RationalCNVTM Analysis Provides Medical Relevance to Variants of Unknown Significance and Novel Variants*
*FOR RESEARCH USE ONLY
About Chromosomal Microarray Analysis
Chromosomal microarray analysis (CMA) is a method of measuring copy number variants (CNVs) – gains and losses of DNA – throughout the human genome. It is a whole-genome screening method that, by the use of a chip called a microarray, can identify major chromosomal abnormalities as well as the location and type of specific genetic changes that are too small to be detected microscopically. It is considered to be a first-tier test in the genetic evaluation of infants and children with unexplained intellectual disability and/or congenital anomalies.
"The vast majority of children with an abnormal phenotype don't receive a diagnosis based on today's cytogenetic testing. The only thing parents of these children want is a diagnosis, even if it is unknown and even if the diagnosis is not medically actionable today."
– KOL, Harvard Medical School
Today’s microarray-based cytogenetic diagnostics (CMAs) are focused on ~200 known syndromes, yet only ~15% of patients that have an abnormality can be identified or confirmed (i.e., the diagnostic yield is only 15%). Thus, 85% of cytogenetic testing leaves families without answers and without information that can lead to better care, treatment and understanding of the disorder.
What Does a Clinician Do if Their Patient’s CMA Test is Negative?
They are faced with a dilemma – what do they do next? There are currently two other options, exome sequencing and whole genome sequencing, both of which are expensive ($5-10K and $15-20K, respectively) and whose results are very complex to interpret. Exome sequencing does not effectively detect CNVs, nor can it detect variations in DNA in the majority of a gene’s sequence (introns) or in sequence between genes (previously termed ‘junk DNA’ but now known to contain regions that control gene expression). Whole genome sequencing does not effectively detect CNVs, and interpreting the additional data on introns and intergenic regions is essentially impossible with today’s research resources (e.g., 1000genomes data).
PB provides researchers / clinicians an opportunity to potentially double the diagnostic yield of a CMA to 30% and perhaps up to 50%. In fact, most clinicians are pragmatic and would prefer to exhaust all options at the CMA testing level before having to consider any method of sequencing because sequencing is fraught with complexity and high cost. PB’s higher diagnostic yield is achieved by using a higher resolution microarray, novel analysis methods, and its proprietary CNV data on normal subjects (apparently healthy controls) – the Normal Variation Engine® database. RationalCNVTM analysis quickly and inexpensively differentiates benign variants from pathological ones.
Providing Meaning to Variants of Unknown Significance (VUS) and Novel Variants
Our high resolution RationalCNVTM analysis reveals two categories of results: 1) better interpretation of VUS found in prior CNV analyses and 2) novel CNVs that are of potential significance to the patient's condition. With the combination of our high-resolution microarray analysis and Normal Variation Engine® interpretation, we can often fine-map a VUS and provide additional details on its potential significance. We can also uncover novel CNVs of smaller size and in genomic regions not surveyed by standard CMAs. Of particular note is our ability to identify small CNVs in genes with known disease association. Our RationalCNVTM analysis also uncovers novel variants that cannot be found with exome sequencing (and when detected via whole genome sequencing cannot be rationally interpreted), such as CNVs within intronic and intergenic regions, which are increasingly found to contain important regulatory sites that influence gene expression or protein structure (e.g., an intronic deletion may be causing aberrant splicing or preclude the binding of transcription factors).
How to Access RationalCNVTM Analysis
If you are a medical geneticist who routinely sees patients that remain undiagnosed after CMA testing, or if you have already pursued exome sequencing and received a negative result, RationalCNVTM analysis may provide an answer. To collaborate with PB on this research use only product / service, you can arrange to send us anonymized DNA samples by contacting us at firstname.lastname@example.org.