Molecular Findings Among Patients Referred for Clinical Whole-Exome Sequencing

Abstract

IMPORTANCE Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders. OBJECTIVE To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome. DESIGN, SETTING, AND PATIENTS Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient’s physician. The patients were primarily pediatric (1756 [88%]; mean age, 6 years; 888 females [44%], 1101 males [55%], and 11 fetuses [1% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay. MAIN OUTCOMES AND MEASURES Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings. RESULTS A molecular diagnosis was reported for 504 patients (25.2%) with 58% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2%; 95% CI, 23.5%–31.2%) for the neurological group, 282/1147 (24.6%; 95% CI, 22.1%–27.2%) for the neurological plus other organ systems group, 30/83 (36.1%; 95% CI, 26.1%–47.5%) for the specific neurological group, and 49/244 (20.1%; 95% CI, 15.6%–25.8%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1%) autosomal dominant, 181 (34.3%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3%) X-linked, and 1 (0.2%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6%) had blended phenotypes resulting from 2 single gene defects. About 30% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6%), including 59 patients (3%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics. CONCLUSIONS AND RELEVANCE Whole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.

Utility of whole‐exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care

“…The first of these was reported by the Baylor College of Medical Genetics Laboratory which demonstrated a 25% molecular diagnostic rate for 250 probands with varying indications (although 80% had a neurologic phenotype) 16. Interestingly, when they increased the number of patients to 2000, the diagnostic rate remained 25% 17. The Lee et al study of 814 patients who underwent WES in a clinical diagnostic laboratory reported a similar diagnostic rate of 22–31% 18.…”

“…Over the past 2–3 years, several large studies have demonstrated the diagnostic utility of WES for a large number of patients analyzed in clinical diagnostic laboratories 16, 17, 18. The first of these was reported by the Baylor College of Medical Genetics Laboratory which demonstrated a 25% molecular diagnostic rate for 250 probands with varying indications (although 80% had a neurologic phenotype) 16.…”

“…The analysis of the largest reported cohort of 2000 patients was primarily as singleton WES 17. Approximately 400 patients in the cohort of 814 underwent trio analysis and this was associated with the higher diagnostic rate of 31% 18.…”

“…The higher diagnostic rate for trios is perhaps not surprising given that de novo mutations are only readily detected by this approach and appear to be enriched in neurodevelopmental cohorts, a common indication for referral to these clinical laboratories. However, the reported diagnostic rates of 22–25% for singleton analysis speaks to the considerable diagnostic utility of WES even in this sequencing paradigm 16, 17, 18. In addition, other approaches may be just as successful.…”

“…For the large studies reported to date 16, 17, 18, such detailed information is not available; however, it is very likely that at a minimum first line testing (karyotype, chromosomal microarray, some single gene testing as indicated) had been completed for these patients prior to WES. Whereas Shashi et al have hypothesized that use of WES and WGS may be economically beneficial when used early in the diagnostic evaluation of a patient 3, it has not yet been determined how the diagnostic rate will be influenced by the timing at which WES is performed.…”