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

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


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.

MeSH terms

  • Adult
  • Cohort Studies
  • Databases, Genetic
  • Exome*
  • Female
  • Heredity
  • Humans
  • Male
  • Molecular Diagnostic Techniques / methods
  • Molecular Diagnostic Techniques / statistics & numerical data*
  • Sequence Analysis, DNA / methods
  • Sequence Analysis, DNA / statistics & numerical data*