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Partner Group: Bujakowska - Massachusetts Eye and Ear (Research Grant awardee)


Investigating the role of rare variants of unknown significance on aberrant splicing

Genetic diagnoses of rare diseases are hindered by our limited understanding of gene function and uncertain pathogenicity of the identified variants. Variants of unknown significance require functional validations to understand their effects on the gene function. However since genome sequencing of rare disease cases can yield 100s of such rare variants, studying them individually is challenging. One way a variant can lead to disease is by causing aberrant pre-mRNA splicing, resulting in deletion of a crucial protein domain or transcript degradation due to premature stop codons. These variants don’t always fall in the canonical splice sites but can be deeper intronic, synonymous or missense changes. Their pathogenicity is often difficult to predict even by the machine learning algorithms developed for this purpose. We propose that rare coding or non-coding variants leading to splicing aberrations are an important contributor to the unsolved rare disease cases. To address this challenge, we developed a high throughput splicing assay (HTSA), which will be used to test the effect on splicing of up to 10,000 rare variants found in the unsolved cases from the GREGoR consortium.

Date approved