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. 2015 Jul;17(7):578-86.
doi: 10.1038/gim.2014.154. Epub 2014 Nov 13.

Enhanced Utility of Family-Centered Diagnostic Exome Sequencing With Inheritance Model-Based Analysis: Results From 500 Unselected Families With Undiagnosed Genetic Conditions

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Enhanced Utility of Family-Centered Diagnostic Exome Sequencing With Inheritance Model-Based Analysis: Results From 500 Unselected Families With Undiagnosed Genetic Conditions

Kelly D Farwell et al. Genet Med. .

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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