RESEMBLE · Long-read sequencing to resolve the missing heritability in patients suspected of PTEN hamartoma tumour syndrome

Long-read sequencing to resolve the missing heritability in patients suspected of PTEN hamartoma tumour syndrome

Individuals with a genetic tumour risk syndrome are at high risk to develop cancer. One of these syndromes is PTEN hamartoma tumour syndrome (PHTS). PHTS is associated with pathogenic variants (PVs) in the PTEN gene. Unfortunately, in the majority of patients suspected of PHTS no PV in PTEN is identified. These patients are considered PHTS-like. The low diagnosis rate in this group of patients suggests the possibility of PVs in regions of PTEN that are not covered in routine diagnostics or suggests that PVs in other genes in the PI3K/AKT/mTOR pathway result in PHTS-like disease. The current state-of-the-art techniques used to detect genetic variants in clinical diagnostics are mainly based on short- read next generation sequencing (NGS). The introduction of short-read NGS technologies into genomic testing pipelines has led to a vast increase in diagnoses and many novel disease-gene associations. Nevertheless, we are still unable to detect complex genetic rearrangements and variants in less accessible regions of the genome, such as promoters and intronic regions, which are more likely to be GC rich and/or harbour repetitive sequences hampering short-read NGS. These limitations can be overcome with the use of newly developed long-read sequencing chemistries, which goes beyond the current state-of-the-art, and allows for more accurate sequencing of structural variants and increased coverage of difficult regions in the genome. This advanced sequencing technology can also be applied in a targeted manner, when there is good phenotypic evidence to suspect alterations in specific genes or genomic regions, or genome-wide to identify new risk loci. Long-read sequencing technologies have shown potential to improve the diagnostic yield of other diseases, such as polycystic kidney disease and intellectual disability. However, this has never been done in PHTS-like patients. Therefore, I aim to develop a long-read sequencing (LRS) approach for PHTS-like patients, which will go beyond the currently state-of-the-art short-read sequencing approaches. I will: - develop a PTEN-targeted LRS assay; - perform this targeted assay on a highly selective cohort of PHTS-like families; - perform whole genome LRS on families that were not solved by targeted LRS to identify novel gene-disease associations; - Functionally validate potential findings. Via this work, I aim to improve the diagnostic yield for PHTS by identifying novel genetic mechanisms and genes underlying disease in PHTS-like patients. The unique interdisciplinary structure of the Department of Human Genetics at Radboudumc will allow to rapidly implement genetic testing for the newly identified genetic causes for PHTS. Identification of the precise underlying cause of PHTS will enable cascade genetic testing of at-risk family members to determine their status for the causal variant and thus, risk of disease to them and any future off-spring. Furthermore, this approach will allow the implementation of preventive care strategies for the family members at risk. Overall, my proposal will facilitate a personalized care approach for PHTS(-like) patients and their families for improved clinical outcomes and reduced disease morbidity.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз