Exome sequencing identified potential causative candidate genes for serrated polyposis syndrome

Sophia Peters1, Christina Trueck1, Claudia Perne1,2, Ronja Adam1,3, Janine Altmueller4,5, Holger Thiele5, Isabel Spier6,2, Stefan Aretz1,2

1Institute of Human Genetics, University of Bonn, Bonn, Germany. 2Center for Hereditary Tumor Syndromes, University of Bonn, Bonn, Germany. 3Center for Experimental and Molecular Medicine, Academic Medical Center Amsterdam, Amsterdam, Netherlands. 4Cologne Center for Genomics, University of Cologne, Cologne, Germany. 5Institute of Human Genetics, University of Cologne, Cologne, Germany. 6Institute of Human Genetics, University of Bo, Bonn, Germany


Objectives: Serrated polyposis syndrome (SPS) is a poorly defined colorectal cancer predisposition syndrome characterized by multiple and/or large serrated lesions throughout the colon. To date, only few molecular signatures have been described and the etiology of the syndrome has not been identified in the vast majority of patients. The aim of this study is to identify causal variants for SPS.

Methods: To uncover causative germline variants, the exomes of 49 SPS patients have been sequenced using leukocyte DNA. The germline variants were filtered for rare (biallelic: MAF ≤1%, monoallelic:  ≤0.1% according to gnomAD) loss of function (LoF) variants. Regarding splice sites, variants up to +/-10 nucleotides from the exon boundaries were analyzed if they showed a combined change of splice efficiency of at least 50% in the variant analysis software Alamut®. A pathway analysis was performed using the reactome software.

Results: Biallelic LoF variants were found in three genes. 548 genes harbored heterozygous LoF variants; 25 were recurrently mutated. 31/551 genes were LoF intolerant (pLi-score ≥0.9). 10/551 genes are involved in DNA repair, 12 in cell cycle control, and one in apoptosis. Interestingly, in two patients LoF variants were found in a gene functioning in the canonical wnt signaling pathway, as does RNF43, in which variants have been shown to be causal for SPS.

Conclusions: Exome sequencing identifies potentially causative germline variants for SPS, however, the data indicate considerable genetic heterogeneity. The current work-up consists of the screening of additional patients, and the inclusion of missense variants and CNVs.