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.

This is a preview of subscription content, access via your institution.

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Fig. 1
Fig. 2


  1. 1.

    Harding AE. Classification of the hereditary ataxias and paraplegias. Lancet. 1983;1(8334):1151–5.

    CAS  Article  Google Scholar 

  2. 2.

    Harding AE. Clinical features and classification of inherited ataxias. Adv Neurol. 1993;61:1–14.

    CAS  PubMed  Google Scholar 

  3. 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 

  4. 4.

    Storey E, du Sart D, Shaw JH, Lorentzos P, Kelly L, McKinley Gardner RJ, et al. Frequency of spinocerebellar ataxia types 1, 2, 3, 6, and 7 in Australian patients with spinocerebellar ataxia. Am J Med Genet. 2000;95(4):351–7.

    CAS  Article  Google Scholar 

  5. 5.

    Pandolfo M. Friedreich ataxia: the clinical picture. J Neurol. 2009;256(Suppl 1):3–8.

    Article  Google Scholar 

  6. 6.

    Ruano L, Melo C, Silva MC, Coutinho P. The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology. 2014;42(3):174–83.

    Article  Google Scholar 

  7. 7.

    Nemeth AH, Kwasniewska AC, Lise S, Parolin Schnekenberg R, Becker EB, Bera KD, et al. Next generation sequencing for molecular diagnosis of neurological disorders using ataxias as a model. Brain. 2013;136(Pt 10):3106–18.

    Article  Google Scholar 

  8. 8.

    Pyle A, Smertenko T, Bargiela D, Griffin H, Duff J, Appleton M, et al. Exome sequencing in undiagnosed inherited and sporadic ataxias. Brain. 2015;138(Pt 2):276–83.

    Article  Google Scholar 

  9. 9.

    Coutelier M, Coarelli G, Monin ML, Konop J, Davoine CS, Tesson C, et al. A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies. Brain. 2017;140(6):1579–94.

    Article  Google Scholar 

  10. 10.

    Coutelier M, Hammer MB, Stevanin G, Monin ML, Davoine CS, Mochel F, et al. Efficacy of exome-targeted capture sequencing to detect mutations in known cerebellar ataxia genes. JAMA Neurol. 2018;75(5):591–99.

    Article  Google Scholar 

  11. 11.

    van de Warrenburg BP, van Gaalen J, Boesch S, Burgunder JM, Durr A, Giunti P, et al. EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood. Eur J Neurol. 2014;21(4):552–62.

    Article  Google Scholar 

  12. 12.

    Ramirez-Zamora A, Zeigler W, Desai N, Biller J. Treatable causes of cerebellar ataxia. Mov Disord. 2015;30(5):614–23.

    Article  Google Scholar 

  13. 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.

    Article  Google Scholar 

  14. 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 

  15. 15.

    Kumar KR, Wali GM, Kamate M, Wali G, Minoche AE, Puttick C, et al. Defining the genetic basis of early onset hereditary spastic paraplegia using whole genome sequencing. Neurogenetics. 2016;17(4):265–70.

    CAS  Article  Google Scholar 

  16. 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. 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.

  18. 18.

    Balreira A, Boczonadi V, Barca E, Pyle A, Bansagi B, Appleton M, et al. ANO10 mutations cause ataxia and coenzyme Q(1)(0) deficiency. J Neurol. 2014;261(11):2192–8.

    CAS  Article  Google Scholar 

  19. 19.

    Battistini S, Stenirri S, Piatti M, Gelfi C, Righetti PG, Rocchi R, et al. A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia. Neurology. 1999;53(1):38–43.

    CAS  Article  Google Scholar 

  20. 20.

    Winkelmann J, Lin L, Schormair B, Kornum BR, Faraco J, Plazzi G, et al. Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy. Hum Mol Genet. 2012;21(10):2205–10.

    CAS  Article  Google Scholar 

  21. 21.

    Lee YC, Durr A, Majczenko K, Huang YH, Liu YC, Lien CC, et al. Mutations in KCND3 cause spinocerebellar ataxia type 22. Ann Neurol. 2012;72(6):859–69.

    CAS  Article  Google Scholar 

  22. 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.

    CAS  Article  Google Scholar 

  23. 23.

    Yamamoto T, Nanba E, Ninomiya H, Higaki K, Taniguchi M, Zhang H, et al. NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C. Hum Genet. 1999;105(1–2):10–6.

    CAS  PubMed  Google Scholar 

  24. 24.

    Roxburgh RH, Marquis-Nicholson R, Ashton F, George AM, Lea RA, Eccles D, et al. The p.Ala510Val mutation in the SPG7 (paraplegin) gene is the most common mutation causing adult onset neurogenetic disease in patients of British ancestry. J Neurol. 2013;260(5):1286–94.

    CAS  Article  Google Scholar 

  25. 25.

    Ishikawa K, Durr A, Klopstock T, Muller S, De Toffol B, Vidailhet M, et al. Pentanucleotide repeats at the spinocerebellar ataxia type 31 (SCA31) locus in Caucasians. Neurology. 2011;77(20):1853–5.

    CAS  Article  Google Scholar 

  26. 26.

    Sato N, Amino T, Kobayashi K, Asakawa S, Ishiguro T, Tsunemi T, et al. Spinocerebellar ataxia type 31 is associated with “inserted” penta-nucleotide repeats containing (TGGAA)n. Am J Hum Genet. 2009;85(5):544–57.

    CAS  Article  Google Scholar 

  27. 27.

    Pedersen AG, Nielsen H. Neural network prediction of translation initiation sites in eukaryotes: perspectives for EST and genome analysis. Proc Int Conf Intell Syst Mol Biol. 1997;5:226–33.

    CAS  PubMed  Google Scholar 

  28. 28.

    Chen DH, Brkanac Z, Verlinde CL, Tan XJ, Bylenok L, Nochlin D, et al. Missense mutations in the regulatory domain of PKC gamma: a new mechanism for dominant nonepisodic cerebellar ataxia. Am J Hum Genet. 2003;72(4):839–49.

    CAS  Article  Google Scholar 

  29. 29.

    Fahey MC, Knight MA, Shaw JH, Gardner RJ, du Sart D, Lockhart PJ, et al. Spinocerebellar ataxia type 14: study of a family with an exon 5 mutation in the PRKCG gene. J Neurol Neurosurg Psychiatry. 2005;76(12):1720–2.

    CAS  Article  Google Scholar 

  30. 30.

    Vandebona H, Kerr NP, Liang C, Sue CM. SPAST mutations in Australian patients with hereditary spastic paraplegia. Intern Med J. 2012;42(12):1342–7.

    CAS  Article  Google Scholar 

  31. 31.

    Kumar KR, Blair NF, Vandebona H, Liang C, Ng K, Sharpe DM, et al. Targeted next generation sequencing in SPAST-negative hereditary spastic paraplegia. J Neurol. 2013;260(10):2516–22.

    Article  Google Scholar 

  32. 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. 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 

  34. 34.

    Jacobi H, du Montcel ST, Bauer P, Giunti P, Cook A, Labrum R, et al. Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: a longitudinal cohort study. Lancet Neurol. 2015;14(11):1101–8.

    Article  Google Scholar 

  35. 35.

    Kuo PH, Gan SR, Wang J, Lo RY, Figueroa KP, Tomishon D, et al. Dystonia and ataxia progression in spinocerebellar ataxias. Parkinsonism Relat Disord. 2017;45:75–80.

    Article  Google Scholar 

  36. 36.

    Galatolo D, Tessa A, Filla A, Santorelli FM. Clinical application of next generation sequencing in hereditary spinocerebellar ataxia: increasing the diagnostic yield and broadening the ataxia-spasticity spectrum. A retrospective analysis. Neurogenetics. 2018;19(1):1–8.

    CAS  Article  Google Scholar 

Download references


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.

Author information



Corresponding author

Correspondence to Kishore R. Kumar.

Ethics declarations

Disclosure of Conflict of Interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Electronic supplementary material


(DOC 319 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kang, C., Liang, C., Ahmad, K.E. et al. High Degree of Genetic Heterogeneity for Hereditary Cerebellar Ataxias in Australia. Cerebellum 18, 137–146 (2019). https://doi.org/10.1007/s12311-018-0969-7

Download citation


  • Hereditary cerebellar ataxia
  • Spinocerebellar ataxia
  • Genetics
  • Triplet repeat expansion
  • Next-generation sequencing
  • Whole genome sequencing