S96 Identifying genetic modifiers of disease severity using whole genome analyses of families with hereditary haemorrhagic telangiectasia recruited to the 100,000 genomes project

Introduction Why individuals with the same disease-causing DNA variant can have very different phenotypes is a puzzle in many conditions inherited as autosomal dominant traits. To explore, we focussed on hereditary haemorrhagic telangiectasia (HHT) in which approximately 50% of patients develop pulmonary arteriovenous malformations (PAVMs). In turn, these PAVMs can vary in severity dramatically within the same HHT family. With the rare opportunity for whole genome analysis of many HHT families recruited to the 100,000 Genomes Project1, examination of potential phenotypic modifiers within families with the same HHT pathogenic variant was a relevant and unique question. Methods Data were analysed within the 100,000 Genomes Project Research Data Embassy, following Illumina pipeline alignments and variant calling. Customised Python script was used to identify families with the same pathogenic HHT variant and extract each affected individual’s DNA variants. Comparisons between affected family members differing markedly in disease severity were then performed using 3 separate methods: comparison of clinical tiered DNA variants, analysis of newly released copy number variants, and comparison of all single nucleotide variants and small indels in patients’ variant call files (vcfs). Results From the initial data set of 193 fully sequenced HHT families taken from Data Release 7 of the 100,000 Genomes Project, we selected those in which one family member had noticeably more severe symptoms recorded by the recruiting Genomic Medicine Centre. In one typical nuclear family with 3 affected members including one with severe PAVMs, within tiered genes of known function, 111 variants were only present in the PAVM-affected patient. Extending to copy number variants identified a further 363 variants that differed between this patient and the less severely affected relatives. Extending to vcf analyses using python script identified 490,225 variants that were only present in the PAVM-affected patient. The combined variant list is being cross-referenced to genomic locations of known gene coding regions and untranslated regulatory regions using in silico prediction tools. Conclusions Whilst HHT is an autosomal dominant trait, these data emphasise the potential extent to which an unaffected parent may affect the disease severity through the influence of other inherited gene variants. Reference : http://www.genomicsengland.co.uk