When genetic testing detects a candidate variant (CV) in a gene that is not known to cause disease in humans, clinicians face a dilemma. Where can they find the additional evidence needed to make a diagnosis? One action a clinician can take is to search for additional patients with a deleterious variant in the same gene. Here we present a case study where the electronic health record (EHR) was used to facilitate genotypic matchmaking to help diagnose a patient at Vanderbilt’s Undiagnosed Disease Network (UDN) 1 clinical site.

A 26-year-old female with unexplained mild intellectual disability (ID), autism spectrum disorder (ASD), obsessive compulsive disorder (OCD), high myopia, and joint hypermobility had exome sequencing (ES) as part of her work-up for the UDN. Interestingly, a de novo MSL2 p. S232Tfs* 10 variant was included in the ES report along with its possible association with ASD. 2 The MSL2 protein had been reported to be part of a complex that plays a major role in chromatin regulation and structure through histone H4 acetylation and H2B ubiquitylation. 3, 4 Due to the participant’s CV being a frameshift, de novo, and the function of the MSL2 protein, the Vanderbilt University Medical Center (VUMC) UDN team considered it an attractive candidate, but the lack of a previously reported role in Mendelian disease precluded it from being diagnostic.