Figure 1

Exome sequencing in APC mutation-negative kindred 0124 revealed positive LOD scores at the APC locus. (A) Affected members of kindred 0124 have classical FAP phenotypes with highly-penetrant, autosomal dominant inheritance across the family. Extra-colonic malignancies were unusually common in this kindred, including duodenal adenocarcinoma (in two members), pancreas adenocarcinoma, gastric adenocarcinoma, breast cancer, leukemia, ovarian adenocarcinoma, endometrioid carcinoma, and neuroendocrine carcinoma. The proband (III-5, arrow) underwent standard genetic testing and no known FAP-causing mutation was identified. Asterisks indicate the eight individuals who underwent exome sequencing. Analysis did not reveal a credible causal mutation within the exonic sequences. Parametric linkage analysis using a rare autosomal dominant model with SNPs identified from the exome sequencing data was then performed. (B) LOD scores are plotted across somatic chromosomes, with positive LOD score regions marked in red and negative scores marked in blue. The maximum LOD of 2.408 occurred at 5q22, which contains the APC locus.