Maternal mosaicism for a second mutational event--a novel deletion--in a familial adenomatous polyposis family harboring a new germ-line mutation in the alternatively spliced-exon 9 region of APC.

Familial Adenomatous Polyposis (FAP) is an autosomal dominant heritable disorder caused by germ-line mutations in the APC gene. To date, more than 300 germ-line mutations within this gene have been described. Using PCR, SSCP and DNA sequencing, we have identified a new mutation in the alternatively spliced region of exon 9 (1042C-->T), which results in a stop signal. This mutation manifested an aggressive form of FAP with onset of symptoms in one proband at age 17. Our results differ from reported exon 9 mutations in the spliced-out portion of the gene manifesting an attentuated form of FAP (AAPC) [Varesco et al 1994; van der Luijt et al. 1995; Curia et al. 1998; Young et al. 1998]. When analyzing this family, we encountered a mutant FAP gene which had undergone a second mutational event, a deletion. In addition to linkage analysis, both the occurrence of the two exon 9 mutation-carrier siblings, of which one is affected, harboring the same novel deletion in one generation of this family, and its absence in both parents indicates the existence of maternal germ-line mosaicism for cells bearing the latter second mutational event. Our study is only the second report of parental mosaicism in the APC gene.