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Fig. 4 | Genome Medicine

Fig. 4

From: A visual and curatorial approach to clinical variant prioritization and disease gene discovery in genome-wide diagnostics

Fig. 4

OMIM Explorer radar map performance on a solved clinical case study (unweighted overlap similarity). The patient in the case (yellow triangle) had indications of sinus bradycardia, pericardial effusion, delayed central nervous system (CNS) myelination, epileptic encephalopathy, gastroesophageal reflux, encephalopathy, microcephaly, intellectual disability, and seizures. The filtered exome identified candidate variation in 145 Online Mendelian Inheritance in Man (OMIM) Morbidmap genes. Variants were ranked via transitive maximum unweighted ancestral term overlap similarity. a Top candidate diseases (TCDs) of the differential intermediate. The 500 TCDs by semantic similarity (colored circles) are represented in the radar map. The reported SCN8A variant [ClinVar: SCV000245399.1] present in the patient is transitively ranked at 4 via the MIM #614558 rank of 13. b TCDs with cataloged causal variants. The 500 TCDs are filtered to those with causal gene variants cataloged in the OMIM Morbidmap. The SCN8A variant is transitively ranked at 4 via the MIM #614558 rank of 12. c Exome-linked TCDs. The Morbidmap TCDs are filtered to 229 diseases associated with genes variant in the patient. The SCN8A variant is transitively ranked 4 via the MIM #614558 rank of 4. d Exome TCDs with mandatory phenotypes. The 229 exome TCDs are filtered to 29 known to present with intellectual disability as observed in the patient. The SCN8A variant is transitively ranked 3 via the MIM #614558 rank of 3. e Interactive curation of exome TCDs. Medical knowledge is used to rule out 16 of the 29 remaining TCDs from the differential owing to the absence of their hallmark features. This improved the transitive rank of the SCN8A variant from 3 to 1. f Display of the variant gene. Early infantile epileptic encephalopathy is caused by variants in SNC8A, which is variant in the patient. The detected variant is rare and has high pathogenicity. g Display of a curatorially excluded TCD. Carpenter syndrome, caused by variants in RAB23, is excluded because characteristic features of skull, hand, or foot abnormalities were not reported

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