Pathological mutations occurring within the extended consensus sequences of exon-intron splice junctions account for ~10 per cent of all inherited lesions logged in The Human Gene Mutation Database (HGMD®; http://www.hgmd.org)[1] and are frequently encountered in mutation screening studies [2]. Mutations residing in other intronic locations (including the canonical branch-point sequence,[3] 5'-YURAY-3'), however, may often go undetected unless patient RNA can be analysed and the mutations in question induce aberrant splicing (eg exon skipping or cryptic splice site utilisation) that is readily distinguishable qualitatively or quantitatively from normal (and/or normal alternative) splicing. Indeed, introns probably represent a substantially larger mutational target than has hitherto been appreciated, on account of their containing a multiplicity of functional elements, including intron splice enhancers and silencers that regulate alternative splicing,[4,5]trans-splicing elements [6] and other regulatory elements, some of which may be deeply embedded within very large introns [7].
