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. 2014 Nov 12;312(18):1880-7.
doi: 10.1001/jama.2014.14604.

Clinical exome sequencing for genetic identification of rare Mendelian disorders

Hane Lee  1 , Joshua L Deignan  1 , Naghmeh Dorrani  2 , Samuel P Strom  1 , Sibel Kantarci  1 , Fabiola Quintero-Rivera  1 , Kingshuk Das  1 , Traci Toy  1 , Bret Harry  3 , Michael Yourshaw  4 , Michelle Fox  4 , Brent L Fogel  5 , Julian A Martinez-Agosto  6 , Derek A Wong  4 , Vivian Y Chang  4 , Perry B Shieh  5 , Christina G S Palmer  7 , Katrina M Dipple  6 , Wayne W Grody  8 , Eric Vilain  9 , Stanley F Nelson  10
Affiliations

Clinical exome sequencing for genetic identification of rare Mendelian disorders

Hane Lee et al. JAMA. .

Abstract

Importance: Clinical exome sequencing (CES) is rapidly becoming a common molecular diagnostic test for individuals with rare genetic disorders.

Objective: To report on initial clinical indications for CES referrals and molecular diagnostic rates for different indications and for different test types.

Design, setting, and participants: Clinical exome sequencing was performed on 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) to effectively detect de novo and compound heterozygous variants or as proband-CES (only the affected individual sequenced) when parental samples were not available.

Main outcomes and measures: Clinical indications for CES requests, molecular diagnostic rates of CES overall and for phenotypic subgroups, and differences in molecular diagnostic rates between trio-CES and proband-CES.

Results: Of the 814 cases, the overall molecular diagnosis rate was 26% (213 of 814; 95% CI, 23%-29%). The molecular diagnosis rate for trio-CES was 31% (127 of 410 cases; 95% CI, 27%-36%) and 22% (74 of 338 cases; 95% CI, 18%-27%) for proband-CES. In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41% (45 of 109; 95% CI, 32%-51%) for trio-CES cases and 9% (2 of 23, 95% CI, 1%-28%) for proband-CES cases. The significantly higher diagnostic yield (P value = .002; odds ratio, 7.4 [95% CI, 1.6-33.1]) of trio-CES was due to the identification of de novo and compound heterozygous variants.

Conclusions and relevance: In this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the effect of this approach on clinical and economic outcomes are warranted.

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Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Lee, Deignan, Dorrani, Strom, Kantarci, Quintero-Rivera, Das, Toy, Grody, and Nelson are part of the Department of Pathology and Laboratory Medicine, which derives revenue from the clinical use of the clinical exome sequencing test. Dr Fogel reports receiving grant funding from the National Institute of Mental Health, the National Institute for Neurological Disorders and Stroke, and the National Ataxia Foundation. Dr Shieh reports that he is a member of the speakers bureau for Grifols. Dr Vilain reports receiving grant funding from the University of California, Los Angeles.

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