Abstract
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.
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References
Harding AE. Classification of the hereditary ataxias and paraplegias. Lancet. 1983;1(8334):1151–5.
Harding AE. Clinical features and classification of inherited ataxias. Adv Neurol. 1993;61:1–14.
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.
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.
Pandolfo M. Friedreich ataxia: the clinical picture. J Neurol. 2009;256(Suppl 1):3–8.
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.
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.
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.
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.
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.
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.
Ramirez-Zamora A, Zeigler W, Desai N, Biller J. Treatable causes of cerebellar ataxia. Mov Disord. 2015;30(5):614–23.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Acknowledgements
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.
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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
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DOI: https://doi.org/10.1007/s12311-018-0969-7