New tools for Mendelian disease gene identification: PhenoDB variant analysis module; and GeneMatcher, a web-based tool for linking investigators with an interest in the same gene

Abstract

Identifying the causative variant from among the thousands identified by whole-exome sequencing or whole-genome sequencing is a formidable challenge. To make this process as efficient and flexible as possible, we have developed a Variant Analysis Module coupled to our previously described Web-based phenotype intake tool, PhenoDB (http://researchphenodb.net and http://phenodb.org). When a small number of candidate-causative variants have been identified in a study of a particular patient or family, a second, more difficult challenge becomes proof of causality for any given variant. One approach to this problem is to find other cases with a similar phenotype and mutations in the same candidate gene. Alternatively, it may be possible to develop biological evidence for causality, an approach that is assisted by making connections to basic scientists studying the gene of interest, often in the setting of a model organism. Both of these strategies benefit from an open access, online site where individual clinicians and investigators could post genes of interest. To this end, we developed GeneMatcher (http://genematcher.org), a freely accessible Website that enables connections between clinicians and researchers across the world who share an interest in the same gene(s).

Keywords: Mendelian disease; mutation; next-generation sequencing; whole-exome sequencing; whole-genome sequencing.

Figure 1

Increase in the number of genes identified as responsible for Mendelian phenotypes per year (source: Online Mendelian Inheritance in Man, OMIM).

Figure 2

Scheme of PhenoDB Modules (gray-rounded rectangles) and Functions (stippled rectangle). The arrows show that the submitter can go to any Module or Function from any Module or Function.

Figure 3

The analysis log of an example autosomal recessive-compound heterozygous analysis (A) and the OMIM diagnosis search results based on the phenotypic features of the proband (B). If any of the candidate genes listed in the “Final count” is responsible for one of the diagnoses suggested by the OMIM search, it will be flagged.

Figure 4

View of the Analyze function page showing the analysis design.

Figure 5

View of the Analyze function page showing the storage of completed analyses.