Poster Presentation 43rd Lorne Genome Conference 2022

Identification of a novel chromosome 14 deletion/duplication in a large Australian pedigree presenting with autosomal dominant slowly progressive late onset ataxia (#248)

Haloom Rafehi 1 2 , Melanie Bahlo 1 2 , Rick Tankard 1 2 , Miriam F Fernandez 3 4 , Robert JM Gardner 5 , Elston Storey 6 7 , Trent Burgess 4 , Amber Boys 4 , Michael Fahey 7 8 , Greta Gillies 3 , Stephen Robertson 5 , Martin Delatycki 2 3 4 7 , Paul J Lockhart 2 3
  1. Population Health and Immunity, WEHI, Parkville, Victoria, Australia
  2. Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
  3. Bruce Lefroy Centre, Murdoch Children’s Research Institute, Parkville, Victoria, Australia
  4. Victorian Clinical Genetics Services, Parkville, Victoria, Australia
  5. University of Otago, North Dunedin, Dunedin, New Zealand
  6. Alfred Hospital, Prahran, Victoria, Australia
  7. Monash University, Clayton, Victoria, Australia
  8. Monash Health, Clayton, Victoria, Australia

The spinocerebellar ataxias (SCAs) are a heterogenetic group of genetic neurological disorders. In this study, we perform genetic investigations in a multigenerational Australian pedigree with mid- to late-onset of autosomal-dominant inheritance relatively pure, slowly evolving ataxia. Three distinct branches of the family were independently ascertained, and linked following the identification of a large duplication/deletion on chr14 (14q32.13) using chromosome microarray. The duplication region is 0.33Mb, and the deletion is 0.16Mb in size. Subsequent linkage analysis identified a single linkage region with LOD of 3.0 which intersected this deletion/duplication.  There are 7 number of genes in the duplication, and three genes in the deletion. RNA-seq analysis on fibroblasts obtained from two second degree-relative with ataxia identified increased expression of the gene GLRX5, which is located in the duplication region, compared to unrelated sex and age matched controls. GLRX5 is also highly expressed in the brain, including the cerebellum and is the strongest candidate gene identified. In conclusion, this is a novel (relatively) pure adult-onset autosomal dominant cerebellar ataxia, caused by a mutation on chr14, although the responsible gene is yet to be determined.