Maternal mosaicism for a second mutational event, a novel deletion, might induce a more severe clinical manifestations in the siblings of a familial adenomatous polyposis family harboring a new germ-line mutation in exon 9, due to the alternative splicing

D Amikam1,4, S Davidson1, L Leshanski1, G Rennert2, S Eidelman3

1 Molecular Oncology Laboratory, Rambam Medical Center, Haifa, Israel, 2 Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel, 3Gastroenterology Institute, Rambam Medical Center, Haifa, Israel, 4Department of Biotechnology in Medicine, Tel-Hai Academic College, Tel-Hai, Israel.

Aims: Analyze and evaluate a complex and incompatible haplotype pattern in a Familial Adenomatous Polyposis family. Methods: Genotyping and APC gene mutation analysis were carried out by standard PCR-SSCP. Results: Familial Adenomatous Polyposis (FAP) is an autosomal dominant heritable disorder caused by germ-line mutations in the APC gene. Using linkage analysis, an incompatible haplotype pattern was revealed. Employing PCR, SSCP and DNA sequencing, we have identified a new germ line mutation in the alternatively spliced region of exon 9 (1042CtoT), Additionally, we encountered a mutant FAP gene which had undergone a second mutational event, a deletion. 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, an observation that clarified the incompatibility previously revealed using linkage analysis. Our results differ from reported exon 9 mutations in the spliced-out portion manifesting an attenuated form of FAP, by exhibiting an aggressive form of FAP. CONCLUSIONS: 1.The severity of the disease in the affected offspring might be expected to increase, due to the harbored deletion, producing a mutated protein from the possibly alternatively spliced wild type transcripts. 2.One could not avoid stressing the importance of using SSCP combined with linkage analyses or sequencing all offspring exons, even though a defined parental mutation is known. This could be crucial for detecting a possible parental germ-line mosaicism harbored by the offspring, dictating a plausible change in the clinical outcome of their disease and, accordingly, necessitating different genetic counseling. Our study is only the second report of parental mosaicism in the APC gene.

KEY WORDS: alternatively spliced region, exon 9, .

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Familial and Hereditary Cancer.