| Title: | Analyzing Mendelian Disease-related Phenotypic Variability using Population-scale Data |
| Lead Institution: | University of California, San Francisco |
| Principal investigator: |
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About
DNA is like an instruction booklet for our bodies. It contains sentences, words, and single letters. This booklet is passed down from parents to children, and it shapes how our bodies grow and develop. Each booklet contains slightly different letters. Most of these genetic differences do not impact our health, but some cause serious problems. In fact, scientific studies have shown that nearly 1% of all people suffer from a disease that's caused by only one or two DNA changes. These are often called Mendelian diseases. Ideally, we would test everyone for the DNA changes that cause Mendelian diseases right after they are born. This way, we would immediately know who is at risk for these disorders. Unfortunately, this is more difficult than it sounds. Some people with DNA changes linked to Mendelian diseases never develop symptoms, and if they do, the symptoms are mild and don't start until adulthood. If we simply tested everyone for all possible Mendelian disease DNA changes at birth, then we would find many people with suspicious findings that would never develop severe symptoms. This would lead to lots of unnecessary testing, treatments, and stress for these patients and their families. As a result, testing everyone for the DNA changes that can cause Mendelian diseases is impractical. In this project, we plan to study the DNA changes that cause Mendelian diseases in greater detail using the UK Biobank. Specifically, our goal is to determine why some people with these changes develop severe symptoms while others seem relatively unaffected. To accomplish this goal, we will first measure the severity of different Mendelian disease symptoms using all the subjects in the UK Biobank. After combining this information with genetic data, we hope to find both severely and mildly affected subjects that carry DNA changes associated with these diseases. By comparing these two groups of people, we plan to identify different factors that predict whether a patient will experience mild or severe symptoms. Examples of such factors include other DNA changes, medications, and environmental exposures like smoking. If successful, our project will provide new information about why people with the same or similar DNA changes develop different symptoms. This will help us provide more personalized healthcare to patients impacted by these disorders. In addition, this information should help us perform DNA testing for Mendelian diseases in more patients, particularly those who have yet to develop symptoms.1 Publication
| Pub ID | Title | Author(s) | Year | Journal |
|---|---|---|---|---|
| 18842 | Residual allelic activity likely underlies the low rates of disease expression for predicted loss-of-function variants in population-scale biobanks | David R Blair (+1) | 2025 | American Journal of Human Genetics |
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