Pulmonary Hypertension, Neonatal, Susceptibility To

A number sign (#) is used with this entry because of evidence that susceptibility to neonatal pulmonary hypertension (PHN) is associated with variation in the CPS1 gene (608307) on chromosome 2q34.

Molecular Genetics

In a study of 31 neonates with persistent pulmonary hypertension, 6 cases of which were idiopathic, Pearson et al. (2001) found an association (p = 0.05) between PHN and a T1405N polymorphism in the carbamoyl phosphate synthetase I gene (608307.0006). The authors suggested that the functional status of carbamoyl phosphate synthetase, an enzyme that controls the rate-limiting step of the urea cycle, has a role in the cardiorespiratory transition at birth.

Canter et al. (2007) prospectively evaluated a consecutive modeling cohort of 131 children with congenital heart defects requiring surgery to determine key factors associated with increased postoperative pulmonary artery pressure (PAP), which was defined as a mean PAP above 20 mm Hg for at least 1 hour during the 48 hours following surgery measured by an indwelling pulmonary artery catheter. Multiple dimensionality reduction (MDR) was used to both internally validate observations and develop optimal 2-variable through 5-variable models that were tested prospectively in a validation cohort of 41 children. Unconditional logistic regression analysis of the modeling chohort revealed that age (OR = 0.92, p = 0.01), CPS1 T1405N (608307.0006) genotype (AC vs AA: OR = 4.08, p = 0.04; CC vs AA: OR = 5.96, p = 0.01), and Down syndrome (OR = 5.25, p = 0.04) were independent predictors of this complex phenotype. MDR predicted that the best 2-variable model consisted of age and CPS1 T1405N genotype (p less than 0.001). This 2-variable model correctly predicted 73% of the outcomes from the validation cohort. A 5-variable model that added race, gender, and Down syndrome was not significantly better than the 2-variable model. Canter et al. (2007) concluded that the CPS1 T1405N genotype appears to be an important risk factor for predicting susceptibility to increased PAP following surgical repair of congenital cardiac defects in children.

Solomon et al. (2011) reported a neonate with VACTERL association (see 192350) who experienced severe pulmonary artery hypertension following heart surgery on his second day of life. Exome sequencing in the infant and his healthy monozygotic twin revealed a novel heterozygous mutation in the CPS1 gene (G530V; 608307.0012), which was not found in 100 ethnically matched control chromosomes. Both twins were also found to carry the CPS1 T1405N polymorphism. Both mutations were inherited from their father.