What are the benefits of choosing Whole Exome Plus test that includes the analysis of del/dups (CNVs)?


Text: Tiia Luukkonen, PhD


When should you choose Whole Exome Plus testing which includes the analysis of exon level and larger deletions and duplications (del/dups)? The answer is always. In approximately 11% of the diagnostic whole exome sequencing cases we’ve interpreted, the pathogenic variant was a del/dup event. If the analysis of del/dups is omitted during the diagnostic process, there is a higher likelihood that the genetic diagnosis will remain unknown. According to Genetic Informatics Scientist, Mikko Muona, a Plus analysis including del/dups is essential for whole exome-based diagnostics as it increases the diagnostic yield and can significantly decrease the time required for the diagnostic process.

What makes Plus different from Whole Exome sequence analysis?

Most pathogenic variants underlying genetic disorders are detectable by either sequence variant analysis or by deletion/duplication (del/dup) analysis. While sequence variants, which include single nucleotide variants and small insertions and deletions, are the most common variant type, larger del/dups explain a significant proportion of patient cases. In particular, large copy number events extending to several genes are a common cause of severe syndromes with intellectual disability and/or multiple congenital structural anomalies. Furthermore, in some specific genetic disorders, del/dups explain most, if not all, mutation positive cases. Small del/dups affecting individual genes are observed throughout a wide spectrum of single gene disorders.

Importantly, many genetic changes can only be detected when del/dup analysis is included and would have been missed by classic sequence analysis alone.

Blueprint Genetics Whole Exome Plus test is a combination of both sequence and del/dup analysis, ensuring the highest diagnostic yield for your patient. Negative test results are more common when sequencing or del/dup analysis are performed on their own. Whole Exome Plus has the potential to prevent unnecessary clinical appointments, shorten the time required for the diagnostic process, and to reduce costs compared to cascade screening. Furthermore, Blueprint Genetics’ Whole Exome Plus test identifies del/dups with higher resolution than conventional microarrays (array CGH), reducing the need for multiple test approaches.

“Importantly, many genetic changes can only be detected when del/dup analysis is included and would have been missed by classic sequence analysis alone. Approximately, 4.4% of all cases seen at Blueprint Genetics, and 11% of diagnostic whole exome cases have received a diagnosis from the analysis of del/dups”, says Mikko Muona.

At a quick glance: What is del/dup (CNV)?

In clinical genetic diagnostics, deletion/duplication (del/dup) analysis is used to detect disease-causing deletions or duplications in the genome. The size of the alteration may vary from single exon (<150-1000 bps) to multiple genes, and up to chromosome level changes visible by light microscopy. Deletions and duplications with a size larger than 1,000 bases (>1 kb) are often referred to as copy-number variations (CNVs).


While the combination of sequence and del/dup analysis is generally recommended, del/dup analysis is considered an adequate first line test for disorders where the frequency of disease-causing deletions/duplications is high such as spinal muscular atrophy, certain congenital heart defects, and Duchenne/Becker muscular dystrophy. Also, testing for deletions and duplications has been found to be useful for diagnosing autosomal recessive conditions when only one variant is identified by sequence analysis.

When is it important to include del/dup (CNV) analysis in your WES test?

  • The patient is suspected of having a genetic disorder mainly caused by deletions and duplications.
  • The patient has a severe syndromic disorder with intellectual disability and/or multiple congenital structural anomalies.
  • The sequence analysis panel is negative.
  • The sequence analysis panel identifies only a single variant for an autosomal recessive disorder.


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Last modified: 12.11.2018