Spinocerebellar ataxias: An example of the challenges associated with genetic databases for dynamic mutations

Authors

  • Joanne E. Martindale,

    1. European Molecular Genetics Network (EMQN), spinocerebellar ataxias (SCAs) External Quality Assessment (EQA) Scheme organizer (JS) and assessors (JEM, SS, SW, JS), Manchester, UK
    2. Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Western Bank, Sheffield, UK
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  • Sara Seneca,

    1. European Molecular Genetics Network (EMQN), spinocerebellar ataxias (SCAs) External Quality Assessment (EQA) Scheme organizer (JS) and assessors (JEM, SS, SW, JS), Manchester, UK
    2. UZ Brussel, Center for Medical Genetics, Research Group Reproduction and Genetics, Vrije Universiteit Brussel (VUB), Brussels, Belgium
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  • Stefan Wieczorek,

    1. European Molecular Genetics Network (EMQN), spinocerebellar ataxias (SCAs) External Quality Assessment (EQA) Scheme organizer (JS) and assessors (JEM, SS, SW, JS), Manchester, UK
    2. Human Genetics, Ruhr-University, Bochum, Germany
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  • Jorge Sequeiros

    Corresponding author
    1. European Molecular Genetics Network (EMQN), spinocerebellar ataxias (SCAs) External Quality Assessment (EQA) Scheme organizer (JS) and assessors (JEM, SS, SW, JS), Manchester, UK
    2. IBMC—Institute for Molecular and Cell Biology; and ICBAS, Universidade do Porto, Porto, Portugal
    • UnIGENe, IBMC, R. Campo Alegre 823, 4150-180 Porto, Portugal
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  • For the Databases in Neurogenetics Special Issue

  • This work was funded in part by FEDER through the Operational Competitiveness Programme – COMPETE and by national funds through FCT – Funda¸ão para a Ciência e a Tecnologia under the project FCOMP-01-0124-“FEDER-022718 (PEst-C/SAU/LA0002/2011)”

Abstract

Locus-specific databases are an important source of information for diagnostic laboratories and a valued means of improving quality of genetic testing. Although increasingly frequent, databases for oligonucleotide repeat expansions are still scarce, due to factors that make them different and the building of databases much more difficult. Definition of what constitutes “the repeat” to measure is not a simple matter and correct sizing is not always straightforward. Reference ranges and penetrance classes are not easy to establish. Acceptable margins of error depend on the disease and allele-size distribution, and vary according to size range and pathogenic significance. Inter- and intralaboratorial variance is well documented and allele distribution may vary among populations. The spinocerebellar ataxias, used only as an example of those difficulties, are also a highly heterogeneous group, which includes loci with both pathogenic repeat expansions and point mutations or insertions/deletions. They display a variable, but often overlapping phenotype, where genotype–phenotype correlation is difficult or nonexistent. Standard (Human Genome Variation Society) nomenclature is not appropriate for oligonucleotide repeats, as established at harmonization among all EMQN (European Molecular Genetics Network) external quality assessment (EQA) schemes for “repeat disorders.” Curation of such databases is a difficult task, but one that needs to be addressed adequately and without much delay. Hum Mutat 33:1359–1365, 2012. © 2012 Wiley Periodicals, Inc.

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