# Paired DNA/RNA testing uncovers a deep intronic PTEN pathogenic variant associated with clinical Cowden Syndrome: a case report

## TL;DR

Combining DNA and RNA testing helps detect PTEN mutations missed by standard DNA tests, improving diagnosis for Cowden Syndrome and related conditions.

## Contribution

Demonstrates the clinical benefit of paired DNA/RNA testing in identifying deep intronic PTEN variants missed by standard DNA sequencing.

## Key findings

- A deep intronic PTEN pathogenic variant was identified using RNA sequencing but missed by DNA panel testing.
- Concurrent DNA and RNA testing improves diagnostic accuracy for patients with clinical Cowden Syndrome.
- Reevaluation of DNA-negative PHTS/CS patients with RNA testing can uncover previously undetected PTEN variants.

## Abstract

Identification of a deep intronic PTEN pathogenic variant, which was not detected by standard DNA-targeted panel sequencing but was uncovered by targeted PTEN RNA sequencing using CaptureSeq technology, illustrates the added value of concurrent DNA and RNA analyses in risk assessment for PTEN Hamartoma Tumor Syndrome (PHTS) and in patients given the diagnosis of clinical Cowden Syndrome (CS). These findings have significant clinical implications, including providing the rationale for testing patients meeting clinical criteria for PHTS/CS with concurrent DNA and RNA testing. It also supports reevaluation of patients who test negative by DNA testing alone but with a clinical diagnosis of PHTS/CS with subsequent RNA testing to identify and clinically interpret previously undetected deep intronic PTEN variants. Where cancer treatment and prevention decisions hinge on correct diagnoses, concurrent DNA and RNA testing rather than stepwise testing can permit faster, more accurate results and earlier clinical actionability.