Researchers at Color have analyzed 50 genes associated with hereditary cancer and cardiovascular disorders using next-generation sequencing and identified at least 828 unique structural variants, including 584 fully characterized structural variants. These findings could help improve health-risk assessments through DNA tests.
Structural variants are a clinically important class of changes in genomic DNA that typically include large stretches of DNA that span anywhere between 50 bases to well beyond 100 kilobases. These are particularly concerning because they typically destroy a protein’s function and can be overlooked in some DNA sequencing tests that assess a person’s risk for hereditary diseases. For instance, whole exome sequencing (WES) can miss up to 80% of structural variants because the edges (breakpoints) of most structural variants are found in noncoding regions of DNA (introns).
“Our findings provide a glimpse into the genomic complexity of clinically relevant structural variants,” said Jeroen Van Den Akker, PhD, lead author and head of bioinformatics at Color. “More importantly, they clearly show that detecting structural variants should be considered an essential component of genetic testing for hereditary disorders, which can have significant implications for patients in the future.”
The findings reported in the article, “Intronic breakpoint signatures enhance detection and characterization of clinically relevant germline structural variants,” published in the Journal of Molecular Diagnostics, provides a better understanding of how structural variants can be detected in an individual’s genome and can help advance how individual risk for some diseases is calculated from genomic data.
“Genetic data can be an important preventative tool, which is why we’re committed to advancing the field,” said Alicia Zhou, CSO at Color. “We are providing individuals with the right information to make informed decisions based on the latest scientific understanding of how genomics influences certain diseases.”
This study analyzes one of the largest cohorts of clinically relevant structural variants in common hereditary disorders that are associated with single genes, the number of individuals tested differed across genes, ranging between 40,416 and 215,522. The study found that almost 40% of copy number variants were less than 5 kb, with one in three deletions affecting only a single exon.
The authors also detected 36 mid-range deletions/duplications (50–250 bp), 21 mobile element insertions, six inversions, and 27 complex rearrangements (including the breast cancer genes BRCA1 and BRCA2). The 1,328 pathogenic structural variants accounted for 14.1% of all unique pathogenic variants in this study, emphasizing the significance of structural variants in hereditary disorders.
The study also adds new insights about how to boost detection of structural variants in gene panels by targeting intronic hotspots for recombination, coupled with algorithms detecting various breakpoint signatures. Incorporating this approach into variant identification algorithms can improve risk assessment.
The authors noted that risk assessment for hereditary diseases can be improved by robust detection of structural variants. This will require algorithms that utilize intron sequences and distinct data features representative of the different types of mutational mechanisms.