Approved Research

Identification of phenotypic associations of rare variants in genes predisposing to rare inherited disorders in UK Biobank exome and genome data.

Lay summary

Part of the chance of whether we are likely to get cancer or develop a rare disease is locked in our DNA, in small packages of genetic information called genes. We can determine the sequence of DNA that makes up these genes using techniques that cover the genes only (exome sequencing) or all of the genome (genes and the DNA in between genes). When we compare the gene sequences between unrelated individuals, we can find numerous differences. Most of these alterations have no impact on health but some rare changes can lead to inherited disorders. A major challenge for medical researchers is determining which rare changes will cause a specific inherited condition. Comparing the genetic changes in individuals diagnosed with an inherited condition and those reported to be healthy is a standard approach to understanding which genes and genetic alterations cause disease. However, for rare variants this can be challenging. So to get a better picture about which changes do and do not cause ill health, it is very helpful to study DNA sequences from large numbers of people and compare the genetic findings (and their medical details) to those in individuals who have been diagnosed with (or suspected of) an inherited condition. We will be comparing genetic alterations between different individuals across a range of inherited conditions to better understand the relationship between gene variants and risk of an inherited condition. The proposed study will last for at least three years.

The aim of our research is to be able to confidently say that a particular genetic alteration causes a specific condition. This information can then be used within NHS genetic testing laboratories to enable earlier diagnosis of inherited disorders, which enables interventions to reduce ill health in those individuals who are at risk of developing the disease.