Curating genomic disease-gene relationships with Gene2Phenotype (G2P)

Abstract

Genetically determined disorders are highly heterogenous in clinical presentation and underlying molecular mechanism. The evidence underpinning these conditions in the peer-reviewed literature requires robust critical evaluation for diagnostic use. Here, we present a structured curation process for Gene2Phenotype (G2P). This draws on multiple lines of clinical, bioinformatic and functional evidence. The process utilises and extends existing terminologies, allows for precise definition of the molecular basis of disease, and confidence levels to be attributed to a given gene-disease assertion. In-depth disease curation using this process will prove useful in applications including in diagnostics, research and development of targeted therapeutics. G2P: www.ebi.ac.uk/gene2phenotype .

Keywords: Disease mechanism; Gene curation; Genomic variant filtering.

Fig. 1

The number of gene-disease association LGMDE threads in G2P, plotted by confidence level and panel [1]. Developmental disorders panel: 1477 definitive entries, 727 strong entries, 158 moderate entries, 375 limited entries. Downloaded 14th October 2024

Fig. 2

DECIPHER protein view for the gene REST [15]. Red (likely loss of function) filled variants in the ClinVar variants track, on the left side of the image, are annotated as pathogenic (squares)/likely pathogenic (triangles). These are associated with predisposition to Wilms tumour [16]. The Predicted NMD Escape track is not filled in this region, indicating these variants are likely to result in NMD. Red/orange areas show areas of Regional Missense Constraint in the corresponding track. Missense variants in the DNA binding domain—shown by the green oval—in this region have also been reported in association with Wilms tumour [16]. The filled red triangles/squares on the right of the image in the ClinVar track are associated with gingival fibromatosis [17]. These are in the final exon and hence predicted not to result in NMD as shown in the Predicted NMD Escape track. This is therefore likely to be a different disease mechanism than for Wilms tumour. There are relatively few gnomAD loss of function variants and none of these correspond to the likely pathogenic/pathogenic ClinVar variants. The DECIPHER protein view allows for all these sources of information to be visualised at once. Further data is available through interaction with the web-based interface at www.deciphergenomics.org, which is regularly updated. Data is pulled from multiple bioinformatic resources. NMD, Nonsense Mediated Decay