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Invitae Study Reveals CNV Contributions to Pathogenic Variation in Mendelian Disease Genes

NEW YORK (GenomeWeb) – Mendelian disease genes may be more prone to deletions, duplications, or other copy number changes than previously appreciated, findings of a new study suggest.

As they reported yesterday in Genetics in Medicine, researchers from the San Francisco-based genetic testing company Invitae and the University of California at San Francisco did targeted panel sequencing on 1,507 genes in more than 143,000 de-identified individuals, tallying up the CNVs falling within the exons of monogenic disease-associated genes. Their analysis unearthed 2,844 of these intragenic CNVs, affecting 384 genes in nearly 2 percent of the individuals tested overall.

But these CNVs were over-represented in the individuals with clinically significant results, the team reported, particularly those affected by neurological conditions. From these and other data, the group got a look at the location, distribution, and consequences of CNVs in the monogenic disease genes, relative to CNVs that did not seem to contribute to the individuals' clinical phenotypes.

"This is one of the largest datasets on intragenic CNVs available in the medical genetics community," corresponding author Swaroop Aradhya, Invitae's head of medical affairs, said in a statement. "In addition to understanding their clinical prevalence, we were able to discern properties of CNVs that help us distinguish between those most likely to cause disease versus those that exist as natural variation in the human genome."

Using Invitae's next-generation sequencing panels and custom oligonucelotide-based exon capture, the researchers profiled 1,507 genes in 143,142 unrelated individuals who had been referred for diagnostic testing.

Based on fiftyfold to three hundred fiftyfold average sequence coverage of each gene, they detected 1,810 intragenic deletions and 1,034 duplications in exons from 384 genes with a bioinformatics pipeline that picked up more than 8 million variants overall — from exonic CNVs or small insertions and deletions to larger indels and structural variants.

"Our data show that a substantial number of pathogenic variants are in fact intragenic CNVs that have not been routinely investigated across a wide range of disease genes in traditional genetic testing," the authors wrote.

Almost 10 percent of individuals with clinically significant panel test results — those with one or more pathogenic or likely pathogenic variant — carried monogenic disease gene intragenic CNVs, the researchers reported, compared to 1.9 percent of individuals overall.

The exonic duplications or deletions made up as few as 4.7 percent and as many as one-third of the pathogenic mutations found in the disease-related genes, peaking at 35 percent in the neurology cases. Certain genes also appeared most prone to the intragenic CNVs: while most of the genes contained a single CNV, the team identified 31 genes with at least 15 CNVs apiece.

More broadly, the researchers noted that the CNV distribution, clinical classification, and affected exons and genes in the clinical cases were distinct from those found when they examined another 4,054 baseline CNVs in 599 clinically unrelated genes from de-identified sequence data. 

Based on these and other results, the authors noted that "clinically relevant CNVs are characteristically different from CNVs that are present as naturally existing variation in the genome."