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Genet Med. 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.

Author information

1
Ambry Genetics, Aliso Viejo, California, USA.
2
1] Ambry Genetics, Aliso Viejo, California, USA [2] Division of Genetics and Metabolism, Department of Pediatrics, University of California, Irvine, Irvine, California, USA.

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.

PMID:
25356970
DOI:
10.1038/gim.2014.154
[Indexed for MEDLINE]
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