Decoding hidden Structural Variants in unsolved Rare Genomic Diseases

Rare Genomic Diseases (RGDs) affect >200 million individuals globally, however less than half of patients receive a molecular diagnosis, forcing millions into year-long diagnostic odysseys, and limiting the possibilities for personalized care.

New studies suggest that forms of DNA mutation affecting many base pairs of at once, so-called 'Structural Variations' (SVs) and 'Short Tandem Repeats' (STRs) may play a dominant role in the biological underpinnings of many undiagnosed RGDs.

The DETECT-SV-RD project will utilise one of the largest-to-date RD-patient datasets, containing >1,400 genomes obtained by latest long-read sequencing and optical genome mapping technologies, to identify the full spectrum of SVs and better understand their impact on disease formation.

To achieve this, a new computational workflow for detecting SVs will be developed, which will have a special focus on mutations that occur in the most complex, repeat-rich regions of the human genome.

Using these technological advances, SVs and STRs will be identified across all patients, and carefully characterized in terms of their rarity, the properties of their breakpoints and likely biological formation mechanisms.

Lastly, these insights will be combined with orthogonal 'omics' and phenotypic data to gain new insights into the underlying biology of rare diseases.

In collaboration with the diagnostic department at Radboudumc, new genetic tests for SVs and STRs will finally be implemented to improve patient care.

The project will, for the first time, assess the effect of SVs and STRs even in complex genomic regions comprehensively and provide an estimate for their involvement in the formation of RDs in general, as well as likely a better understanding of previously undiagnosed RDs.

The project will thus contribute to improving the rate of correct RD diagnoses in the future, providing substantial emotional and physical relief to affected patients and their families.