Approved Research

Functional-genomic characterization of telomere biology disorders

Lay summary

Telomeres are repetitive sequences at the ends of DNA that progressively shorten as we age and our cells divide. Multiple proteins help to ensure proper replication and maintenance of telomeres throughout life. Inherited mutations that impair proper telomere maintenance lead to accelerated aging and an increased risk of blood cancers. This group of conditions is collectively referred to as telomere biology disorders (TBD). We have previously found that TBDs are clinically under-recognized, and we have developed laboratory tools to identify individuals with telomere-associated gene variants with decreased function. The impact of telomere biology disorder among individuals without a known a telomere biology disorder is unknown. Furthermore, the ways by which patients with TBD patients develop blood cancers has not been studied in detail.

In Aim 1, we will identify individuals in UKBiobank with inherited genetic variants in the telomere gene TERT and determine how well these variants are able to extend telomeres in cells. We will then assess whether individuals with TERT variants that have decreased function have unique characteristic or medical conditions compared to individuals who do not have an impaired TERT variant.

In Aim 2, we will identify a group of individuals who likely have a telomere biology disorder based on specific genetic characteristics. We will then test if this group of patients are more likely to have detected blood mutations, referred to as clonal hematopoiesis, that carry an increased risk of progression to blood cancers. Lastly, we will determine the proportion of likely TBD patients who developed a blood cancer and the specific gene mutations most associated with the risk of blood cancer.

Scientific rationale: Interpreting genetic variants is a central challenge across biomedical disciplines, and assessment of a genetic variant's function is essential to determining if it contributes to a particular disease. Our approach allows us to determine the function of any TERT variant and our data will greatly enhance the interpretation of TERT variants observed in patients. Additionally, our work will identify the ways by which patients with TBD develop blood cancers and facilitate new ways to identify and treat blood cancers at the earliest possible timepoint to improve patient survival.

Project duration: The duration of this project will be 3 years.

Public health impact: A broader understanding of the impact of inherited telomere gene mutations on human disease will facilitate improved diagnosis, monitoring, and treatment of patients with telomere biology disorders.