Embracing New Strategies to Determine the Genetic Basis of Mendelian Disorders

The Gene Discovery Core (GDC) of The Manton Center for Orphan Disease Research at Boston Children’s Hospital (BCH) has been enrolling individuals and families with rare and unknown disorders into an IRB-approved protocol for the past six years. We focus on individual cases (“n of one”) with a suspected monogenic cause, in addition to building large cohorts of various rare conditions with no currently known genetic cause.

We aim to determine the genetic and molecular basis for these conditions using various technologies including whole exome and genome sequencing (WES/WGS), bioinformatic analysis, and cellular and animal modeling. While the majority of our enrolled families undergo research WES, we are increasingly enrolling families without a diagnosis despite clinical WES. This has presented a challenge requiring integration of new strategies in order to find diagnoses.

To date, we have enrolled 1085 probands and >3000 family members from six continents and 46 states. For enrolled patients where WES reveals no pathogenic variants or variants of unknown significance (VUS), our team of researchers reanalyze the raw WES data using our in-house analytical pipeline for potential candidate mutations. In addition, we submit those variants to the MatchMaker Exchange database to identify additional patients with similar genetic defects and phenotypes from around the world.  

Our WES pipeline has successfully identified disease-causing genetic variants in novel and known genes previously not reported on clinical WES. Additionally, connecting with researchers around the globe through the MatchMaker Exchange platform has enabled us to identify the genetic basis of disease for several of our “n of one” patients (9/28 patients) and narrow down causative genes (4/28) when more than one gene is a candidate. 

By creating an interdisciplinary research infrastructure, embracing the role of WES data reanalysis, and sharing candidate genes on MatchMaker Exchange, we have been able to determine the genetic basis of disease in several patients with previously unrevealing WES. As clinical WES becomes more common, these strategies will be essential to advance pediatric rare disease diagnostics.