Identification of a novel pathogenic deep intronic variant in PTEN resulting in pseudoexon inclusion in a patient
Anne Marie Jelsig1, Karina Rønlund2, Lene Bjerring Gede3
1Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark. anne.marie.jelsig@regionh.dk.
Insights
A novel PTEN gene variant causing pseudoexon inclusion was identified in a patient with colorectal juvenile polyps. This finding aids in diagnosing PTEN-hamartoma tumor syndrome when clinical signs are ambiguous.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Colorectal juvenile polyps can be associated with hereditary syndromes like Juvenile polyposis syndrome and PTEN-hamartoma tumor syndrome.
- Distinguishing between these syndromes based solely on clinical presentation is challenging.
- Next-generation sequencing (NGS) panels are commonly employed to assist in diagnosis.
Observation:
- A 59-year-old male with colorectal juvenile polyps presented with normal genetic analysis from an NGS panel.
- He met clinical criteria for Juvenile polyposis syndrome but not PTEN-hamartoma tumor syndrome.
- Whole Genome Sequencing revealed a novel intronic PTEN variant (chr10:89687361 A>G).
Findings:
- RNA analysis demonstrated that the PTEN variant leads to pseudoexon inclusion, causing a frameshift and premature stop codon.
- This variant was classified as likely pathogenic.
- The patient was subsequently diagnosed with PTEN-hamartoma tumor syndrome.
Implications:
- This case highlights the importance of comprehensive genetic analysis, including Whole Genome Sequencing, for diagnosing rare genetic conditions.
- It reports the first instance of a PTEN variant causing pseudoexon inclusion.
- Accurate diagnosis of PTEN-hamartoma tumor syndrome is crucial for appropriate patient management and genetic counseling.
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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