1. Diagnostic Yield and Utility of Clinical Exome Sequencing

Diagnostic Yield and Utility of Clinical Exome Sequencing

Alekhya Narravula 1 Nickias Kienle 1 Iris Hövel, PhD 1 Antonio Romito, PhD 1 Aida M. Bertoli-Avella, MD 1 Zafer Yüksel, MD 1 Omid Paknia, PhD 1 Krishna Kumar Kandaswamy, PhD 1 S Nampoothiri 2 F Hadipour 3 Z Hadipour 3 Florian Vogel 1 Gabriela-Elena Oprea, PhD 1 Shivendra Kishore, PhD 1 Prof. Peter Bauer, MD 1, 4 Prof. Arndt Rolfs, MD 1, 5
1 CENTOGENE AG 2 Amrita Institute of Medical Sciences (AIMS), Cochin, India 3 Sarem Cell Research Center & Hospital, Tehran, Iran 4 University Hospital of Tübingen 5 University of Rostock
April 11, 2018

These findings were presented at the American College of Medical Genetics and Genomics (ACMG ) annual meeting 2017.

1. Introduction

  • Clinical exome sequencing (CES) is sequencing and analysis of the exons of only clinically-relevant genes compared to sequencing the exons of all 20,000 genes in whole exome sequencing (WES).
  • CentoDx Plus™ is a customized CES test targeting ~6,700 genes with 100% coverage of the exons of >4000 genes.

                • It is the largest NGS panel covering genes within all disease specialties.

                • Boosted coverage of regions of clinical interest allows better and more uniform coverage compared to WES.

  • Due to good coverage and affordability, CES is suitable for patients and physicians in regions where high cost is a significant barrier to uptake of genetic testing and diagnosis.

2. Aim

To assess the clinical utility of CES (CentoDx Plus™) at CENTOGENE using diagnostic yield as a measure.

3. Methods

  • CES was performed on 206 patients utilizing Illumina technology and custom probes for ~6,700 genes.
  • Reported cases were analyzed to determine cases with diagnostic variants.

Figure 2. CES workflow and analysis of cases. The indication for testing were either diagnostic testing of affected individuals or carrier screening for individuals with history of previous affected offspring. Confirmed diagnosis =1 or 2 (likely) pathogenic variants detected confirming the diagnosis; Probable diagnosis = 1 or 2 variants of unknown significance (VUS) detected; Confirmed carrier = 1 (likely) pathogenic variant detected; Probable carrier = 1 VUS detected.

4. Results

  • The diagnostic rate (confirmed diagnoses) of CES in this cohort was 53.4% (110 of 206 cases).
  • If the additional 35.9% of cases (74/206) with relevant VUS findings are considered, the overall diagnostic rate is as high as 89.3%.

5. Conclusions

  • The high diagnostic yield of CES is evident in this small cohort of samples.
  • The higher yield compared to a WES is likely due to using the test to diagnose both – patients with known, suspected diagnoses (in lieu of sequential single gene testing or one or more NGS panels) and undiagnosed cases with unknown, complex phenotypes (instead of a WES).
  • CES is a single, versatile test yielding a higher diagnostic rate and clinically useful result for a variety of diagnostic indications and needs.
  • Due to the cost- and time-efficient nature, good coverage & high diagnostic rate, CES is a good alternative to sequential testing, NGS panels or even a WES.
  • Especially in regions with economic barriers to genetic testing, CES should be considered a prime test of choice for patient undergoing genetic testing.