Instability of the EPM1 minisatellite

Inherited mutations in the cystatin B gene (CSTB) are responsible for progr essive myoclonus epilepsy type 1 (EPM1; MIM 254800), This autosomal recessi ve disease is characterized by variable progression Ito mental retardation, dementia and ataxia, The majority of EPM1 alleles identified to date conta in expansions of a dodecamer repeat located upstream of the transcription s tart site of the CSTB gene, Normal alleles contain two or three copies of t he repeat, whereas pathogenic alleles contain >40 repeats, We examined the meiotic stability of pathogenic, expanded EPM1 alleles from 17 EPM1 familie s by employing a fluorescence-based PCR-based genotyping assay capable of d etecting single dodecamer repeat unit differences on an automated DNA seque ncer. We followed 74 expanded allele transmissions to 30 affected individua ls and 22 carriers. Thirty-five of 74 expanded allele transmissions demonst rated either contraction or expansion of the minisatellite, typically by a single repeat unit, Thus expanded alleles of the EPM1 minisatellite demonst rate a mutation rate of 47%, the highest yet observed for pathogenetic alle les of a human minisatellite.