Acronym: PAAGE
Data controller: Brain Institute
Study coordinator: Alexandra DURR
Spinocerebellar degenerations are rare hereditary neurodegenerative diseases. These disorders constitute a broad clinico-genetic spectrum with more than 150 causal genes identified. Despite advances in high-throughput sequencing, the causal mutation remains unknown in nearly half of all families. Moreover, the marked clinical heterogeneity—sometimes even for the same variant within a single family—has prompted the search for genetic modifiers that modulate the phenotypic expression of a pathogenic variant.
The aim of this project is to identify new types of pathogenic variants as well as modifier variants involved in spinocerebellar degenerations through genome sequencing.
Genome sequencing is effective for detecting most known variants, which typically consist of base substitutions or small insertions/deletions in the coding sequence or at intron–exon junctions. Larger structural variants, repeat-expansion mutations, and mobile-element insertions (transposons) are rarely analyzed during conventional genome reading but can be detected through specific processing of short-read sequencing data. More generally, variants located in non-coding intronic and intergenic regions remain difficult to interpret, but progress in understanding gene-regulatory and epigenetic mechanisms is improving their characterization.
We propose to search for these variants in unresolved genomes and to build on the team’s expertise in bioinformatic approaches and clinico-genetic knowledge of spinocerebellar degenerations to select the best candidate variants.
Genetic modifier variants of pathogenic variants—either previously identified or discovered during this research project—will also be investigated. These modifiers are of particular interest for identifying therapeutic avenues aimed at modulating the severity of the effect of a causal pathogenic variant.