Enhanced utility of family-centered diagnostic exome sequencing with inheritance model–based analysis: results from 500 unselected families with undiagnosed genetic conditions

TLDR

Diagnostic exome sequencing can rapidly diagnose patients when conventional methods fail. In a cohort of 500 unselected families, family‑based exome sequencing yielded a 30% diagnostic rate—including 7.5% novel gene discoveries—with the highest yields in ataxia, congenital anomalies, and epilepsy, and a 37% rate for trios versus 21% for singletons, demonstrating the method’s superior detection capability.

Abstract

Diagnostic exome sequencing was immediately successful in diagnosing patients in whom traditional technologies were uninformative. Herein, we provide the results from the first 500 probands referred to a clinical laboratory for diagnostic exome sequencing.Family-based exome sequencing included whole-exome sequencing followed by family inheritance-based model filtering, comprehensive medical review, familial cosegregation analysis, and analysis of novel genes.A positive or likely positive result in a characterized gene was identified in 30% of patients (152/500). A novel gene finding was identified in 7.5% of patients (31/416). The highest diagnostic rates were observed among patients with ataxia, multiple congenital anomalies, and epilepsy (44, 36, and 35%, respectively). Twenty-three percent of positive findings were within genes characterized within the past 2 years. The diagnostic rate was significantly higher among families undergoing a trio (37%) as compared with a singleton (21%) whole-exome testing strategy.Overall, we present results from the largest clinical cohort of diagnostic exome sequencing cases to date. These data demonstrate the utility of family-based exome sequencing and analysis to obtain the highest reported detection rate in an unselected clinical cohort, illustrating the utility of diagnostic exome sequencing as a transformative technology for the molecular diagnosis of genetic disease.