The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as “#S” (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as “S.”
About the Gene Scoring Module
Our gene scoring system takes into account all available evidence supporting a gene's relevance to ASD risk and places each gene into a category reflecting the overall strength of that evidence.
SFARI Gene is a comprehensive database that includes any gene associated with autism risk, regardless of the nature of the evidence supporting its link to ASD. Given this approach and the potentially large number of false-positives it invites, we recognize the importance of establishing a ranking system that gives users an estimate of the strength of the evidence in favor of each gene. In collaboration with our curators at MindSpec and a team of expert autism geneticists, we've established a set of criteria that allows us to rank genes into one of seven categories, enabling users to easily identify the genes whose association with autism risk is most likely to hold up over time.
number of reports
- More Genes
- Less Genes
Category 1(High Confidence)
1.1 Genes in this category require evidence of recurrent and convincing mutations accompanied by a rigorous statistical comparison with the mutation frequency in controls, confirmed via independent replication. Full sequencing of a comparable number of cases and controls is also required. “Convincing” is defined as “likely to be functional,” or showing perfect segregation of mutations and phenotype in a large pedigree.
1.2 Results from association studies must reach genome-wide significance, uniquely implicating a single gene, and be independently replicated, or reach genome-wide significance via meta-analysis of all current association studies. For genome-wide significant variants in an intergenic region, a nearby flanking gene would be included if it’s the only gene in strong linkage disequilibrium (LD) with the intergenic variant, or if the variant is also associated with altered expression of a particular flanking gene (or another line of strong evidence implicating this gene).
Category 2(Strong Candidate)
2.1 These genes are rare mutations that are recurrent and convincing, accompanied by a rigorous statistical comparison with the mutation frequency in controls. Independent replication is not required. Full sequencing of a comparable number of cases and controls is required. “Convincing” is defined as “likely to be functional,” or showing perfect segregation of mutations and phenotype in a large pedigree. Rare de novo variants, likely to be disruptive, in three or more unrelated cases would qualify here.
2.2 Results from association studies must reach genome-wide significance, uniquely implicating a single gene, but with no independent replication. For genome-wide significant variants in an intergenic region, a nearby flanking gene would be included if it’s the only gene in strong LD with the intergenic variant, or if the variant is also associated with altered expression of a particular flanking gene (or another line of strong evidence implicating this gene).
2.3 Genes in this category require a consistently replicated association of the same allele, falling short of genome wide significance, and must be accompanied by evidence that the risk variant has a relevant functional effect in humans. “Consistently replicated” means replication of the same variant in each follow-up association study that is appropriately powered and involves a population of the same ancestry, or it has been found inconsistent but overall significant by meta-analysis. In this regard, “gene-based” tests of association are acceptable as evidence of an association if performed in the original study, but would not be considered as evidence simply to “rescue” a subsequent study that finds a variant association that is different from the associated variant in the original study.
Category 3(Suggestive Evidence)
3.1 Genes that meet at least two of criteria 4.1, 4.2, and 4.3, or meet one of those criteria and at least one line of category 4 accessory evidence are included here.
3.2 These genes meet category 2.3 criteria, but without accompanying functional evidence.
3.3 Rare de novo variants, likely to be disruptive, in two or more unrelated cases are placed in this category.
Category 4(Minimal Evidence)
4.1 Any gene in an ASD-associated multi-genic CNV (including syndromic) for which there is no other independent evidence is included here.
4.2 Genes proximal to genome-wide significant intergenic variants that don’t meet category 1 or 2 criteria are placed here.
4.3 This category contains any significant, convincing, but unreplicated association study data, along with any instances of multiple but inconsistent reports of association that are not overall significant by meta-analysis.
4.4 Genes with a series of two or more putative mutations identified (e.g., non-synonymous substitutions, single-gene deletion, duplication, disruption by translocation) for which there is not rigorous statistical comparison with controls are included here.
4.5 This category contains single rare de novo variants, likely to be disruptive.
The presence of certain accessory evidence may raise a gene from category 4 to category 3. Such evidence includes:
- Altered expression or function in ASD cases vs. controls in any tissue, whether as a function of genotype or not.
- Strong evidence for involvement in a related phenotype or disorder, specifically including ADHD, ASD-related endophenotypes (e.g., language impairment), bipolar disorder, epilepsy, intellectual disability, schizophrenia.
- Genes shown to be associated with ASD risk via genetic epistasis with another gene.
5.1 This category includes genes for which the only evidence comes from studies of model organisms, without statistical or genetic support in human studies.
5.2 Genes in a region of linkage with no unique evidence for that gene versus others nearby are included here.
5.3 Genes in category 5.3 are shown only to functionally interact with category 1-3 ASD candidate genes.
5.4 Genes with a single rare variant observed in a single ASD case/family are placed here.