Figure 5.
Phevor Analyses of Three Clinical Cases
Plotted on the x axes of each Manhattan plot are the genomic coordinates of the candidate genes. The y axes show the log10 value of the ANNOVAR score, VAAST p value, or Phevor score depending upon the panel. Black, filled circles denote top ranked gene(s), all of which had either the same ANNOVAR score or the same VAAST p value. Red circles denote the gene containing disease-causing allele(s). For purposes of comparison to VAAST, we transformed the ANNOVAR scores to frequencies by dividing the number of gene candidates identified by ANNOVAR by the total number of annotated human genes.
(A) Phevor identified NFKB2 as a disease-associated gene. (Top) Results of running ANNOVAR (left) and VAAST (right) on the union of variants identified in affected members of family A and those in the affected individual from family B. Both ANNOVAR and VAAST identified a large number of equally likely candidate genes. NFKB2 (shown in red) was among them in both cases. (Bottom) Phevor identified a single best candidate, NFKB2, by using the VAAST output, and NFKB2 was ranked second with the ANNOVAR output (two other genes were tied for first place).
(B) Phevor identified a de novo variant in STAT1 as responsible for a previously undescribed phenotype in an already disease-associated gene. (Top) Results of running ANNOVAR (left) and VAAST (right) on the single affected individual’s exome. Both ANNOVAR and VAAST identified multiple candidate genes. STAT1 (shown in red) was among them in both cases. (Bottom) Phevor identified a single best candidate, STAT1, by using the VAAST output. STAT1 was the third best candidate with the ANNOVAR output.
(C) Phevor identified a mutation in ABCB11, a known disease-associated gene. (Top) Results of running ANNOVAR (left) and VAAST (right) on the single affected child’s exome. Both ANNOVAR and VAAST identified a number of equally likely candidate genes. ABCB11 (shown in red) was among them. (Bottom) Phevor identified a single best candidate, ABCB11, by using the ANNOVAR and VAAST outputs.