A deep intronic mutation in CDKN2A is associated with disease in a subset of melanoma pedigrees.

Germline mutations of CDKN2A at 9p21 have been shown to predispose to disease in melanoma pedigrees worldwide. However, there remains a significant proportion of melanoma pedigrees with evidence of linkage to 9p21 in which mutations in CDKN2A have not been detected. Investigation of other potential tumour suppressor genes at 9p21 and the promotor of CDKN2A has been unable to explain genetic predisposition to melanoma in these pedigrees. Here we describe a mutation, IVS2-105 A/G, deep in intron 2 of CDKN2A, detected in six English melanoma pedigrees. The mutation creates a false GT splice donor site 105 bases 5' of exon 3 and has been demonstrated to result in aberrant splicing of the mRNA. This is the most common mutation identified in English families to date. The presence of this deep intronic mutation in a relatively large number of kindreds, indicates that it may account for a significant proportion of 9p21-linked melanoma pedigrees with no detectable mutations in the coding region of CDKN2A. In addition, the identification of one deep intronic mutation in CDKN2A indicates the possibility of the existence of other similar splicing mutations located elsewhere in the CDKN2A introns.