Heritable pulmonary arterial hypertension: new genetic findings and environmental triggers

Our plain-English summary of Heritable pulmonary arterial hypertension: new genetic findings and environmental triggers, by M. Shaukat, E. Grünig, S. Haas, et al (Scientific Reports, 2026).

The study

• Authors: M. Shaukat, E. Grünig, S. Haas, J. Haas, M. Panahi, M. Granzow, T.J. Lange, S. Stadler, N. Sommer, P. Dorfmüller, B. Meder, S. Harutyunova, B. Egenlauf, P. Xanthouli, K. Hinderhofer, C.A. Eichstaedt
• Journal: Scientific Reports
• Published: 2026;16(1):4121
• Read it: PubMed · Publisher · Free full text

Abstract

Our goal was to identify new environmental or genetic causes in heritable pulmonary arterial hypertension (HPAH) families outside the 18 known diagnostics PAH genes. PAH gene panel sequencing was performed for 47 HPAH families which revealed pathogenic variants in 39 families. Five of the remaining families agreed to whole exome sequencing and to fill in a drug and toxin exposure questionnaire. In Family 1 and 2, mother and daughter with HPAH carried a likely pathogenic variant in the CYBA gene and a variant of uncertain significance in the FKBP1A gene, respectively, following ACMG guidelines. In Family 3, we detected a likely pathogenic variant in the PTGR2 gene. These genes could play part in PAH pathogenesis but further functional analyses are required to corroborate these findings. In the remaining two families, we could not identify any plausible genetic cause. However, a father and son with PAH reported exposure to trichloroethylene, asbestos and tramadol in Family 4. In Family 5, two brothers with pulmonary veno-occlusive disease showed occupational toxin exposure. Thus, our findings indicate that not only a genetic predisposition but also environmental triggers should be investigated for HPAH patients.

© 2026. The Author(s).

In plain English

This German study looked for the causes of pulmonary arterial hypertension (PAH), a disease of the small lung arteries, in families where it affected more than one member. Of 47 such families enrolled from 2017 to 2020, 39 had disease-causing variants in known PAH genes. Five of the remaining families had whole exome sequencing (nine patients and four healthy relatives) and filled in a drug and toxin exposure questionnaire. In three families the authors found variants in genes not yet linked to PAH (CYBA, FKBP1A, PTGR2) and said functional studies are needed. In Family 4 no likely genetic cause was found. A father, a mechanic diagnosed at 71, and his son, who disposed of hazardous waste and was diagnosed at 46, both had work exposure to trichloroethylene and asbestos dust, and both had taken the opioid tramadol. The authors concluded that trichloroethylene most likely caused their PAH, with asbestos and tramadol as potential additional triggers. They said an added genetic predisposition could not be ruled out. In Family 5, two brothers with pulmonary veno-occlusive disease had worked in a paint factory with organic solvent exposure.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Family-based genetic study: gene panel sequencing, then whole exome sequencing, plus an exposure questionnaire and medical and occupational history, in families with heritable PAH
• Who was studied: 47 heritable PAH families enrolled 2017 to 2020 at Heidelberg and other German PH centers. Whole exome sequencing was done in 5 families without variants in known genes: nine patients and four healthy relatives.
• Exposure: Genetic variants. Drug and toxin exposures recorded by questionnaire. In Family 4, occupational trichloroethylene and asbestos dust exposure, plus tramadol use; the son was also exposed to plutonium and radioactive isotopes, while wearing protective gear. In Family 5, organic solvents in a paint factory.
• Main results:
  • 39 of the 47 families carried (likely) pathogenic variants in a known PAH gene.
  • Family 1 (mother and daughter): a likely pathogenic splice site variant in CYBA.
  • Family 2 (mother and daughter): a missense variant in FKBP1A, classified as a variant of uncertain significance.
  • Family 3: a splice site variant in PTGR2, classified as likely pathogenic.
  • Family 4: no (likely) pathogenic variants were found.
  • Family 4: the father, a mechanic, was diagnosed with PAH at 71.
  • Family 4: the father smoked about 80 pack-years.
  • Family 4: the son, responsible for hazardous waste disposal, was diagnosed with PAH at 46.
  • Family 4: both father and son had common occupational long-term exposure to trichloroethylene and asbestos dust.
  • Family 4: the son took tramadol for more than 10 years before PAH onset; the father took it for 1 year, 19 years before onset.
  • Family 5: two brothers with pulmonary veno-occlusive disease had more than 20 years of exposure in a paint factory to dust containing organic solvents.
  • Family 5: autopsy tissue from one brother confirmed an unusual form of pulmonary veno-occlusive disease.
• The authors' conclusion: The authors concluded that in Family 4, long-term trichloroethylene exposure most likely led to PAH, with opioid intake and asbestos exposure as potential additional triggers, mimicking a hereditary disease. Workplace exposures to trichloroethylene or paint dust were the most likely causes in the two families without a genetic finding.
• Limitations the authors state:
  • Functional mechanisms of the candidate variants were not studied.
  • Co-segregation data were limited because some affected relatives had died.
  • ACMG classification may be misleading.
  • Regulatory and non-coding variants were only partially captured.
  • An additional genetic predisposition could not be ruled out in the two exposure families.
  • Unreported environmental exposure could not be excluded in families with genetic findings.
  • The 39 families with variants in known genes did not receive the exposure questionnaire.

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