Table 2 Genetic Variants Relevant to Persistent Pulmonary Hypertension of the Newborn.

From: Phenotyping persistent pulmonary hypertension of the newborn: recognition of its persistence across world symposium on pulmonary hypertension classifications

Pathway

Genes / Disorders

Brief clinical relevance

Surfactant production and alveolar epithelial function

ATP Binding Cassette Subfamily A Member 3 (ABCA3); Surfactant Protein B (SFTPB); Surfactant Protein C (SFTPC); NK2 Homeobox 1 (NKX2-1)

Disruption of surfactant synthesis, processing, or regulation leading to severe neonatal respiratory failure that may present with or mimic PPHN.

Pulmonary vascular development and angiogenesis

Bone Morphogenetic Protein Receptor Type 2 (BMPR2); Activin A Receptor Like Type 1 (ACVRL1); Endoglin (ENG); Growth Differentiation Factor 2 (GDF2); Caveolin 1 (CAV1); ATPase 13A3 (ATP13A3); Aquaporin 1 (AQP1); Neurogenic locus notch homolog protein 3 (NOTCH3), Trisomy 21

Abnormal pulmonary vascular growth, endothelial dysfunction, and impaired vasoreactivity associated with heritable or neonatal-onset PH

Transforming growth factor–β (TGF-β)/Bone morphogenetic protein (BMP) signaling cascade

SMAD Family Member 9 (SMAD9); Eukaryotic Translation Initiation Factor 2 Alpha Kinase 4 (EIF2AK4)

Dysregulated TGF-β/BMP signaling resulting in abnormal vascular remodeling and pulmonary hypertension.

Pulmonary mesenchymal and airway development

Forkhead Box F1 (FOXF1); SRY-Box Transcription Factor 17 (SOX17); T-Box Transcription Factor 4 (TBX4); Alveolar Capillary Dysplasia (ACD); Congenital Acinar Dysplasia (CAD); Congenital Alveolar Dysplasia (CADys)

Abnormal distal lung, airway, and pulmonary vascular morphogenesis resulting in severe neonatal respiratory failure, early pulmonary hypertension, and misaligned pulmonary veins; FOXF1 variants are associated with ACD.

Ion channel and vascular tone regulation

Potassium Two-Pore Domain Channel Subfamily K Member 3 (KCNK3)

Altered pulmonary arterial smooth muscle cell membrane potential leading to impaired vasodilation and increased pulmonary vascular resistance.

Metabolic disorders influencing neonatal pulmonary hypertension

Carbamoyl-Phosphate Synthase 1 (CPS1)

CPS1 deficiency causes hyperammonemia, which can secondarily precipitate neonatal pulmonary hypertension and hypoxemic respiratory failure.

  1. PPHN persistent pulmonary hypertension of the newborn.
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