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).

Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort

“…Several matchmaking tools have been developed to address this bottleneck, e.g., GeneMatcher and MIMmatcher. 33,34 Reporting detailed clinical and genomic analyses of a large series of apparently novel dysmorphology syndromes will likely lead to a trend of accelerating the establishment of novel syndromes and their underlying genes. Such a trend will catalyze matchmaking such that the proposed novel phenotype is established and its candidate gene is confirmed independently.…”

Axons to Exons: the Molecular Diagnosis of Rare Neurological Diseases by Next-Generation Sequencing

“…For example, PhenomeCentral summarizes information about other phenotypically similar patients with deleterious-appearing variants in the same candidate gene and allows these researchers to contact each other when a match is made (http://phenomecentral.org). Other similar Bmatchmaking^databases have been developed, such as GeneMatcher [52], which connects investigators based on their interest in the same gene, and DECIPHER [53], which allows investigators to search coded phenotypic and genotypic data to identify possible matches. The University of Miami GEM.app i s a d a t a b a s e t h a t sh a r e s e x o m e r e s u l t s f r o m researchers internationally to identify clinically relevant variants in a number of neurological disorders (e.g., hereditary spastic paraplegia, Charcot-Marie-Tooth disease, amyotrophic lateral sclerosis) to identify novel genes [54].…”

Mutations in SPATA5 Are Associated with Microcephaly, Intellectual Disability, Seizures, and Hearing Loss

“…In ten affected children from seven unrelated families, we identified variants in SPATA5 as potentially causative for the phenotype. Through GeneMatcher, 6 we identified four additional probands from three families, giving us a total of 14 affected children in ten families. Twelve of the individuals are of European descent, and two (individuals 6 and 7) are Hispanic.…”