Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases.

Farwell Hagman KD1, Shinde DN1, Mroske C1, Smith E1, Radtke K1, Shahmirzadi L1, El-Khechen D1, Powis Z1, Chao EC1,2, Alcaraz WA1, Helbig KL1,Sajan SA1, Rossi M1, Lu HM1, Huether R1, Li S1, Wu S1, Nuñes ME3, Tang S1.

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Abstract

PURPOSE:

Diagnostic exome sequencing (DES) is now a commonly ordered test for individuals with undiagnosed genetic disorders. In addition to providing a diagnosis for characterized diseases, exome sequencing has the capacity to uncover novel candidate genes for disease.

METHODS:

Family-based DES included analysis of both characterized and novel genetic etiologies. To evaluate candidate genes for disease in the clinical setting, we developed a systematic, rule-based classification schema.

RESULTS:

Testing identified a candidate gene among 7.7% (72/934) of patients referred for DES; 37 (4.0%) and 35 (3.7%) of the genes received evidence scores of "candidate" and "suspected candidate," respectively. A total of 71 independent candidate genes were reported among the 72 patients, and 38% (27/71) were subsequently corroborated in the peer-reviewed literature. This rate of corroboration increased to 51.9% (27/52) among patients whose gene was reported at least 12 months previously.

CONCLUSIONS:

Herein, we provide transparent, comprehensive, and standardized scoring criteria for the clinical reporting of candidate genes. These results demonstrate that DES is an integral tool for genetic diagnosis, especially for elucidating the molecular basis for both characterized and novel candidate genetic etiologies. Gene discoveries also advance the understanding of normal human biology and more common diseases.Genet Med advance online publication 11 August 2016Genetics in Medicine (2016); doi:10.1038/gim.2016.95.