Abstract Body (Do not enter title and authors here): Background Hereditary hemorrhagic telangiectasia (HHT) and hereditary pulmonary arterial hypertension (HPAH) are genetic diseases that affect the pulmonary vasculature. HHT and HPAH are due to a haploinsufficiency in components of the bone morphogenetic protein receptor type 2 (BMPR2) pathway. Despite shared genetics, HHT and HPAH cause different pulmonary vascular lesions. In HHT, pulmonary arteriovenous malformations (pAVMs) can occur. These are abnormal shunts between arteries and veins that can lead to stroke. HPAH is characterized by extensive remodeling of the lung including the formation of plexiform lesions, convolutes of vascular channels that were described as a pathological hallmark of PAH. The pathobiology of pAVMs and plexiform lesions is incompletely understood. Recent studies suggest that a local bi-allelic loss of HHT causing genes in clonally expanding endothelial cells (ECs) might be required for AVMs to form in patients with HHT. In plexiform lesions, clonal EC expansion was also described.
Hypothesis We hypothesized that local somatic mutations in ECs might be involved in the pathogenesis of pulmonary vascular lesions in HHT and HPAH.
Aims We here aimed at detecting somatic mutations in pulmonary vascular lesions of a patient with HHT and end-stage PAH caused by a mutation in ENG.
Methods Targeted deep sequencing of 3 HHT causing genes and 11 vascular malformation associated genes was performed on 4 pAVMs and 14 plexiform lesions of the patient.
Results The disease-causing germline mutation in ENG was detected in every sample. No somatic mutation in the functional allele of ENG was detected in the pulmonary vascular lesions. However, we identified a somatic mutation in the gene encoding for Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Alpha (PIK3CA) in one of the plexiform lesions. This mutation is a confirmed activating somatic mutation in the Catalogue Of Somatic Mutations In Cancer that was previously functionally confirmed as a moderately potent oncogenic mutation.
Conclusion and Outlook We here describe a rare case of an ENG mutation carrier with HHT and HPAH. We identified a somatic activating mutation in PIK3CA in one of her plexiform lesions. To explore if the mutation contributes to the overgrowth of ECs in a plexiform lesion on a background of a haploinsufficiency in ENG, we are performing functional studies on iPSC-derived ECs from this patient after introduction of the mutation in PIK3CA by Crispr/Cas9.