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

Fiche publication

Date publication

février 2025

Journal

Familial cancer

Auteurs

Membres identifiés du Cancéropôle Est :
Dr MAUGARD Christine

Tous les auteurs :
Boedec M, Aucouturier C, Cavaillé M, Leman R, Castéra L, Delhomelle H, Uhrhammer N, Bernard V, Giraud S, Lasseaux E, Jones N, Bidart M, Boutry-Kryza N, Noguès C, Colas C, Maugard C, Krieger S, Bouras A

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/39920402

Résumé

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.