We have invented a computational system that uses the genetic information of two prospective parents to determine the risk of disease in potential children. Our method computes a Variant Gene Dysfunction (VGD) score for every variant found in each parent. These scores are subsequently used to generate thousands of digitally simulated genomes, or Virtual Progeny, to quantify a family’s risk of passing on a serious heritable disease to a future child.
A conventional carrier test has only two outcomes based on the outdated assumption that every DNA variant is either disease-causing or benign. GenePeeks integrates data from multiple sources to compute the degree to which any variant, known or novel, reduces normal gene function. The combination of Variant Gene Dysfunction (VGD) scores found in a virtual progeny provides an estimate of disease likelihood and severity.
Genetic test results are typically limited to two possible outcomes: positive or negative. By treating variant pathogenicity as an all-or-none phenomenon, the impact of allelic heterogeneity on disease severity, penetrance and expressivity can be lost. To generate our VGD scores, variant attributes from a diverse set of publicly available resources are combined in a novel process to compute a single summary damage score for each variant.
Each of the variant-characterizing data sources is a node in our network; we integrate them together with a weighted sum, utilizing variant-specific weights to quantify our confidence in each statistic.
Virtual Progeny Analytics (VPA) simulates human reproduction by creating “virtual sperm” and “virtual egg” DNA sequences that are then combined to create novel genomes called “virtual progeny” (VP). Each VP is examined for potentially dysfunctional genes to assess a couple’s risk of conceiving a child with disease. By targeting the genomes of hypothetical children, we interpret disease at the level at which it may occur.
VPA is the only method that creates virtual genomes of hypothetical children to evaluate the combined reproductive risk of two potential parents. This innovative approach allows us to overcome the limitations of carrier screening by: (1) quantifying the gene effects of variants, most of which are not found in the clinical literature and (2) integrating the total variant impact on gene function rather than examining variants in isolation.
The VP process quantifies the level of gene dysfunction in digital offspring genomes. For every analyzed gene in each VP, we accumulate the disease risk quantified by VGD and evaluate the corresponding gene product’s functionality. Importantly, we calibrate the combined allele dysfunction relative to the scoring distribution of clinically validated variants within the same gene to account for differing levels of gene tolerance.
The GenePeeks Preconception Screen examines a set of genes that are associated with over 1000 life-threatening or life-altering genetic diseases. Rather than a targeted mutation screen, we use next-generation sequencing to analyze the entire coding region of every gene, covering millions of DNA positions.View List
In the spirit of sharing information and advancing the progress and practice of human genetics, we created the publicly accessible GenePeeks Research Browser (GPRB). GPRB is an interactive web application intended for comprehensive variant, gene, and disease curation. The centerpiece of GPRB is a novel graphic display integrating population and clinical data with Variant Gene Dysfunction (VGD) scores.View Browser