PDGFD

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: ClinGen

PDGFD was first reported in relation to autosomal dominant pulmonary arterial hypertension (PAH) in 2020 (Gelinas et al., PMID:33187088). Ten unique variants (all missense) reported in 10 probands in 2 publications (PMIDs: 33187088, 33971972) are included in this curation. Nine of these variants were observed in a cohort of 1647 idiopathic pulmonary arterial hypertension (IPAH) patients of European Ancestry as part of a case-control study. Variant aggregation analysis revealed a significant burden (p=0.0000172) of likely gene damaging PDGFD variants in the IPAH cohort as compared to a group of 18,819 European controls (PMID:33971972). This gene-disease relationship is supported by GTEx data demonstrating expression in human lung tissue. Gladh et al. (PMID:27032083) reported a transgenic mouse model with a phenotype of increased blood pressure but PH-specific phenotypes were not assessed. There is currently no functional evidence demonstrating a damaging effect of any of the reported PDGFD variants in humans. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Pulmonary Hypertension GCEP on the meeting date 08/30/2022 (SOP Version 9). The gene-disease relationship was re-evaluated on 09/09/2026 by the ClinGen Pulmonary Hypertension Gene Curation Expert Panel (SOP v11). The previously reported genetic evidence was re-assessed, including the PDGFD missense variants reported by Zhu et al. (PMID: 33971972) and Gelinas et al. (PMID: 33187088). The PDGFD variant p.(Glu184Lys) reported by Gelinas et al. was re-evaluated based on updated in silico evidence, including a REVEL score of 0.199, resulting in the removal of the previously assigned 0.1 points. In addition, a large 2026 cohort of approximately 950 PAH cases did not identify any PDGFD variants (Miranda-Alcaraz et al., 2026), providing no additional genetic support for the association. As a result, the total genetic evidence was revised from 2.1 to 2.0 points. Experimental evidence was also re-evaluated following publication of work by Tannenberg et al. (PMID: 41323293), which demonstrated PDGF-D expression in human pulmonary vascular lesions, particularly in smooth muscle cells and, to a lesser extent, endothelial cells, and showed that PDGF-D can induce proliferation of human and mouse pulmonary artery smooth muscle cells. However, the Pdgfd knockout mouse model did not show significant differences in intra-acinar vessel muscularization or pulmonary vascular remodeling under normoxic or chronic hypoxic conditions. However, this cannot be considered as contradictory evidence since it cannot rule out a GoF model for PDGFD variants and PAH. Based on the re-evaluation, 0.5 points were awarded for experimental evidence. A 2026 preprint reporting PDGFD as an effector gene for pulmonary artery diameter in a large GWAS was not considered scoreable because it was focus on COPD patients, not in PAH patients. The final score was therefore 2.5 points (2.0 genetic and 0.5 experimental evidence), with no replication over time and no valid contradictory evidence identified. The gene-disease relationship remains classified as Limited.

Inheritance Pattern: AD

Disease ID:MONDO:0015924

Submitter: PanelApp Australia