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Application of genomic bioinformatic tools in clinical psychiatry and counseling

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Description of pathogenicity criteria.
CriterionDescriptionExample
Variant database analysisReview of genomic repositories (such as OMIM or ClinVar) to determine whether a variant has been previously reported, whether it is associated with known diseases, and whether its pathogenicity has been established by the scientific community.For the SETD1A C>T variant, a search in ClinVar immediately classified it as a previously known pathogenic mutation.
Genetic segregation studiesAnalysis of the family pedigree to determine whether the variant segregates with the disease; that is, whether all affected relatives carry the mutation whereas unaffected relatives do not.For the C>A variant, this criterion ruled out pathogenicity because the mother carried the variant whereas the father did not.
Allele frequencyEvaluation of the frequency of the variant in the general population. Variants with a frequency greater than 5% are considered benign, whereas extremely rare or absent variants suggest pathogenicity.Neither the C>A nor the C>T variant had allele frequency data available in gnomAD, supporting their potential pathogenicity.
In silico toolsComputational prediction of the impact of the variant at different biological levels, from transcription to protein formation.Analysis of the C>A variant using PolyPhen-2 classified it as possibly damaging.
Evolutionary conservationComparison of the genetic sequence across different species. A region that is highly conserved among species is likely to have an important biological function; therefore, mutations affecting that region are more likely to be pathogenic.For the C>T variant, the affected region was identical in chimpanzees and partially conserved in cats and pufferfish, strengthening the evidence that the mutation is deleterious.

OMIM, Online Mendelian Inheritance in Man.

Source: Prepared by the authors based on Richards et al. [6].