Exome sequencing as a diagnostic tool in a case of undiagnosed juvenile-onset GM1-gangliosidosis

Tyler Mark Pierson, David A. Adams, Thomas Markello, Gretchen Golas, Sandra Yang, Murat Sincan, Dimitre R. Simeonov, Karin Fuentes Fajardo, Nancy F. Hansen, Praveen F. Cherukuri, Pedro Cruz, Jamie K. Teer, James C. Mullikin, Cornelius F. Boerkoel, William A. Gahl, Cynthia J. Tifft

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Objective: To utilize high-throughput sequencing to determine the etiology of juvenile-onset neurodegeneration in a 19-year-old woman with progressive motor and cognitive decline. Methods: Exome sequencing identified an initial list of 133,555 variants in the proband's family, which were filtered using segregation analysis, presence in dbSNP, and an empirically derived gene exclusion list. The filtered list comprised 52 genes: 21 homozygous variants and 31 compound heterozygous variants. These variants were subsequently scrutinized with predicted pathogenicita programs and for association with appropriate clinical syndromes. Results: Exome sequencing data identified 2 GLB1 variants (c.602G>A, p.R201H; c.785G>T, p.G262V). β-Galactosidase enzyme analysis prior to our evaluation was reported as normal; however, subsequent testing was consistent with juvenile-onset GM1-gangliosidosis. Urine oligosaccharide analysis was positive for multiple oligosaccharides with terminal galactose residues. Conclusions: We describe a patient with juvenile-onset neurodegeneration that had eluded diagnosis for over a decade. GM1-gangliosidosis had previously been excluded from consideration, but was subsequently identified as the correct diagnosis using exome sequencing. Exome sequencing can evaluate genes not previously associated with neurodegeneration, as well as most known neurodegeneration-associated genes. Our results demonstrate the utilita of "agnostic" exome sequencing to evaluate patients with undiagnosed disorders, without prejudice from prior testing results.

Original languageEnglish (US)
Pages (from-to)123-126
Number of pages4
JournalNeurology
Volume79
Issue number2
DOIs
StatePublished - Jul 10 2012

ASJC Scopus subject areas

  • Clinical Neurology

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    Pierson, T. M., Adams, D. A., Markello, T., Golas, G., Yang, S., Sincan, M., Simeonov, D. R., Fajardo, K. F., Hansen, N. F., Cherukuri, P. F., Cruz, P., Teer, J. K., Mullikin, J. C., Boerkoel, C. F., Gahl, W. A., & Tifft, C. J. (2012). Exome sequencing as a diagnostic tool in a case of undiagnosed juvenile-onset GM1-gangliosidosis. Neurology, 79(2), 123-126. https://doi.org/10.1212/WNL.0b013e31825f047a