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

Aryun Kim, Kishore R. Kumar, 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

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)781-790
Number of pages10
JournalCerebellum
Volume18
Issue number4
DOIs
StatePublished - 15 Aug 2019

Fingerprint

Cerebellar Ataxia
Paraplegia
Genome
Hereditary Spastic Paraplegia
Overlapping Genes
Spinocerebellar Degenerations
Ataxia
Nucleotides
Phenotype
Genes
Spastic Ataxia

Keywords

  • Ataxia
  • Cerebellar
  • Diagnosis
  • Hereditary spastic paraplegia
  • Spastic
  • Whole-genome sequencing

Cite this

Kim, Aryun ; Kumar, Kishore R. ; Davis, Ryan L. ; Mallawaarachchi, Amali C. ; Gayevskiy, Velimir ; Minoche, Andre E. ; Walls, Zachary ; Kim, Han-Joon ; Jang, Mihee ; Cowley, Mark J. ; Choi, Ji Hyun ; Shin, Chaewon ; Sue, Carolyn M. ; Jeon, Beomseok. / Increased Diagnostic Yield of Spastic Paraplegia with or Without Cerebellar Ataxia Through Whole-Genome Sequencing. In: Cerebellum. 2019 ; Vol. 18, No. 4. pp. 781-790.
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abstract = "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.",
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author = "Aryun Kim and Kumar, {Kishore R.} and Davis, {Ryan L.} and Mallawaarachchi, {Amali C.} and Velimir Gayevskiy and Minoche, {Andre E.} and Zachary Walls and Han-Joon Kim and Mihee Jang and Cowley, {Mark J.} and Choi, {Ji Hyun} and Chaewon Shin and Sue, {Carolyn M.} and Beomseok Jeon",
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Kim, A, Kumar, KR, Davis, RL, Mallawaarachchi, AC, Gayevskiy, V, Minoche, AE, Walls, Z, Kim, H-J, Jang, M, Cowley, MJ, Choi, JH, Shin, C, Sue, CM & Jeon, B 2019, 'Increased Diagnostic Yield of Spastic Paraplegia with or Without Cerebellar Ataxia Through Whole-Genome Sequencing', Cerebellum, vol. 18, no. 4, pp. 781-790. https://doi.org/10.1007/s12311-019-01038-0

Increased Diagnostic Yield of Spastic Paraplegia with or Without Cerebellar Ataxia Through Whole-Genome Sequencing. / Kim, Aryun; Kumar, Kishore R.; Davis, Ryan L.; Mallawaarachchi, Amali C.; Gayevskiy, Velimir; Minoche, Andre E.; Walls, Zachary; Kim, Han-Joon; Jang, Mihee; Cowley, Mark J.; Choi, Ji Hyun; Shin, Chaewon; Sue, Carolyn M.; Jeon, Beomseok.

In: Cerebellum, Vol. 18, No. 4, 15.08.2019, p. 781-790.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Increased Diagnostic Yield of Spastic Paraplegia with or Without Cerebellar Ataxia Through Whole-Genome Sequencing

AU - Kim, Aryun

AU - Kumar, Kishore R.

AU - Davis, Ryan L.

AU - Mallawaarachchi, Amali C.

AU - Gayevskiy, Velimir

AU - Minoche, Andre E.

AU - Walls, Zachary

AU - Kim, Han-Joon

AU - Jang, Mihee

AU - Cowley, Mark J.

AU - Choi, Ji Hyun

AU - Shin, Chaewon

AU - Sue, Carolyn M.

AU - Jeon, Beomseok

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