Germline pathogenic variants in RNF43 in patients with and without serrated polyposis syndrome

Area of Science:

• Genetics
• Gastroenterology
• Oncology

Background:

• Serrated Polyposis Syndrome (SPS) involves numerous serrated polyps and increased colorectal cancer (CRC) risk.
• RNF43 gene variants are implicated in a subset of SPS cases, but their penetrance and phenotypic spectrum are unclear.

Purpose of the Study:

• To investigate the penetrance and clinical presentation of individuals with likely pathogenic variants (LPVs) in the RNF43 gene.
• To assess the association between RNF43 variants and Serrated Polyposis Syndrome (SPS) or colorectal cancer (CRC).

Main Methods:

• Genetic testing using custom next-generation sequencing (NGS) gene panels including RNF43.
• Analysis of eight patients from four families with suspected hereditary cancer and RNF43 LPVs.
• Comparison of findings with existing literature on RNF43 variants and associated phenotypes.

Main Results:

• Three distinct RNF43 LPVs (one deletion, two nonsense variants) were identified in four families.
• Only one family exhibited a history of CRC and serrated polyps; the other three had no history of polyposis or CRC.
• Colonoscopies in probands from families without polyposis history revealed no serrated polyps or CRC, even in older individuals.

Conclusions:

• The penetrance of RNF43-related disease appears significantly lower than previously estimated.
• The direct link between RNF43 variants and SPS/CRC requires further investigation due to variable expressivity.
• Genetic counseling for RNF43-positive families, especially those without polyposis, is complex and necessitates careful consideration of these findings.