# A Rare Case of Profound Pulmonary Venous Malformation in an Elderly Individual With Three Major Comorbidities: Genetic Insights

## TL;DR

This paper reports a rare case of an elderly man with an unusual number of pulmonary veins and multiple health issues, revealing genetic factors that may link heart and cancer conditions.

## Contribution

The study identifies novel genetic variants and potential pleiotropic genes associated with anomalous pulmonary venous development and comorbid heart and cancers.

## Key findings

- Whole exome sequencing identified 80 rare genes with pathological variants linked to angiogenesis, cardiogenesis, and cancer.
- The CRACD gene is highlighted as potentially important in anomalous pulmonary venous development.
- A heart failure↔colorectal/prostate cancer axis is suggested involving the C2ORF88 gene.

## Abstract

Pulmonary veins play a very important role in normal human physiology by providing oxygenated blood flow to the heart, as well as in human pathophysiology by inducing and controlling atrial fibrillation and participating in the propagation of pulmonary neoplasms, such as non-small cell lung cancer. Gaining additional insights into the mechanism(s) of pulmonary venous development (PVD) would benefit our understanding of heart and lung function under normal and clinical conditions. In the current report, we present the results of postmortem genetic screening of an 87-year-old male with a remarkably high number of pulmonary veins - 12 in total - with normal connection, who died of arteriosclerotic heart disease and heart failure with additional comorbidities being prostate and colon cancers. To advance our understanding of molecular mechanisms underlying such anomalous PVD, genetic screening was performed by whole exome sequencing (WES) using the Illumina next-generation sequencing (NGS) platform. The screening revealed 80 genes with rare (minor allele frequency, MAF ≤ 0.01) pathological/deleterious variants. The functional annotation of the affected genes allowed their grouping into subcategories, including angiogenesis, cardiogenesis, cardiovascular disease, heart failure, prostate cancer, and colon cancer. The respective results were consistent with the polygenic nature of the present case, with a significant pleiotropic component and pointed toward an important role of the CRACD gene in the observed anomalous PVD. The other important finding in our study was the apparent existence of a heart failure↔colorectal/prostate cancer axis with a potential involvement of the pleiotropic C2ORF88 gene. The latter, by virtue of its involvement in cardiogenesis and, hence, angiogenesis, could also serve as a hub gene in the putative angiogenesis↔heart failure↔cancer network, which merits further investigation using a large clinical database(s).