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<p>Pulmonary arterial hypertension (PAH) is a severe disease characterized by elevated pulmonary artery pressure, leading to heart failure and premature death if untreated. Genetic factors significantly contribute to PAH, and several genes have been linked to its development. According to the ClinGen PH-GCEP group, 12 genes have definitive evidence of association with PAH, three have moderate evidence, six have limited evidence, and five remain disputed due to insufficient genetic data. The aim of this study was to analyze variants in genes without definitive evidence in a cohort of 1480 individuals (954 PAH patients and 526 relatives) by next-generation sequencing (NGS). Variants were prioritized through a custom pipeline developed in-house and classification was performed according to ACMG guidelines. A total of 32 different variants were identified in 42 individuals (32 patients and 10 relatives, five of whom developed the disease): Two pathogenic or likely pathogenic variants in <i>ABCC8</i> and 30 variants of unknown significance (VUS) in 10 genes (<i>ABCC8, AQP1, BMPR1A, BMPR1B, BMP10, FBLN2, NOTCH3, SMAD1, SMAD4 and TET2</i>). On the opposite, no candidate variants were detected in <i>GGCX</i>, <i>KLF2</i>, <i>KLK1</i> or <i>PDGFD</i> genes. These findings provide further genetic evidence supporting the association of <i>ABCC8</i> and related genes with PAH, while no candidate variants were detected in <i>GGCX, KLF2, KLK1</i>, or <i>PDGFD</i>. Further research is needed to confirm the functional impact of these variants.</p>

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Expanding the genetic burden of low-evidence genes in pulmonary arterial hypertension

  • 期刊论文

  • 发表日期：

    2026年3月25日

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  • Lucía Miranda-Alcaraz,
  • Mónica Mora-Gómez,
  • Natalia Gallego-Zazo,
  • Alejandro Cruz-Utrilla,
  • María Jesús del Cerro Marín,
  • Nuria Ochoa Parra,
  • Irene Martín de Miguel,
  • Eva Gutiérrez Ortiz,
  • Juan Andrés Jiménez-Estrada,
  • Alejandro Parra,
  • Mario Cazalla,
  • Sergio Ramos,
  • Manuel Rodríguez-Canó,
  • Cristina Silván,
  • Valeria Vásquez-Amell,
  • Pedro Arias,
  • Julián Nevado,
  • Vinicio de Jesús Pérez,
  • Pablo Lapunzina,
  • Pilar Escribano-Subías,
  • Jair Tenorio-Castano

摘要

Pulmonary arterial hypertension (PAH) is a severe disease characterized by elevated pulmonary artery pressure, leading to heart failure and premature death if untreated. Genetic factors significantly contribute to PAH, and several genes have been linked to its development. According to the ClinGen PH-GCEP group, 12 genes have definitive evidence of association with PAH, three have moderate evidence, six have limited evidence, and five remain disputed due to insufficient genetic data. The aim of this study was to analyze variants in genes without definitive evidence in a cohort of 1480 individuals (954 PAH patients and 526 relatives) by next-generation sequencing (NGS). Variants were prioritized through a custom pipeline developed in-house and classification was performed according to ACMG guidelines. A total of 32 different variants were identified in 42 individuals (32 patients and 10 relatives, five of whom developed the disease): Two pathogenic or likely pathogenic variants in ABCC8 and 30 variants of unknown significance (VUS) in 10 genes (ABCC8, AQP1, BMPR1A, BMPR1B, BMP10, FBLN2, NOTCH3, SMAD1, SMAD4 and TET2). On the opposite, no candidate variants were detected in GGCX, KLF2, KLK1 or PDGFD genes. These findings provide further genetic evidence supporting the association of ABCC8 and related genes with PAH, while no candidate variants were detected in GGCX, KLF2, KLK1, or PDGFD. Further research is needed to confirm the functional impact of these variants.