Abstract
Colorectal, hamartomatous juvenile polyps occur as part of different hereditary syndromes, including Juvenile polyposis syndrome and PTEN-hamartoma tumour syndrome. However, based on clinical manifestations alone, it is difficult to differentiate between the syndromes, and genetic analysis with an NGS-panel is often used to aid diagnostics. We report a 59-year-old male with colorectal juvenile polyps, who had been referred to genetic testing but had normal genetic analysis. He did not fulfil the clinical criteria of PTEN- hamartoma tumour syndrome, but the clinical criteria of Juvenile polyposis syndrome. With Whole Genome Sequencing we detected a novel intronic variant of unknown significance in PTEN (NC_000010.11:g.89687361 A > G(chr10, hg19), NM_000314.8:c.209 + 2047 A > G). RNA analysis classified the variant as likely pathogenic as it results in a pseudoexon inclusion introducing a frameshift and a premature stop codon. The patient was then diagnosed with PTEN-hamartoma Tumour syndrome. To our knowledge this is the first report of a variant resulting in pseudoexon inclusion in PTEN.
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References
Jelsig AM, Qvist N, Brusgaard K, Nielsen CB, Hansen TP, Ousager LB. Hamartomatous polyposis syndromes: a review. Orphanet J Rare Dis. 2014;9:101.
Jass JR, Williams CB, Bussey HJ, Morson BC. Juvenile polyposis-a precancerous condition. Histopathology .1988;13:619–30.
Byrjalsen A, Hansen TVO, Stoltze UK, Mehrjouy MM, Barnkob NM, Hjalgrim LL, et al. Nationwide germline whole genome sequencing of 198 consecutive pediatric cancer patients reveals a high incidence of cancer prone syndromes. PLoS Genet. 2020;16:e1009231.
Montalban G, Bonache S, Moles-Fernández A, Gadea N, Tenés A, Torres-Esquius S, et al. Incorporation of semi-quantitative analysis of splicing alterations for the clinical interpretation of variants in BRCA1 and BRCA2 genes. Hum Mutat. 2019;40:2296–317.
Mester JL, Ghosh R, Pesaran T, Huether R, Karam R, Hruska KS, et al. Gene-specific criteria for PTEN variant curation: recommendations from the ClinGen PTEN Expert Panel. Hum Mutat. 2018;39:1581–92.
Walker LC, de la Hoya M, Wiggins GA, Lindy A, Vincent LM, Parsons M, et al. Application of the acmg/amp framework to capture evidence relevant to predicted and observed impact on splicing: recommendations from the clingen svi splicing subgroup. medRxiv. 2023;2023.02.24.23286431. https://doi.org/10.1101/2023.02.24.23286431
Smerdel MP, Skytte AB, Jelsig AM, Ebbehøj E, Stochholm K. Revised Danish guidelines for the cancer surveillance of patients with Cowden syndrome. Eur J Med Genet. 2020;63:103873.
Boland CR, Idos GE, Durno C, Giardiello FM, Anderson JC, Burke CA, et al. Diagnosis and management of cancer risk in the gastrointestinal hamartomatous polyposis syndromes: recommendations from the U.S. multi-society task force on colorectal cancer. Gastrointest Endosc. 2022;95:1025–47.
Petersen USS, Doktor TK, Andresen BS. Pseudoexon activation in disease by non-splice site deep intronic sequence variation - wild type pseudoexons constitute high-risk sites in the human genome. Hum Mutat. 2022;43:103–27.
Landrith T, Li B, Cass AA, Conner BR, LaDuca H, McKenna DB, et al. Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes. NPJ Precis Oncol. 2020;4:4.
Acknowledgements
We like to thank Lone Sandbjerg Hindbæk, Anne Marie Høgh Lauridsen, and Pia Hougaard for excellent technical assistance.
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This project was funded by the Research Foundation from the University Hospital of Copenhagen, Rigshospitalet.
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Jelsig, A.M., Rønlund, K., Gede, L.B. et al. Identification of a novel pathogenic deep intronic variant in PTEN resulting in pseudoexon inclusion in a patient with juvenile polyps. J Hum Genet 68, 721–724 (2023). https://doi.org/10.1038/s10038-023-01174-w
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DOI: https://doi.org/10.1038/s10038-023-01174-w