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Hum Mutat. 2012 Sep;33(9):1359-65. doi: 10.1002/humu.22156. Epub 2012 Aug 1.

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

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European Molecular Genetics Network (EMQN), spinocerebellar ataxias (SCAs) External Quality Assessment (EQA) Scheme organizer (JS) and assessors, Manchester, UK.


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.

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