Genetic diagnosis in Lafora disease: genotype-phenotype correlations and diagnostic pitfalls.
Lafora disease (LD) can be diagnosed by skin biopsy, but this approach has both false negatives and false positives. Biopsies of other organs can also be diagnostic but are more invasive. Genetic diagnosis is also possible but can be inconclusive, for example, in patients with only one heterozygous EPM2A mutation and patients with apparently homozygous EPM2B mutations where one parent is not a carrier of the mutation. We sought to identify occult mutations and clarify the genotypes and confirm the diagnosis of LD in patients with apparent nonrecessive disease inheritance. We used single nucleotide polymorphism, quantitative PCR, and fluorescent in situ hybridization analyses. We identified large EPM2A and EPM2B deletions undetectable by PCR in the heterozygous state and describe simple methods for their routine detection. We report a coding sequence change in several patients and describe why the pathogenic role of this change remains unclear. We confirm that adult-onset LD is due to EPM2B mutations. Finally, we report major intrafamilial heterogeneity in age at onset in LD.
Lohi
H
H
Program in Genetics and Genomic Biology and Division of Neurology, Hospital for Sick Children, Toronto, Ontario, Canada.
Turnbull
J
J
Zhao
X C
XC
Pullenayegum
S
S
Ianzano
L
L
Yahyaoui
M
M
Mikati
M A
MA
Quinn
N P
NP
Franceschetti
S
S
Zara
F
F
Minassian
B A
BA
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001483:Base Sequence / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D002874:Chromosome Mapping / Q000379:methods; D004252:DNA Mutational Analysis / Q000379:methods; D003951:Diagnostic Errors / Q000517:prevention & control*; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D020192:Lafora Disease / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D016133:Polymerase Chain Reaction / Q000379:methods; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D044767:Ubiquitin-Protein Ligases
D002352:Carrier Proteins; D005819:Genetic Markers; C478960:NHLRC1 protein, human; D044767:Ubiquitin-Protein Ligases; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human