Multiple Lesion-Specific Somatic Mutations and Bi-Allelic Loss of ACVRL1 in a single patient with Hereditary Haemorrhagic Telangiectasia

Background Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by mucocutaneous telangiectasias and arteriovenous malformations (AVMs) in internal organs. It is mainly caused by heterozygous pathogenic variants in ENG , ACVRL1 or SMAD4 . Somatic mosaic mutations in the functional allele of HHT-causing genes have been identified in skin telangiectasias and AVMs of HHT patients, which is suspected to drive formation of telangiectasias and AVMs. Our objective was to further support and clarify the pathogenetic mechanism of HHT lesion genesis by analysing several HHT lesion biopsies; all from a single HHT patient caused by a germline deletion of the entire ACVRL1 gene. Methods Deep exome sequencing was performed on DNA from multiple fresh tissue biopsies from the same HHT patient; six hepatic AVM samples, two macroscopic normal hepatic control samples, and three mucocutaneous telangiectasia biopsies. Results Somatic mosaic lesion-specific ACVRL1 variants were identified in four hepatic AVM samples and in one telangiectasia. Two different somatic variants were identified in several lesions from the same liver. Additionally, a third lesion-specific somatic variant was identified in one skin telangiectasia. Conclusion We identified in total 3 different somatic variants, which are expected to contribute to the pathogenesis of HHT vascular lesions. These data further support the second-hit pathophysiological mechanism to explain the multifocality of vascular lesions in HHT. This is the first report to perform deep sequencing on multiple samples from both several visceral AVMs and telangiectasias originating from one single HHT patient.