Insufficient Evidence for "Autism-Specific" Genes

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.

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Figure 1

Genes with ≥10 cases with de novo pLOF variants in the Geisinger Developmental Brain Disorder Genes Database The number of individuals with intellectual disability (ID) without autism spectrum disorder (ASD) (ID_only), ASD without ID (ASD_only), and both ID and ASD (ID_ASD) is plotted for each of the 59 genes for which there are at least 10 total probands with de novo pLOF variants in the Geisinger Developmental Brain Disorder (DBD) Genes Database (see Web Resources). The DBD Genes Database is a curated resource providing genotype and phenotype data from six neurodevelopmental disorders (ID, ASD, attention-deficit/hyperactivity disorder, schizophrenia, bipolar disorder, and epilepsy) obtained from published literature.