Rapid and reliable detection of exon rearrangements in various movement disorders genes by multiplex ligation‐dependent probe amplification

Because of the occurrence of different types of mutations, comprehensive genetic testing for Parkinson's disease (PD), dopa‐responsive dystonia (DRD), and myoclonus‐dystonia (M‐D) should include screening for small sequence changes and for large exonic rearrangements in disease‐associated genes. In diagnostic and research settings, the latter is frequently omitted or performed by laborious and expensive quantitative real‐time PCR (qPCR). Our study aimed to evaluate the utility of a novel method, multiplex ligation‐dependent probe amplification (MLPA), in molecular diagnostics of movement disorders. We have analyzed, by MLPA, genomic DNA from 21 patients affected with PD, DRD, or M‐D, in which the presence of exon rearrangement(s) (n = 20) or of a specific point mutation (detectable by MLPA, n = 1) had been established previously by qPCR or sequencing. In parallel, we have studied, in a blinded fashion, DNA from 49 patients with an unknown mutational status. Exon rearrangements were evident in 20 samples with previously established mutations; in the 21st sample the known specific point mutation was detected. We conclude that MLPA represents a reliable method for large‐scale and cost‐effective gene dosage screening of various movement disorders genes. This finding reaches far beyond a simple technical advancement and has two major implications: (1) By improving the availability of comprehensive genetic testing, it supports clinicians in the establishment of a genetically defined diagnosis; (2) By enabling gene dosage testing of several genes simultaneously, it significantly facilitates the mutational analysis of large patient and control populations and thereby constitutes the prerequisite for meaningful phenotype–genotype correlations. © 2007 Movement Disorder Society

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