Genetic hallmarks of patients with congenital portosystemic shunts and portopulmonary hypertension: protocol for a multicentre exploratory study

Introduction: Congenital portosystemic shunts (CPSS) are rare vascular malformations, with an estimated prevalence of 1/30000 live births, that cause portal blood to partly bypass the liver. CPSS frequently occur with congenital heart disease and other malformations, suggesting a shared developmental or genetic basis. Severe acquired clinical manifestations are present in a large proportion of patients with CPSS. Portopulmonary hypertension (PoPH), the most lifethreatening, has been reported in as many as 7 to 14% of CPSS patients. Mounting evidence indicates that PoPH can arise early in life, particularly in children with CPSS, yet paediatric PoPH remains understudied. This project aims to identify genetic variants associated with PoPH in CPSS patients through whole genomes, focusing primarily on known pathogenic genes for pulmonary arterial hypertension (PAH), congenital heart disease (CHD), Hereditary Haemorrhagic Telangiectasia (HHT), SNPs previously associated with PoPH in adults, and ultimately novel genomic variants. The overarching goal of the study is to improve personalised risk assessment and inform clinical decisions regarding elective shunt closure in individuals potentially at risk of developing PoPH. Methods and analysis: The aim is to perform an international multi-centre exploratory genome analysis of patients with CPSS and PoPH identified through the International Registry of Congenital Portosystemic Shunts (IRCPSS). Whole-genome sequencing will be utilized to analyse both coding and non-coding regions in a predominantly paediatric cohort. Targeted analysis of established pathogenic genes associated with PAH, CHD, HHT, and PoPH will be complemented by a genome wide approach to identify novel, potentially pathogenic variants, with variant classification assessed according to American College of Medical Genetics (ACMG) criteria. Family-based analyses, including trio analyses and segregation studies, will enable the identification of dominant, recessive, and de novo variants, facilitating a comprehensive evaluation of variant inheritance pattern and pathogenic potential. Ethics and dissemination: This study has been approved by the CCER (Geneva cantonal ethics committee for research) and poses minimal risk to participants, limited to blood sampling performed as part of routine clinical care for patients. Genetic data will be securely stored and analysed in compliance with GDPR. Clinically significant findings will be communicated through recruiting physicians, in accordance with participant preference regarding incidental findings. Study results will be disseminated through open-access peer-reviewed publications and scientific conferences to advance understanding and management of PoPH in individuals with CPSS and potentially other chronic liver diseases associated with portosystemic bypass.