Genetic analysis and clinical phenotype of pulmonary arterial hypertension in an Algerian population

BACKGROUND:
Pulmonary arterial hypertension (PAH) involves progressive obstruction of small pulmonary vessels due to vascular remodeling. Although the genetic architecture of PAH is increasingly understood, it remains poorly characterized in Algeria due to limited studies and the absence of molecular diagnostic infrastructure.


OBJECTIVES:

To identify pathogenic variants in
BMPR2
and other PAH-related genes in Algerian patients, enabling targeted screening of high-risk individuals, refined classification of variants of uncertain significance (VUS), and early, personalized clinical management.



DESIGN:
Cross-sectional study using targeted next-generation sequencing (NGS) of 15 PAH-associated genes


SETTING:
Multicenter (3 university hospitals in Algiers)


PATIENTS AND METHODS:
Thirty adults with confirmed pre-capillary PAH (Group 1) of unknown etiology, diagnosed according to clinical guidelines, and 30 age- and sex-matched healthy controls were enrolled. Peripheral blood was collected for genetic analysis, and pathogenic variants were identified using targeted NGS. IL-6 plasma levels were quantified by immunoassay.


MAIN OUTCOME MEASURES:
Contribution to the genetic characterization of PAH and potential implications for personalized clinical management.


SAMPLE SIZE:
30 patients and 30 controls


RESULTS:

Pathogenic variants were identified in 6 out of 30 patients (20%) involving
BMPR2, SOX17, TBX4, ATP13A3
, and
EIF2AK4
. Homozygosity for the
EIF2AK4
variant led to a revised diagnosis of Pulmonary Veno-Occlusive Disease/Pulmonary Capillary Hemangiomatosis (PVOD/PCH). Carriers of pathogenic variants were younger at diagnosis (30 vs. 49 years,
P
=.0115) and exhibited more severe hemodynamic profiles. Most patients (80%) were in New York Heart Association (NYHA) functional class III or IV. Mean pulmonary arterial pressure (mPAP) was 59 (45–64) vs. 46 (39.7–59) mmHg in patients without variants. IL-6 levels were significantly higher in patients than in controls (
P
<.0001).



CONCLUSION:
This first genetic study in Algerian PAH patients highlights the relevance of genetic testing for diagnosis and management. The findings support the development of national genetic infrastructure and confirm the role of inflammation in PAH.


LIMITATIONS:
Modest sample size and the lack of family segregation data limited the assessment of Variant of Unknown Significance (VUS) and heritability.