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Inactivating APC mutations cause familial adenomatous polyposis, classically characterized by hundreds to thousands of adenomatous colorectal polyps and cancer. Historically, 98% of pathogenic alterations in APC are nonsense or frameshift mutations; however, few reported series have used techniques that test for large deletions or duplications. Splice site mutations are only rarely documented. Consecutive cases (n = 1591) submitted for complete APC gene analysis during a 4-year period were reviewed. Testing included mutation screening (Sanger sequencing or conformation sensitive gel electrophoresis and protein truncation testing) with reflex confirmation sequencing. Gene deletion or duplication analysis was performed in 1421 cases by multiplex ligation-dependent probe amplification. Testing yielded 411 pathogenic, 20 likely pathogenic, 15 variant of uncertain significance, 140 likely benign, and 1005 negative reports. Identified were 168 novel variants (103 pathogenic, 5 likely pathogenic, 12 variant of uncertain significance, and 48 likely benign). Of the 431 pathogenic or likely pathogenic mutations, frameshift, nonsense, splice site, and large deletion or duplication mutations represented 43%, 42%, 9%, and 6% of cases, respectively. This is the largest report of clinical APC testing experience with concurrent multiplex ligation-dependent probe amplification. In addition to nonsense and frameshift mutations, large deletions or duplications and canonical splice site mutations are a significant cause of familial adenomatous polyposis. Despite technological advances, broad allelic, locus, and phenotypic heterogeneity continue to pose challenges for genetic testing of patients with colorectal adenomatous polyposis.

We studied 22 twin pairs in which one or both twins had dementia of the Alzheimer type (DAT). In four twins, diagnosis was confirmed by autopsy. Seven monozygotic (MZ) pairs were concordant for DAT; 10 MZ pairs were discordant. Two dizygotic (DZ) pairs were concordant for DAT, and 3 DZ pairs were discordant. The current concordance rate was 41% for MZ twins and 40% for DZ twins. The study supports the belief that, etiologically, DAT cannot be entirely accounted for by a single autosomal dominant gene. The data also suggest that in certain genetic circumstances, disease expression may be delayed in females.

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