The Cerebellum

, Volume 18, Issue 4, pp 781–790 | Cite as

Increased Diagnostic Yield of Spastic Paraplegia with or Without Cerebellar Ataxia Through Whole-Genome Sequencing

  • Aryun Kim
  • Kishore R. KumarEmail author
  • Ryan L. Davis
  • Amali C. Mallawaarachchi
  • Velimir Gayevskiy
  • Andre E. Minoche
  • Zachary Walls
  • Han-Joon Kim
  • Mihee Jang
  • Mark J. Cowley
  • Ji-Hyun Choi
  • Chaewon Shin
  • Carolyn M. Sue
  • Beomseok Jeon
Original Paper


Inherited disorders of spasticity or ataxia exist on a spectrum with overlapping causative genes and phenotypes. We investigated the use of whole-genome sequencing (WGS) to detect a genetic cause when considering this spectrum of disorders as a single group. We recruited 18 Korean individuals with spastic paraplegia with or without cerebellar ataxia in whom common causes of hereditary cerebellar ataxia and hereditary spastic paraplegia had been excluded. We performed WGS with analysis for single nucleotide variants, small insertions and deletions, copy number variants (CNVs), structural variants (SVs) and intronic variants. Disease-relevant variants were identified in ABCD1 (n = 3), CAPN1 (n = 2), NIPA1 (n = 1) and PLA2G6 (n = 1) for 7/18 patients (38.9%). A ‘reverse phenotyping’ approach was used to clarify the diagnosis in individuals with PLA2G6 and ABCD1 variants. One of the ABCD1 disease-relevant variants was detected on analysis for intronic variants. No CNV or SV causes were found. The two males with ABCD1 variants were initiated on monitoring for adrenal dysfunction. This is one of only a few studies to analyse spastic-ataxias as a continuous spectrum using a single approach. The outcome was improved diagnosis of unresolved cases for which common genetic causes had been excluded. This includes the detection of ABCD1 variants which had management implications. Therefore, WGS may be particularly relevant to diagnosing spastic ataxias given the large number of genes associated with this condition and the relatively high diagnostic yield.


Whole-genome sequencing Spastic Ataxia Cerebellar Hereditary spastic paraplegia Diagnosis 



DNA for this study was provided by the Seoul National University Hospital Human Biobank, a member of the National Biobank of Korea, which is supported by the Ministry of Health and Welfare. All samples derived from the National Biobank of Korea were obtained with informed consent under institutional review board-approved protocols. We would like to thank Dr. Sarah Kummerfeld, Garvan Institute of Medical Research, for reviewing the manuscript.


Whole-genome sequencing was funded by a University of Sydney Kickstarter Grant awarded to KRK. RLD and MJC are supported by Early-Mid Career New South Wales Health Fellowships. CMS is supported by a National Health and Medical Research Council Practitioner Fellowship.

Compliance with Ethical Standards

All patients provided written informed consent according to the Declaration of Helsinki. The objectives and procedures of the study were approved by the institutional review board (Seoul National University Hospital: reference number 1601-048-733).

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

This article does not contain any studies with animals performed by any of the authors.

Supplementary material

12311_2019_1038_MOESM1_ESM.docx (469 kb)
ESM 1 (DOCX 469 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Aryun Kim
    • 1
  • Kishore R. Kumar
    • 2
    • 3
    • 4
    • 5
    Email author
  • Ryan L. Davis
    • 2
    • 3
  • Amali C. Mallawaarachchi
    • 6
  • Velimir Gayevskiy
    • 2
  • Andre E. Minoche
    • 2
  • Zachary Walls
    • 2
    • 7
  • Han-Joon Kim
    • 8
  • Mihee Jang
    • 9
  • Mark J. Cowley
    • 2
    • 10
    • 11
  • Ji-Hyun Choi
    • 8
  • Chaewon Shin
    • 12
  • Carolyn M. Sue
    • 3
    • 4
  • Beomseok Jeon
    • 8
  1. 1.Department of NeurologyChungbuk National University HospitalCheongju-siSouth Korea
  2. 2.Kinghorn Centre for Clinical GenomicsGarvan Institute of Medical ResearchDarlinghurstAustralia
  3. 3.Department of Neurogenetics, Kolling InstituteUniversity of Sydney Faculty of Medicine and Health Northern Clinical School and Royal North Shore HospitalSt LeonardsAustralia
  4. 4.Department of NeurologyRoyal North Shore Hospital, Northern Sydney Local Health DistrictSt LeonardsAustralia
  5. 5.Molecular Medicine LaboratoryConcord HospitalSydneyAustralia
  6. 6.Division of Genomics and EpigeneticsGarvan Institute of Medical ResearchSydneyAustralia
  7. 7.Faculty of Engineering & Information TechnologiesThe University of SydneySydneyAustralia
  8. 8.Department of Neurology, Movement Disorder Center, Seoul National University HospitalSeoul National University College of MedicineSeoulSouth Korea
  9. 9.Department of NeurologyPresbyterian Medical CenterJeonjuSouth Korea
  10. 10.St Vincent’s Clinical SchoolUNSW SydneySydneyAustralia
  11. 11.Children’s Cancer InstituteUNSW SydneySydneyAustralia
  12. 12.Department of NeurologyKyung Hee University Medical CenterSeoulSouth Korea

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