Exome variant analysis in 40 mexican pulmonary arterial hypertension patients

Abstract

Pulmonary arterial hypertension (PAH) is a rare and detrimental disease with a strong genetic component, yet most studies have focused on European or Asian populations. Consequently, little is known about the genetic landscape of PAH in Mexico or whether certain variants have been underrepresented due to ancestry bias in other datasets. This work integrates a set of bioinformatic tools to identify and interpret genetic variants from Whole Exome Sequencing (WES) data of 40 Mexican patients diagnosed with the disease. All patients were recruited by Dr. Carlos Jerjes Díaz Sánchez, the primary clinical col- laborator and data provider for this study. The workflow covered all major steps of data processing, including quality control, read mapping, variant calling, and annotation. These procedures were automated through a custom pipeline implemented in Nextflow, ensuring reproducibility. Subsequently, the analytical phase integrated domain-specific knowledge to interpret variant relevance. First, we systematically examined variants present in 21 PAH-related genes. Second, we explored additional variants based three computational methods: ClinVar annotations, Gene Ontology (GO) terms, and computational predictions. This approach enabled a comprehensive assessment of potential pathogenic variants. Among the 21 PAH-related genes, BMPR2 showed the strongest evidence of pathogenicity, with two variants classified as pathogenic and one of uncertain significance, represent- ing 8% of unrelated individuals. Variants of uncertain significance were also found in eight other PAH-related genes (NOTCH3, EDN1, KCNA5, NOS2, SMAD9, TBX4, and TOPBP1), distributed across 10 of the 39 patients. Additional variants with strong but partially conflicting evidence were identified in HPGDS, TLR4, HSPB9, and other genes. These findings reinforce the central role of BMPR2 in PAH while highlighting po- tential modulatory roles of additional genes involved in inflammation and stress response pathways. Notably, not a single variant was assigned to more than four patients, suggesting that most variants were recently acquired in the family or that those individuals are the first in their families.