2.5 years’ experience of GeneMatcher data-sharing: a powerful tool for identifying new genes responsible for rare diseases

Exome sequencing (ES) powerfully identifies the molecular bases of heterogeneous conditions such as intellectual disability and/or multiple congenital anomalies (ID/MCA). Current ES analysis, combining diagnosis analysis restricted to disease-causing genes reported in OMIM database and subsequent research investigation extended to other genes, indicated causal and candidate genes around 40% and 10%. Nonconclusive results are frequent in such ultrarare conditions that recurrence and genotype-phenotype correlations are limited. International data-sharing permits the gathering of additional patients carrying variants in the same gene to draw definitive conclusions on their implication as disease causing. Several web-based tools have been developed and grouped in Matchmaker Exchange. In this study, we report our current experience as a regional center that has implemented ES as a first-line diagnostic test since 2013, working with a research laboratory devoted to disease gene identification. We used GeneMatcher over 2.5 years to share 71 novel candidate genes identified by ES. Matches occurred in 60/71 candidate genes allowing to confirm the implication of 39% of matched genes as causal and to rule out 6% of them. The introduction of user-friendly gene-matching tools, such as GeneMatcher, appeared to be an essential step for the rapid identification of novel disease genes responsible for ID/MCA.