Description of a novel deep intronic GAA•TTC repeat expansion in FGF14 as a common cause of late-onset cerebellar ataxia

Late-onset cerebellar ataxias (LOCAs) are genetically heterogeneous neurodegenerative disorders characterized by progressive cerebellar dysfunction manifesting after age 30. A large proportion of cases remain undiagnosed due to limitations in detecting non-coding repeat expansions using standard short-read sequencing technologies. This thesis aimed to identify the genetic basis of unsolved familial LOCAs using advanced genetic technologies. Short-read genome sequencing and ExpansionHunter Denovo analysis in six French-Canadian individuals from three families revealed a novel heterozygous GAA•TTC repeat expansion in the first intron of FGF14, which was subsequently validated by targeted long-read nanopore sequencing in 128 LOCA patients from diverse populations. A pathogenic threshold of (GAA•TTC)≥250 was established, with strong associations observed in French-Canadian (OR 105.60, P