants of large effect size that are thought to account for the observed phenotypes. We present a divergent interpretation of published evidence; discuss practical and theoretical issues related to studying the relationships between rare, large-effect deleterious variants and neurodevelopmental phenotypes; and describe potential future directions of this research. We argue that there is currently insufficient evidence to establish meaningful ASD specificity of any genes based on large-effect rare-variant data.

Keywords: ▪▪▪.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

MeSH terms

Autism Spectrum Disorder / diagnosis*
Autism Spectrum Disorder / genetics*
Cohort Studies
Genetic Testing
Genotype
Humans
Reproducibility of Results
Uncertainty*

Abstract

Publication types

MeSH terms

Grants and funding