Germline variants in Hamartomatous Polyposis Syndrome-associated genes from patients with one or few hamartomatous polyps

Abstract

Objective: A subgroup of patients with hamartomatous polyps in the GI tract has a hereditary Hamartomatous Polyposis Syndrome with an increased risk of cancer. The distinction between patients with one or few polyps and patients with a syndrome can be difficult. A pathogenic germline mutation can be detected in a majority of HPS patients. This study investigates whether patients with one or few hamartomatous polyps could have a syndrome based on genetic screening of relevant genes.

Methods: We designed a gene panel including 26 hamartomatous polyposis-associated genes. Using targeted Next Generation Sequencing, DNA samples from 77 patients with 84 hamartomatous polyps were sequenced. The detected germline variants were classified into pathogenicity classes.

Results: We detected several germline variants, among them three in ENG, two in BMPR1A, one in PTEN, and one in SMAD4. Although some of the detected variants have been reported previously none could be definitely pathogenic or likely pathogenic.

Conclusions: Our study points towards that genetic testing for the Hamartomatous Polyposis Syndromes in patients with one or few polyps does not improve diagnostics, however we illustrate that the clinical significance of genetic variants can be difficult to interpret. A family history of polyps, cancer, or extraintestinal findings or a minimum of 3–5 polyps seems to be relevant information to include before genetic testing.

Keywords:

• Genetic variants
• high-throughput nucleotide sequencing
• Juvenile polyposis syndrome
• Peutz–Jeghers syndrome
• polyps

Acknowledgements

We would like to acknowledge Jette Møller for excellent technical assistance with the genetic analysis.

Disclosure statement

The authors declare no conflict of interest.

Funding information

The Region of Southern Denmark, The Aase and Ejnar Danielsen Foundation, and Odense University Hospital, Frie Forskningsmidler, financially supported the study.