Approved Research

Validation of variant pathogenicity and penetrance for genetic screening applications

Lay summary

Rare diseases can be difficult to recognize, with patients spending an average of 4.8 years to receive an accurate diagnosis (Engel et al., 2013). Rare diseases that are caused by variants in the sequence of a single gene can be identified by genetic sequencing. Sequencing the entire genome, or all segments coding for proteins, can be used to screen for these rare genetic diseases in the general population. To be successful, this genetic screening must be able to identify a wide array of pathogenic genetic variants (i.e., have high sensitivity), while also excluding variants that are benign or have low penetrance (i.e., have high specificity). These two criteria are often in tension, however, as the scientific evidence supporting the pathogenicity genetic variants can be ambiguous.

Our aim is to improve the specificity of genetic screening using the UK Biobank's sequencing and diagnostic data. We will examine the sequencing data to determine if variants reported to be pathogenic occur in the population with a frequency that is too high given the prevalence of the disease. We will also examine clinical records to see whether individuals with a supposed disease-causing combination of variants actually have signs of the disease. These two pieces of evidence can reveal whether a given variant may be inappropriate to include in a genetic screen, because it may lead to disease only infrequently or not at all.

Our initial study will be carried out over the course of one year, but we will continue to update the results over the course of several years as additional sequencing data and analyses continue to be added to UK Biobank. By increasing the specificity of genetic screening, our study will enable healthcare providers to efficiently identify patients with rare genetic disease while avoiding potentially costly and stressful misdiagnoses.