Clinical Exome Sequencing for Genetic Identification of Rare Mendelian Disorders

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% (2of 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.

Clinical application of whole-exome sequencing across clinical indications

“…7,8 This difference is probably due to the inclusion of likely pathogenic variants before consensus emerged about interpretation of the ACMGG guidelines to report secondary findings and other groups utilizing more stringent criteria for calling a variant pathogenic or likely pathogenic.…”

“…[2][3][4][5][6] The yield of WES in clinical series ranges from 22 to 26%; however, it is still unclear which clinical indications are most likely to yield a diagnosis using WES. [7][8][9][10][11] For example, the diagnostic yield in patients with ataxia was 12.8% in one clinical case series and 44.1% in another. 7,8 Furthermore, because WES is comprehensive and unbiased in its analysis of all known disease-causing genes, it has the advantage of identifying more than one genetic condition even when the clinical presentation does not make it obvious that there is more than one diagnosis.…”

“…[7][8][9][10][11] For example, the diagnostic yield in patients with ataxia was 12.8% in one clinical case series and 44.1% in another. 7,8 Furthermore, because WES is comprehensive and unbiased in its analysis of all known disease-causing genes, it has the advantage of identifying more than one genetic condition even when the clinical presentation does not make it obvious that there is more than one diagnosis. 8,9 As a clinical diagnostic laboratory, we sought to review our experience analyzing 3,040 consecutive cases utilizing WES over the past 3 years to better understand the clinical contexts in which WES can provide a plausible explanation for the presenting symptoms.…”

Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature

“…3 Given this, several studies have investigated the benefits arising from the application of WES and WGS in the clinic. These studies have primarily focused on intellectual learning disability 4 or Mendelian conditions more broadly, 3,[5][6][7][8][9] consistently reporting diagnostic yields between 25 and 30%. In addition, WES and WGS have often informed prognoses or treatment of patients, for example in inflammatory bowel disease 10 and epilepsies.…”

Navigating the current landscape of clinical genetic testing for inherited retinal dystrophies

“…Trio testing can increase the detection rate of exome sequencing by allowing the laboratory to set phase for variants associated with autosomal-recessive conditions and to investigate the possibility of a de novo variant when identified in a gene associated with an autosomal-dominant condition and no known family history. 26 However, trio testing is not always possible in families from which relatives may be unavailable, such as in the case of adoption, or are unwilling to undergo testing. Proband-only testing can still be informative, but it may lead to a higher percentage of variants of unknown significance.…”