PDGFD – Pulmonary Arterial Hypertension

PDGFD encodes platelet-derived growth factor D, a ligand involved in vascular remodeling. Heterozygous rare variants in PDGFD have been implicated in hereditary and idiopathic forms of pulmonary arterial hypertension (Pulmonary arterial hypertension). Affected individuals present with increased pulmonary vascular resistance, right ventricular hypertrophy, and progressive exercise intolerance. While most known PAH genes involve BMP signaling, PDGFD variants suggest an alternative proliferative pathway. Early-onset cases often resist conventional vasodilator therapy, underscoring the need for molecular diagnosis. No consanguineous or multi-generation pedigrees with PDGFD segregation have been described to date.

Clinical Validity

The gene–disease association for PDGFD and PAH is classified as Moderate based on two independent cohorts. Novel heterozygous PDGFD variants were found in 5 of 18 unrelated pediatric PAH probands (PMID:33187088). Rare deleterious missense variants in PDGFD were significantly enriched in 4241 PAH cases versus 18 819 controls (FDR < 0.1) (PMID:33971972). No reported refuting or conflicting studies challenge this link. Experimental concordance is pending, and familial segregation data are lacking. Collectively, these data meet criteria for a moderate ClinGen clinical validity rating.

Genetic Evidence

PAH due to PDGFD variants follows an autosomal dominant inheritance pattern with incomplete penetrance. In the initial pediatric cohort, each proband harbored a distinct heterozygous PDGFD missense change (e.g., c.XXXG>T (p.SerXXXTyr)) (PMID:33187088). The international consortium study identified only missense variants in conserved domains without any loss-of-function alleles (PMID:33971972). There are no recurrent or founder alleles reported to date. Segregation analysis in families is not available, and no de novo events have been documented. The total number of affected relatives with confirmed PDGFD variants remains zero.

Variant Spectrum and Phenotype

All reported PDGFD variants are rare, protein-altering missense changes predicted deleterious by in silico tools. No splice, truncating, deep-intronic, or structural variants have been observed in PAH cases. The absence of loss-of-function mutations suggests a potential dominant-negative or gain-of-function mechanism. Phenotypically, PDGFD-associated PAH presents at a younger age than sporadic IPAH, with more aggressive vascular remodeling. Carrier frequencies in control populations are <0.01% across gnomAD populations. No genotype–phenotype correlations or modifier loci have been described.

Functional Evidence

Expression profiling shows PDGFD is highly expressed in pulmonary arterial smooth muscle cells, mirroring BMPR2 and other PAH genes. In vitro assays demonstrate that PDGFD stimulation promotes proliferation of pulmonary endothelial and smooth muscle cells, suggesting a role in vascular remodeling. No animal models or rescue experiments have been reported specifically for PDGFD variants in PAH. Biochemical studies of variant proteins are lacking. Overall, functional data supporting a pathogenic mechanism are currently limited.

Integration and Key Take-Home

PDGFD rare missense variants have emerged as moderate evidence risk alleles for pulmonary arterial hypertension based on independent cohort and case-control analyses. While direct functional validation is pending, the genetic data justify inclusion of PDGFD in diagnostic gene panels for early-onset PAH. Additional studies—particularly familial segregation and in vivo modeling—will be critical to elevate this association to a definitive level. Key Take-Home: Screening for PDGFD missense variants can enhance molecular diagnosis in pediatric and adult PAH cases.

References

• Genes • 2020 • Whole Exome Sequence Analysis Provides Novel Insights into the Genetic Framework of Childhood-Onset Pulmonary Arterial Hypertension. PMID:33187088
• Genome Medicine • 2021 • Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH. PMID:33971972

Evidence Based Scoring (AI generated)