RELEASE: Introducing a new standard for quality: Updated panels significantly improve sequencing depth and sensitivity

March 5, 2018

Blueprint Genetics is setting a new standard for quality with the introduction of new and improved panels. A total of 157 panels have been updated and 21 new panels launched.

A transition has been made to a new production platform where all the panels are sliced from customized high-quality whole exome sequencing data. The update will also improve sequencing coverage and diagnostic yield from difficult-to-sequence regions.

“We now have improved coverage in clinically relevant and challenging genes such as PKD1 and RPGR (ORF15). Mutations in these genes are associated with polycystic kidney disease and a severe form of retinal degeneration, respectively. In these genes, we have attained extremely high sequencing quality in both coverage and mapping quality. We have achieved a high diagnostic rate in internal clinical validation even at the most challenging part, the central region of RPGR ORF15”, says Laboratory Director and Chief Medical Officer Juha Koskenvuo.

The updated panels include an increased number of clinically relevant genes and 1,479 rare deep intronic variants catalogued in the ClinVar and HGMD professional databases. Thus, the new assay compares very favorably against high-quality whole genome sequencing in diagnostic performance without providing a high number of variants of uncertain significance (from the non-coding regions).

“The new assay introduces many beneficial components that together enable high-quality sequence data from difficult-to-sequence regions where most previous NGS-derived solutions have had limited sensitivity. The three most important components of success are longer paired-end read lengths (2×150 bp) with NovaSeq that improves mapping quality, more extensive custom capture oligo-design for difficult-to-sequence regions enabling more coverage, and customized bioinformatics”, Koskenvuo continues.

The assay provides high sensitivity for single nucleotide variants (SNVs), insertions and deletions (indels) and copy number variations (CNVs) in one single test. In addition to almost one hundred clinical samples with CNVs used in the validation, a computational validation approach employing sex chromosomal data was developed for CNVs. This approach also allows us to track the sensitivity of the samples in production. Separate algorithms were developed for calling both small and large CNVs in the new CNV pipeline to ensure we reach top performance for each CNV size.

In total, over 660 carefully curated genes have been added to the updated panels.

“For example, the Dilated Cardiomyopathy (DCM) Panel has increased from 27 genes to 69. Also, in ophthalmology we are seeing great results with major clinical utility. In the Retinal Dystrophy Panel, a diagnostic yield was 52% in the second half of 2017. We expect even higher results with the current update as this panel has grown from 181 genes to 266”, Koskenvuo says.

Blueprint Genetics has been working towards improving the quality and performance of genetic diagnostic testing in addition to best-possible variant interpretation not only in their own laboratory but across the industry. Full transparency regarding all the processes and quality metrics of panels, including limitations, is vital in reaching a successful molecular genetic diagnosis.

Analytic validation data:

  • Mean sequencing depth at nucleotide level 174x
  • 99.7% sensitivity and 99.9% specificity for single nucleotide variation (SNV) detection, and 97.1% sensitivity for INDEL detection (1-50 bps INDELs)
  • Best-in-class sensitivity for detecting copy number variation (CNV), with 92.3% sensitivity to detect 1 exon deletions and 100% sensitivity to detect 2 exon level deletions and duplications

Further information
Chief Medical Officer Juha Koskenvuo,
Communication Manager Juulia Simonen, tel. +358503059018,

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