Pedigrees of families found to carry <i>UACA</i> and <i>TWSG1</i> truncating variants.

<p>Carrier status is depicted for all the cases for whom readily extracted DNA was available. The individuals that underwent exome sequencing are marked with an arrow. Numbers represent the age at diagnosis of the affected individuals. The following abbreviations are used: CRC, colorectal cancer; BCC, basal cell carcinoma, MG, meningioma; HD, Hodgkin lymphoma; PC, prostate cancer; MM, melanoma and LC, lung cancer.</p

Examples of DNA sequence chromatograms.

<p>Chromatograms on the top demonstrate c.3346C>T, p.Q1116X in <i>UACA</i>. Chromatograms on the bottom demonstrate c.121C>T, p.Q41X in <i>TWSG1</i>. DNA extracted from tumor tissue shows LOH with retention of the mutated alleles (right). The wild-type alleles can still be seen in the tumor chromatograms, due to normal tissue contamination in the tumor samples.</p

Candidate colorectal cancer predisposing genes with Sanger validated truncating variants in familial CRC cases.

<p>Gene, transcript and chromosomal positions taken from Ensembl build 37 (<a href="http://www.ensembl.org" target="_blank">http://www.ensembl.org</a>).</p>a<p>fs = frameshift insertion and deletion variant, sp = splice site variant.</p>b<p>Counts include both exome data controls and Sanger sequenced controls.</p

Schematic representation of the overall study design.

<p>We performed exome sequencing analysis of germline DNA from 96 independent familial CRC cases. Initially, quality, frequency and control filtering were applied to the exome data. Next, genes with putative truncating loss-of-function variants in at least 2/96 cases were validated by Sanger sequencing. Confirmed truncating variants were then screened in Finnish population matched controls. Loss of heterozygosity was analyzed in the respective tumor tissues. Variants in genes showing loss of the wild-type allele in tumor tissue were genotyped in a set of validation phase samples. Overall, 11 novel candidate CRC predisposing genes were identified. CRC, colorectal cancer; MAF, minor allele frequency; LOH, loss of heterozygosity.</p

Clinical characteristics of the 96 cases with familial colorectal cancer.

<p>NOTE: some of the numbers do not match due to missing data.</p><p>Abbreviations: MSI, microsatellite instability; MSS, microsatellite stable.</p>*<p>Distal, from splenic flexure to rectum; proximal, from cecum to transverse colon.</p