Exome sequencing as a diagnostic tool in a case of undiagnosed juvenile-onset GM1-gangliosidosis.
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 pathogenicity 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 utility of "agnostic" exome sequencing to evaluate patients with undiagnosed disorders, without prejudice from prior testing results.
NIH Undiagnosed Diseases Program, NIH Office of Rare Diseases Research, Neurogenetics Branch, Bethesda, MD, USA. Tyler.Pierson@cshs.org
Tyler Mark
TM
Pierson
David A
DA
Adams
Thomas
T
Markello
Gretchen
G
Golas
Sandra
S
Yang
Murat
M
Sincan
Dimitre R
DR
Simeonov
Karin
K
Fuentes Fajardo
Nancy F
NF
Hansen
Praveen F
PF
Cherukuri
Pedro
P
Cruz
Jamie K
JK
Teer
James C
JC
Mullikin
Cornelius F
CF
Boerkoel
William A
WA
Gahl
Cynthia J
CJ
Tifft
D002648:Child; D004252:DNA Mutational Analysis / Q000379:methods*; D059472:Exome / Q000235:genetics*; D005260:Female; D016537:Gangliosidosis, GM1 / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics*; D005838:Genotype; D006801:Humans; D019636:Neurodegenerative Diseases / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics; D055815:Young Adult