Genome-first evaluation with exome sequence and clinical data uncovers underdiagnosed genetic disorders in a large healthcare system

• Published in: Cell reports. Medicine Vol. 5; no. 5; p. 101518
• Main Authors: Forrest, Iain S., Duffy, Áine, Park, Joshua K., Vy, Ha My T., Pasquale, Louis R., Nadkarni, Girish N., Cho, Judy H., Do, Ron
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.05.2024; Elsevier
• Subjects: Adolescent; Adult; Aged; American College of Medical Genetics and Genomics; biobank; breast cancer; cardiomyopathy; Delivery of Health Care; electronic health record; Electronic Health Records; Exome - genetics; exome sequence; Exome Sequencing - methods; Female; Genetic Diseases, Inborn - diagnosis; Genetic Diseases, Inborn - epidemiology; Genetic Diseases, Inborn - genetics; Genetic Predisposition to Disease; Genetic Testing - methods; Genome, Human; genome-first; Genomics - methods; Humans; Male; Middle Aged; penetrance; precision medicine; underdiagnosis; Young Adult; genome-first; exome sequence; penetrance; breast cancer; precision medicine; cardiomyopathy; American College of Medical Genetics and Genomics; biobank; electronic health record; underdiagnosis
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2024.101518

Population-based genomic screening may help diagnose individuals with disease-risk variants. Here, we perform a genome-first evaluation for nine disorders in 29,039 participants with linked exome sequences and electronic health records (EHRs). We identify 614 individuals with 303 pathogenic/likely pathogenic or predicted loss-of-function (P/LP/LoF) variants, yielding 644 observations; 487 observations (76%) lack a corresponding clinical diagnosis in the EHR. Upon further investigation, 75 clinically undiagnosed observations (15%) have evidence of symptomatic untreated disease, including familial hypercholesterolemia (3 of 6 [50%] undiagnosed observations with disease evidence) and breast cancer (23 of 106 [22%]). These genetic findings enable targeted phenotyping that reveals new diagnoses in previously undiagnosed individuals. Disease yield is greater with variants in penetrant genes for which disease is observed in carriers in an independent cohort. The prevalence of P/LP/LoF variants exceeds that of clinical diagnoses, and some clinically undiagnosed carriers are discovered to have disease. These results highlight the potential of population-based genomic screening. [Display omitted] •Persons with disease-risk variants and exome and clinical phenotype data are evaluated•3 in 4 observations of variants lack a corresponding diagnosis, 15% of which show symptoms•Exome analysis enables targeted phenotyping and new diagnoses missing from clinical care Forrest et al. pilot a genome-first strategy for assessing individuals genetically predisposed to disease who may be missing a diagnosis in their routine healthcare. Participants carrying disease-risk variants are identified and undergo targeted phenotyping with laboratory measurements, electrophysiology, imaging, and physician notes to uncover new diagnoses in previously undiagnosed individuals.