TABLE II.

Levels of Evidence for Neurodevelopmental Gene-Phenotype Associations in DBDB

Level 1: Strongest gene-phenotype association More than one patient series (of more than three patients each) published from different groups demonstrating that mutations within the gene are associated repeatedly with a specific phenotype, AND Animal models have demonstrated that mutations in the relevant gene are associated with the phenotype, AND In vitro work has demonstrated that mutations within the gene are associated with impaired neuronal function and/or morphology compatible with the phenotype.

Level 2: Moderate gene-phenotype association Single patient series demonstrating that mutations within the gene are associated with a specific phenotype, AND ONE OF THE FOLLOWING Animal models have demonstrated that mutations within the gene are associated with a similar phenotype, OR In vitro work has demonstrated that mutations within the gene are associated with impaired neuronal function and/or morphology.

Level 3: Weak gene-phenotype association Any number of patient reports demonstrating that mutations within the gene are associated with a specific phenotype.

Copy number studies in which a gene is deleted/duplicated as part of a multi-gene copy number variant, or genome-wide association studies of single/simple nucleotide polymorphisms with phenotypes, or “burden” of variants/polymorphisms/copy number variations, or where the phenotype is not specific are considered below Level 3 and are not included in DBDB.

Also not included are genes where an animal model demonstrated a gene-phenotype association, but an association in humans has not been reported.