Copy number variation in pediatric multiple sclerosis

J. P. McElroy, L. B. Krupp, B. A. Johnson, Jacob L McCauley, Z. Qi, S. J. Caillier, P. A. Gourraud, J. Yu, L. Nathanson, A. L. Belman, S. L. Hauser, E. Waubant, D. J. Hedges, J. R. Oksenberg

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: Pediatric onset multiple sclerosis (MS) accounts for 2-4% of all MS. It is unknown whether the disease shares the same underlying pathophysiology found in adult patients or an extreme early onset phenotype triggered by distinct biological mechanisms. It has been hypothesized that copy number variations (CNVs) may result in extreme early onset diseases because CNVs can have major effects on many genes in large genomic regions. Objectives and methods: The objective of the current research was to identify CNVs, with a specific focus on de novo CNVs, potentially causing early onset MS by competitively hybridizing 30 white non-Hispanic pediatric MS patients with each of their parents via comparative genomic hybridization (CGH) analysis on the Agilent 1M CGH array. Results and discussion: We identified 10 CNVs not overlapping with any CNV regions currently reported in the Database of Genomic Variants (DGV). Fifty-five putatively de novo CNVs were also identified: all but one common in the DGV. We found the single rare CNV was a private variation harboring the SACS gene. SACS mutations cause autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) disease. Additional clinical review revealed that the patient with the SACS gene CNV shared some features of both MS and ARSACS. Conclusions: This is the first reported study analyzing pediatric MS CNVs. While not yielding causal variation in our initial pediatric dataset, our approach confirmed diagnosis of an ARSACS-like disease in addition to MS in the affected individual, which led to a more complete understanding of the patient's disease course and prognosis.

Original languageEnglish
Pages (from-to)1014-1021
Number of pages8
JournalMultiple Sclerosis
Volume19
Issue number8
DOIs
StatePublished - Jul 1 2013

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Multiple Sclerosis
Pediatrics
Comparative Genomic Hybridization
Databases
Gene Dosage
Genes
Parents
Phenotype
Mutation
Research
Spastic ataxia Charlevoix-Saguenay type

Keywords

  • copy number variation
  • Multiple sclerosis
  • pediatric

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

McElroy, J. P., Krupp, L. B., Johnson, B. A., McCauley, J. L., Qi, Z., Caillier, S. J., ... Oksenberg, J. R. (2013). Copy number variation in pediatric multiple sclerosis. Multiple Sclerosis, 19(8), 1014-1021. https://doi.org/10.1177/1352458512469696

Copy number variation in pediatric multiple sclerosis. / McElroy, J. P.; Krupp, L. B.; Johnson, B. A.; McCauley, Jacob L; Qi, Z.; Caillier, S. J.; Gourraud, P. A.; Yu, J.; Nathanson, L.; Belman, A. L.; Hauser, S. L.; Waubant, E.; Hedges, D. J.; Oksenberg, J. R.

In: Multiple Sclerosis, Vol. 19, No. 8, 01.07.2013, p. 1014-1021.

Research output: Contribution to journalArticle

McElroy, JP, Krupp, LB, Johnson, BA, McCauley, JL, Qi, Z, Caillier, SJ, Gourraud, PA, Yu, J, Nathanson, L, Belman, AL, Hauser, SL, Waubant, E, Hedges, DJ & Oksenberg, JR 2013, 'Copy number variation in pediatric multiple sclerosis', Multiple Sclerosis, vol. 19, no. 8, pp. 1014-1021. https://doi.org/10.1177/1352458512469696
McElroy JP, Krupp LB, Johnson BA, McCauley JL, Qi Z, Caillier SJ et al. Copy number variation in pediatric multiple sclerosis. Multiple Sclerosis. 2013 Jul 1;19(8):1014-1021. https://doi.org/10.1177/1352458512469696
McElroy, J. P. ; Krupp, L. B. ; Johnson, B. A. ; McCauley, Jacob L ; Qi, Z. ; Caillier, S. J. ; Gourraud, P. A. ; Yu, J. ; Nathanson, L. ; Belman, A. L. ; Hauser, S. L. ; Waubant, E. ; Hedges, D. J. ; Oksenberg, J. R. / Copy number variation in pediatric multiple sclerosis. In: Multiple Sclerosis. 2013 ; Vol. 19, No. 8. pp. 1014-1021.
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abstract = "Background: Pediatric onset multiple sclerosis (MS) accounts for 2-4{\%} of all MS. It is unknown whether the disease shares the same underlying pathophysiology found in adult patients or an extreme early onset phenotype triggered by distinct biological mechanisms. It has been hypothesized that copy number variations (CNVs) may result in extreme early onset diseases because CNVs can have major effects on many genes in large genomic regions. Objectives and methods: The objective of the current research was to identify CNVs, with a specific focus on de novo CNVs, potentially causing early onset MS by competitively hybridizing 30 white non-Hispanic pediatric MS patients with each of their parents via comparative genomic hybridization (CGH) analysis on the Agilent 1M CGH array. Results and discussion: We identified 10 CNVs not overlapping with any CNV regions currently reported in the Database of Genomic Variants (DGV). Fifty-five putatively de novo CNVs were also identified: all but one common in the DGV. We found the single rare CNV was a private variation harboring the SACS gene. SACS mutations cause autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) disease. Additional clinical review revealed that the patient with the SACS gene CNV shared some features of both MS and ARSACS. Conclusions: This is the first reported study analyzing pediatric MS CNVs. While not yielding causal variation in our initial pediatric dataset, our approach confirmed diagnosis of an ARSACS-like disease in addition to MS in the affected individual, which led to a more complete understanding of the patient's disease course and prognosis.",
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AU - Hedges, D. J.

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N2 - Background: Pediatric onset multiple sclerosis (MS) accounts for 2-4% of all MS. It is unknown whether the disease shares the same underlying pathophysiology found in adult patients or an extreme early onset phenotype triggered by distinct biological mechanisms. It has been hypothesized that copy number variations (CNVs) may result in extreme early onset diseases because CNVs can have major effects on many genes in large genomic regions. Objectives and methods: The objective of the current research was to identify CNVs, with a specific focus on de novo CNVs, potentially causing early onset MS by competitively hybridizing 30 white non-Hispanic pediatric MS patients with each of their parents via comparative genomic hybridization (CGH) analysis on the Agilent 1M CGH array. Results and discussion: We identified 10 CNVs not overlapping with any CNV regions currently reported in the Database of Genomic Variants (DGV). Fifty-five putatively de novo CNVs were also identified: all but one common in the DGV. We found the single rare CNV was a private variation harboring the SACS gene. SACS mutations cause autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) disease. Additional clinical review revealed that the patient with the SACS gene CNV shared some features of both MS and ARSACS. Conclusions: This is the first reported study analyzing pediatric MS CNVs. While not yielding causal variation in our initial pediatric dataset, our approach confirmed diagnosis of an ARSACS-like disease in addition to MS in the affected individual, which led to a more complete understanding of the patient's disease course and prognosis.

AB - Background: Pediatric onset multiple sclerosis (MS) accounts for 2-4% of all MS. It is unknown whether the disease shares the same underlying pathophysiology found in adult patients or an extreme early onset phenotype triggered by distinct biological mechanisms. It has been hypothesized that copy number variations (CNVs) may result in extreme early onset diseases because CNVs can have major effects on many genes in large genomic regions. Objectives and methods: The objective of the current research was to identify CNVs, with a specific focus on de novo CNVs, potentially causing early onset MS by competitively hybridizing 30 white non-Hispanic pediatric MS patients with each of their parents via comparative genomic hybridization (CGH) analysis on the Agilent 1M CGH array. Results and discussion: We identified 10 CNVs not overlapping with any CNV regions currently reported in the Database of Genomic Variants (DGV). Fifty-five putatively de novo CNVs were also identified: all but one common in the DGV. We found the single rare CNV was a private variation harboring the SACS gene. SACS mutations cause autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) disease. Additional clinical review revealed that the patient with the SACS gene CNV shared some features of both MS and ARSACS. Conclusions: This is the first reported study analyzing pediatric MS CNVs. While not yielding causal variation in our initial pediatric dataset, our approach confirmed diagnosis of an ARSACS-like disease in addition to MS in the affected individual, which led to a more complete understanding of the patient's disease course and prognosis.

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