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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

Kelly D Farwell  1 , Layla Shahmirzadi  1 , Dima El-Khechen  1 , Zöe Powis  1 , Elizabeth C Chao  2 , Brigette Tippin Davis  1 , Ruth M Baxter  1 , Wenqi Zeng  1 , Cameron Mroske  1 , Melissa C Parra  1 , Stephanie K Gandomi  1 , Ira Lu  1 , Xiang Li  1 , Hong Lu  1 , Hsiao-Mei Lu  1 , David Salvador  1 , David Ruble  1 , Monica Lao  1 , Soren Fischbach  1 , Jennifer Wen  1 , Shela Lee  1 , Aaron Elliott  1 , Charles L M Dunlop  1 , Sha Tang  1
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Free article

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. 2015 Jul.
Free article

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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