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Integration of genomics and transcriptomics to identify DNA damage defects in PID patients prone to cancer

Boekbijdrage - Boekabstract Conferentiebijdrage

Introduction: Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders caused by genetically determined defects of the immune system, predisposing to life-threatening complications such as severe and recurrent infections, auto-immunity and malignancies. A subset of PIDs is caused by pathogenic germline variants in DNA repair genes. As a consequence these patients are radiosensitive and present with increased cancer risk. Since PID patients are exposed to radiation for several reasons (bone marrow transplantation, radiotherapy, diagnostic imaging), identification of the genetic defect is important for risk stratification and improved therapeutic management. As in only 5-20% of the patients pathogenic variants are found in currently known PID genes, we hypothesize that defects in additional DNA damage response genes may be involved in PID patients prone to malignancies.Materials and Methods: WES data is analyzed by a DNA damage response panel consisting of +/- 1230 genes. Extensive filtering results in a long list of variants of unknown clinical significance (VUS). To facilitate variant prioritization we are complementing WES with transcriptomics on RNA extracted from short term lymphocyte cultures. We search for expression and splicing outliers in the transcriptome.Results: Using this approach we identified a homozygous intronic variant, outside the canonical splice sites, in a DNA repair gene not previously linked to PID. RNA-seq revealed out-offrame exon skipping. Further functional validations to establish a link with the phenotype are ongoing.Conclusions: These first findings encourage the implementation of transcriptomics in the workup of PID patients to improve diagnosis and patient management.
Boek: European Society of Human Genetics (ESHG) Conference, Abstracts
Aantal pagina's: 1
Jaar van publicatie:2021