High Degree of Genetic Heterogeneity for Hereditary Cerebellar Ataxias in Australia
Genetic testing strategies such as next-generation sequencing (NGS) panels and whole genome sequencing (WGS) can be applied to the hereditary cerebellar ataxias (HCAs), but their exact role in the diagnostic pathway is unclear. We aim to determine the yield from genetic testing strategies and the genetic and phenotypic spectrum of HCA in Australia by analysing real-world data. We performed a retrospective review on 87 HCA cases referred to the Neurogenetics Clinic at the Royal North Shore Hospital, Sydney, Australia. Probands underwent triplet repeat expansion testing; those that tested negative had NGS-targeted panels and WGS testing when available. In our sample, 58.6% were male (51/87), with an average age at onset of 37.1 years. Individuals with sequencing variants had a prolonged duration of illness compared to those with a triplet repeat expansion. The detection rate in probands for routine repeat expansion panels was 13.8% (11/80). NGS-targeted panels yielded a further 11 individuals (11/32, 34.4%), with WGS yielding 1 more diagnosis (1/3, 33.3%). NGS panels and WGS improved the overall diagnostic rate to 28.8% (23/80) in 14 known HCA loci. The genetic findings included novel variants in ANO10, CACNA1A, PRKCG and SPG7. Our findings highlight the genetic heterogeneity of HCAs and support the use of NGS approaches for individuals who were negative on repeat expansion testing. In comparison to repeat disorders, individuals with sequencing variants may have a prolonged duration of illness, consistent with slower progression of disease.
KeywordsHereditary cerebellar ataxia Spinocerebellar ataxia Genetics Triplet repeat expansion Next-generation sequencing Whole genome sequencing
K.R.K. is supported by a NHMRC Early Career Fellowship. R.D. was supported by a NHMRC Early Career Fellowship and is now supported by a NSW Health Early Career Fellowship. MJC is supported by a NSW Health Early Career Fellowship. We would like to thank the participating patients and referring clinicians. We would like to acknowledge the following laboratories for performing genetic testing; Molecular Medicine Laboratory Concord Hospital, Centogene, Oxford Molecular Genetics Laboratory and Genome.One.
Compliance with Ethical Standards
Disclosure of Conflict of Interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
- 3.Bird TD. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al., editors. Hereditary Ataxia Overview. Seattle: GeneReviews((R)); 1993.Google Scholar
- 13.Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24.CrossRefGoogle Scholar
- 14.Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A, et al. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline. Curr Protoc Bioinformatics. 2013;43:11 0 1–33.Google Scholar
- 16.Gayevskiy V, Roscioli T, Dinger ME, Cowley MJ. Seave: a comprehensive web platform for storing and interrogating human genomic variation. Bioinformatics, bty540. bioRxiv. https://doi.org/10.1101/258061.
- 17.Census: Australian Bureau of Statistics, 2016, Census of population and housing: Australia revealed, cat. no. 2024.0, viewed 28 June 2018, http://www.abs.gov.au/ausstats/abs@.nsf/Latestproducts/2024.0Main%20Features22016.
- 22.Millat G, Bailo N, Molinero S, Rodriguez C, Chikh K, Vanier MT. Niemann-Pick C disease: use of denaturing high performance liquid chromatography for the detection of NPC1 and NPC2 genetic variations and impact on management of patients and families. Mol Genet Metab. 2005;86(1–2):220–32.CrossRefGoogle Scholar
- 32.Garden G. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, LJH B, Stephens K, et al., editors. Spinocerebellar Ataxia Type 7. Seattle: GeneReviews((R)); 1993.Google Scholar
- 33.Patterson M. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al., editors. Niemann-Pick Disease Type C. Seattle: GeneReviews((R)); 1993.Google Scholar