Evidence suggests that germline RNF43 mutations are a rare cause of serrated polyposis

We read with interest the work by Yan et al published in Gut .1 The serrated (hyperplastic) polyposis syndrome (SPS) is a heterogeneous disease defined by the presence of multiple serrated polyps throughout the colon,2 causing an increased risk (16%) of colorectal cancer (CRC).3 By performing whole-exome sequencing in 20 SPS families, Gala et al identified a germline mutation, c.338C>A (p.R113*), in the RING-type E3 ubiquitin ligase RNF43, an inhibitor of the Wnt pathway, in two independent families.4 The c.394C>T (p.R132*) mutation was subsequently identified in two SPS-affected members of one family, supporting a causal role in SPS.5 In the study by Yan et al whole-exome sequence analysis of four SPS families identified a deleterious germline mutation, c.953–1G>A (p.E318fs), in six members of one family, five fulfilling the WHO criteria for SPS.1 Buchanan et al assessed the mutation status of RNF43 in 74 selected SPS families, identifying two rare missense variants, c.443C>G (p.A148G) and c.640C>G (p.L214V), predicted deleterious by in silico algorithms, in two families. No carriers of p.R113* or p.R132* were detected in 221 additional patients with SPS.6 Mutation screening of RNF43 was carried out by Sanger sequencing in …