TY - JOUR
T1 - Exome sequencing as a diagnostic tool in a case of undiagnosed juvenile-onset GM1-gangliosidosis
AU - Pierson, Tyler Mark
AU - Adams, David A.
AU - Markello, Thomas
AU - Golas, Gretchen
AU - Yang, Sandra
AU - Sincan, Murat
AU - Simeonov, Dimitre R.
AU - Fajardo, Karin Fuentes
AU - Hansen, Nancy F.
AU - Cherukuri, Praveen F.
AU - Cruz, Pedro
AU - Teer, Jamie K.
AU - Mullikin, James C.
AU - Boerkoel, Cornelius F.
AU - Gahl, William A.
AU - Tifft, Cynthia J.
N1 - Funding Information:
Study funding: T.M.P., D.A., T.M., K.F.F., C.F.B., and C.T. were supported by the NIH Undiagnosed Diseases Program and T.M., G.G., S.Y., M.S., D.R.S., N.F.H., P.F.C., P.C., J.K.T., J.C.M., and W.A.G. were supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health
PY - 2012/7/10
Y1 - 2012/7/10
N2 - 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.
AB - 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.
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U2 - 10.1212/WNL.0b013e31825f047a
DO - 10.1212/WNL.0b013e31825f047a
M3 - Article
C2 - 22675082
AN - SCOPUS:84866258332
VL - 79
SP - 123
EP - 126
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 2
ER -