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<p><i>PTEN</i> Hamartoma Tumor Syndrome (PHTS) is an autosomal dominant disorder characterized by high penetrance and significant phenotypic variability. In most patients, targeted high-throughput sequencing (HTS) approaches enable the detection of loss-of-function pathogenic variants in <i>PTEN</i>, a tumor suppressor gene acting as a negative regulator of the <i>PI3K</i>-<i>AKT</i> pathway. We describe a patient exhibiting a clinical phenotype strongly indicative of PHTS, yet lacking a molecular diagnosis through <i>PTEN</i>-targeted HTS. After several years of diagnostic uncertainty, trio whole genome sequencing (WGS) ultimately identified a de novo germline deep intronic 98&#xa0;bp deletion in <i>PTEN</i> intron 5 (c.492 + 1671_492 + 1768del). Targeted RNA sequencing revealed the inclusion of a pseudoexon, resulting in a frameshift and predicted protein truncation at codon 171 (p.Val166Asnfs*6). These data underline the importance of WGS approaches in detecting deep intronic structural variants, that may be overlooked by conventional methods.</p>

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Identification of a germline deep intronic PTEN-deletion leading to exonization through whole genome and targeted RNA sequencing

  • 期刊论文

  • 发表日期：

    2025年2月7日

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  • Morgane Boedec,
  • Camille Aucouturier,
  • Mathias Cavaillé,
  • Raphaël Leman,
  • Laurent Castéra,
  • Hélène Delhomelle,
  • Nancy Uhrhammer,
  • Virginie Bernard,
  • Sophie Giraud,
  • Eulalie Lasseaux,
  • Natalie Jones,
  • Marie Bidart,
  • Nadia Boutry-Kryza,
  • Catherine Noguès,
  • Chrystelle Colas,
  • Christine Maugard,
  • Sophie Krieger,
  • Ahmed Bouras

摘要

PTEN Hamartoma Tumor Syndrome (PHTS) is an autosomal dominant disorder characterized by high penetrance and significant phenotypic variability. In most patients, targeted high-throughput sequencing (HTS) approaches enable the detection of loss-of-function pathogenic variants in PTEN, a tumor suppressor gene acting as a negative regulator of the PI3K-AKT pathway. We describe a patient exhibiting a clinical phenotype strongly indicative of PHTS, yet lacking a molecular diagnosis through PTEN-targeted HTS. After several years of diagnostic uncertainty, trio whole genome sequencing (WGS) ultimately identified a de novo germline deep intronic 98 bp deletion in PTEN intron 5 (c.492 + 1671_492 + 1768del). Targeted RNA sequencing revealed the inclusion of a pseudoexon, resulting in a frameshift and predicted protein truncation at codon 171 (p.Val166Asnfs*6). These data underline the importance of WGS approaches in detecting deep intronic structural variants, that may be overlooked by conventional methods.