Exome and Genome Sequencing in a Heterogeneous Population of Patients with Rare Disease: Identifying Predictors of a Diagnosis.

Purpose: Exome (ES) and genome sequencing (GS) are increasingly being utilized for individuals with rare and undiagnosed diseases; however, guidelines on their use remain limited. This study aimed to identify factors associated with diagnosis by ES and/or GS in a heterogeneous population of patients with rare and undiagnosed diseases. Methods: In this case control study, we reviewed data from 400 diagnosed and 400 undiagnosed randomly selected participants in the Undiagnosed Diseases Network, all of whom had undergone ES and/or GS. We analyzed factors associated with receiving a diagnosis by ES and/or GS. Results: Factors associated with a decreased odds of being diagnosed included adult symptom onset, singleton sequencing, and having undergone ES and/or GS before acceptance to the Undiagnosed Diseases Network (48%, 51%, and 32% lower odds, respectively). Factors that increased the odds of being diagnosed by ES and/or GS included having primarily neurological symptoms and having undergone prior chromosomal microarray testing (44% and 59% higher odds, respectively). Conclusion: We identified several factors that were associated with receiving a diagnosis by ES and/or GS. This will ideally inform the utilization of ES and/or GS and help manage expectations of individuals and families undergoing these tests. (c) 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.