Familial Adenomatous Polyposis (FAP [OMIM 175100]) is an autosomal dominant colorectal cancer predisposition syndrome characterized by hundreds to thousands of colonic polyps and, if untreated by a combination of screening and/or surgical intervention, a ~99% lifetime risk of colorectal cancer. A subset of FAP patients develop an attenuated form of the condition characterized by lower numbers of colonic polyps (highly variable, but generally less than 100) and a lower lifetime risk of colorectal cancer, on the order of 70%. We report the diagnosis of three attenuated FAP families due to a 1.4-kb deletion within intron 14 of the APC, originally reported clinically as a variant of unknown significance (VUS). Sequence analysis suggests that this arose through an Alu-mediated recombination event with sequences from chromosome 6q22.1. This mutation tracks to members who presented with an attenuated FAP phenotype, with variable age of onset and severity. Sequence analysis of mRNA revealed an increase in the level of aberrant splicing of exon 14, resulting in the generation of an exon13-exon15 splice-form that is predicted to lead to a frameshift and protein truncation at codon 673. The relatively mild phenotypic presentation and the intra-familial variation are consistent with the leaky nature of exon 14 splicing in normal APC. The inferred founder of these three families may account for as-yet undetected affected branches of this kindred. This and similar types of intronic mutations may account for a significant proportion of FAP cases where APC clinical analysis fails because of the current limitations of testing options.
Cytogenetic analysis of products of conception has identified trisomies for all human chromosomes except for chromosome 1. Presented here is a patient with clinical signs of pregnancy, including increasing hCG levels and evidence of a gestational sac on ultrasound. However, the pregnancy was lost between 8-9 weeks post-LMP with the diagnosis of a blighted ovum. Cytogenetic analysis of cultured chorionic villi demonstrated a 47,XY,؉1 chromosome complement in all cells. This is the first reported case of nonmosaic trisomy 1 in a clinically recognized human pregnancy. Am. J. Med. Genet. 68:98, 1997
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