WHOLE GENOME SEQUENCING OF PATIENTS WITH PULMONARY ARTERIOVENOUS MALFORMATIONS AND HEREDITARY HAEMORRHAGIC TELANGIECTASIA

BackgroundThe personalisation of medicine to target genetic modifications may benefit patients. A well characterised complex disease with a large variation in phenotype and whole genome sequencing could be used to determine new genetic links to disease manifestations. Pulmonary arteriovenous malformations (AVMs) provide one such disease, especially for the patients with underlying hereditary haemorrhagic telangiectasia (HHT). Both diseases were specifically recruited to the 100,000 Genomes Project.MethodsLiterature searches for relevant genes that could impact on the variable phenotypes were performed. The genes of interest were investigated within the Research Environment of the 100,000 Genomes Project using LabKey. For each variant, potential pathogenicity was assigned using general population allele frequencies (GnomAD v3.1.1) and Combined Annotation Dependent Depletion (CADD) scores. Anonymised, categorised data were exported through the Research Environment Airlock in order to integrate with detailed blood results and sub-phenotypes.ResultsThe 75 genes of interest were split into five groups by their activity. 56 of these genes (75%) had variants within the participants. All variants were rare with allele frequencies less than 0.003. CADD scores ranged from 0–42 where scores above 15 are commonly considered to indicate likely deleteriousness. There was a difference in CADD scores between the gene categories (Kruskal Wallis p=0.0073), and the categories and genes with a greater variant burden in the study cohort also had higher gene damage indices in the general population. There was no difference in variants or genes according to the HHT gene (most commonly ENG or ACVRL1). Examination in relation to patient phenotypes is ongoing.ConclusionsPatients with pulmonary AVMs and HHT commonly have rare variants in genes of potential relevance to their phenotype. Phenotypic associations are required to establish if this is by chance or of pathophysiological importance.AcknowledgementsThis research was made possible through access to the data and findings generated by the 100,000 Genomes Project, managed by Genomics England Limited funded by the Department of Health and Social Care, the National Institute for Health Research (NIHR) and NHS England.