Gene Scoring
EAGLE Score Curation
The EAGLE scoring system implements a multi-disciplinary consensus-based method for the curation of genes putatively associated with likelihood to develop ASD. The ultimate objective of EAGLE is to enable the development of a comprehensive evidence-based list of genes involved in ASD.
Interpretation
The interpretation of the EAGLE score (evaluating evidence for ASD) compared to existing curation frameworks evaluating evidence of association with the broader neurodevelopmental phenotype can be summarized as follows:
I. A high evidence score resulting from curation in the existing frameworks can, but does not necessarily imply that the gene is also related to ASD.
II. A high evidence score resulting from curation with the EAGLE scoring framework confirms a gene’s relationship with ASD, but does not rule out a relationship with any other neurodevelopmental phenotypes.
From the preceding follows that EAGLE curation of evidence of association with ASD does not necessitate nor imply the existence of “ASD-specific” genes.
The EAGLE Curation process does not apply a ceiling for definitive scores. Consequently, the degree with which a score exceeds 12 (->definitive) can be interpreted as a measure of additional strength of the underlying evidence.
Curation Steps
Evidence collection: Genotype information. Curators collect all published clinical cases, and document genotyping method, variant(s) reported, mode of inheritance, observed variant frequency and their predicted impact. Any evidence, functional or otherwise, that supports pathogenicity of the reported variant, is used to score the case, not scored separately under experimental evidence.
Evidence Collection: Phenotype information. Curators also extract relevant phenotype information for each case, with special attention to how diagnosis of ASD was reached and any information on additional phenotypes of relevance such as intellectual disability.
Scoring: System. Based on this information, curators then score each case, following the ClinGen scoring framework. Default scores may be adjusted based on various aspects of each case report, such as confidence level of ASD phenotyping or frequency in gnomAD.
Scoring: Category Assignment. Individual case scores are added up to a total score which is subsequently categorized in a limited, moderate, or strong/definitive classification:
