S96 Pulmonary arteriovenous malformations – genetic versus clinical evidence of underlying hereditary haemorrhagic telangiectasia

Abstract

<h3>Introduction and Objectives</h3> Pulmonary arteriovenous malformations (PAVMs) result in early onset but preventable strokes and other complications. Patients know that PAVMs can be a familial condition, most commonly due to hereditary haemorrhagic telangiectasia (HHT). Since the April 2020 NHS National Genomic Test Directory launch, patients with PAVMs are eligible for gene testing only if they already meet a definite clinical diagnosis of HHT, requiring two further Curaçao Criteria from nosebleeds, mucocutaneous telangiectasia, or first-degree relative with HHT. Our goal was to test the validity of this requirement. <h3>Methods</h3> We audited ClinVar-listed variants in the major HHT genes, and with ethical approval, case notes of patients with PAVMs who had undergone NHS genetic testing. Tests were ordered predominantly between 2015–2019 through Mainstreaming Genomics initiatives via gene-test panels, or whole genome sequencing through the 100,000 Genomes Project. <h3>Results</h3> ClinVar lists 2,804 variants in <i>ENG, ACVRL1</i> and<i> SMAD4</i>, including 909 likely pathogenic/pathogenic variants that diagnose HHT. Most are loss-of-function frameshift, stop-gain and splice site variants (390/645 [60%] for <i>ENG/SMAD4</i>; 126/264 [47%] for <i>ACVRL1</i>). At least 50% of people with one of these variants would be expected to have PAVMs. At our institution, 124 patients with PAVMs were the first in their family to have a gene test. Of these, 83 (67%) tested positive for HHT, i.e. were found to be heterozygous for a likely pathogenic or pathogenic variant in <i>ENG, ACVRL1</i> or <i>SMAD4.</i> Focussing on the 83 patients with PAVMs and genetically-diagnosed HHT, only 63/83 (76%) met three or more Curaçao criteria. For the remaining 20 patients with PAVMs and a positive HHT gene test, none met the family history criterion for HHT. While 14 (70%) described nosebleeds as an adult, only 3 (15%) had classical HHT telangiectasia, and the cohort included families where pulmonary AVMs (single or multiple) were the only HHT clinical feature across individuals with <i>ENG</i> pathogenic variants in two generations. <h3>Conclusions</h3> There is a high burden of deleterious variants in HHT genes. Two-thirds of unselected PAVM patients have genetically-confirmed HHT, but of these, 1 in 4 display few if any clinical features of HHT. Wider gene testing is recommended.