Abstract
BackgroundPersistent pulmonary hypertension of the newborn (PPHN) is a severe clinical problem among neonatal intensive care unit (NICU) patients. The genetic pathogenesis of PPHN is unclear. Only a few genetic polymorphisms have been identified in infants with PPHN. Our study aimed to investigate the potential genetic etiology of PPHN.MethodsThis study recruited PPHN patients admitted to the NICU of the Children’s Hospital of Fudan University from Jan 2016 to Dec 2017. Exome sequencing was performed for all patients. Variants in reported PPHN/pulmonary arterial hypertension (PAH)-related genes were assessed. Single nucleotide polymorphism (SNP) association and gene-level analyses were carried out in 74 PPHN cases and 115 non-PPHN controls with matched baseline characteristics.ResultsAmong the patient cohort, 74 (64.3%) patients were late preterm and term infants (≥ 34 weeks gestation) and 41 (35.7%) were preterm infants (< 34 weeks gestation). Preterm infants with PPHN exhibited low birth weight and a high frequency of bronchopulmonary dysplasia, respiratory distress syndrome (RDS) and mortality. Nine patients (only one preterm infant) were identified as harboring genetic variants, including three with pathogenic/likely pathogenic variants in TBX4 and BMPR2 and six with variants of unknown significance in BMPR2, SMAD9, TGFB1, KCNA5 and TRPC6. Three SNPs (rs192759073, rs1047883 and rs2229589) in CPS1 and one SNP (rs1044008) in NOTCH3 were significantly associated with PPHN (p < 0.05). CPS1 and SMAD9 were identified as risk genes for PPHN (p < 0.05).ConclusionsIn this study, we identified genetic variants in PPHN patients, and we reported CPS1, NOTCH3 and SMAD9 as risk genes for late preterm and term PPHN in a single-center Chinese cohort. Our findings provide additional genetic evidence of the pathogenesis of PPHN and new insight into potential strategies for disease treatment.
Highlights
Persistent pulmonary hypertension of the newborn (PPHN) is a severe clinical problem among neonatal intensive care unit (NICU) patients
Single nucleotide polymorphisms (SNPs) in the corticotropin-releasing hormone receptor 1 (CRHR1) and corticotropinreleasing hormone-binding protein (CRHBP) genes were significantly associated with PPHN [5]
Three SNPs in CPS1 and one SNP in NOTCH3 were significantly associated with PPHN (Table 3)
Summary
Persistent pulmonary hypertension of the newborn (PPHN) is a severe clinical problem among neonatal intensive care unit (NICU) patients. A few genetic polymorphisms have been identified in infants with PPHN. Persistent pulmonary hypertension of the newborn (PPHN) is caused by a failure in the normal circulatory transition at birth and is characterized by elevated pulmonary vascular resistance (PVR), which leads to right-to-left shunting and hypoxemia. PPHN can be idiopathic or may be caused by multiple pulmonary diseases including perinatal asphyxia, meconium aspiration syndrome (MAS), respiratory distress syndrome (RDS), pulmonary dysplasia and congenital diaphragmatic hernia [2]. Only a few genetic polymorphisms have been identified in infants with PPHN. A homozygous missense variant (L326R) in the ABCA3 gene was identified in a newborn with severe hypoxemic respiratory failure and refractory pulmonary hypertension [4]. Rs2070699 in endothelin 1 (EDN1) was found to increase the risk of PPHN with respiratory distress [6]
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