Research question
What is the frequency and phenotypic spectrum associated with deleterious variants in genes that are known to cause monogenic disorders in UK Biobank, and what are the genetic and environmental factors that influence disease expression?
We aim to address this question for the genetic disorders that are the focus of translational and fundamental research and patient care in the Leiden University Medical Center (LUMC) in the Netherlands. These LUMC-expertise monogenic disorders include: hereditary stroke and dementia syndromes, chromatinopathies, hereditary cancer, muscle disorders and DNA-repair disorders.
Objectives
To utilize linked genetic and phenotypic information in UK Biobank in order to:
1) determine the frequency of deleterious variants in genes associated with LUMC-expertise monogenic disorders
2) determine the phenotypic spectrum associated with these deleterious variants
3) identify genetic and environmental modifiers that play a role in disease expression
Data from UK Biobank will be combined with data from LUMC in-house patient registries, and with disease-relevant external databases. In this way, the full phenotypic spectrum is included, thereby increasing the power for the detection of modifying factors.
Scientific rationale
With the increasing use of whole exome and whole genome sequencing in routine clinical care, milder phenotypes associated with variants in genes known to cause severe monogenic disorders are increasingly recognised and identified. This creates challenges for patient and family counselling, but also opportunities for understanding disease pathomechanisms and identifying modifiers. An example is the research on NOTCH3 variants performed by the LUMC under UK Biobank application no. 74162, which has resulted in improved disease prediction in the clinic through the identification of a strong genotype-phenotype correlation (Rutten et al. Neurology 2020; Hack et al. Brain 2023).