Abstract
AimsPersistent pulmonary hypertension of the newborn (PPHN) is characterized by sustained high levels of pulmonary vascular resistance after birth with etiology unclear; Arterial blood oxygen saturation of Tibetan newborns at high latitudes is higher than that of Han newborns at low latitudes, suggesting that genetic adaptation may allow sufficient oxygen to confer Tibetan populations with resistance to pulmonary hypertension; We have previously identified genetic factors related to PPHN through candidate gene sequencing; In this study, we first performed whole exome sequencing in PPHN patients to screen for genetic-related factors.Methods and resultsIn this two-phase genetic study, we first sequenced the whole exome of 20 Tibetan PPHN patients and compared it with the published genome sequences of 50 healthy high-altitude Tibetanshypoxia-related genes, a total of 166 PPHN-related variants were found, of which 49% were from 43 hypoxia-related genes; considering many studies have shown that the differences in the genetic background between Tibet and Han are characterized by hypoxia-related genetic polymorphisms, so it is necessary to further verify whether the association between hypoxia-related variants and PPHN is independent of high-altitude life. During the validation phase, 237 hypoxia-related genes were sequenced in another 80 Han PPHN patients living in low altitude areas, including genes at the discovery stage and known hypoxia tolerance, of which 413 variants from 127 of these genes were shown to be significantly associated with PPHN.hypoxia-related genes.ConclusionsOur results indicates that the association of hypoxia-related genes with PPHN does not depend on high-altitude life, at the same time, 21 rare mutations associated with PPHN were also found, including three rare variants of the tubulin tyrosine ligase-like family member 3 gene (TTLL3:p.E317K, TTLL3:p.P777S) and the integrin subunit alpha M gene (ITGAM:p.E1071D). These novel findings provide important information on the genetic basis of PPHN.
Highlights
Persistent pulmonary hypertension of the newborn (PPHN) affects 1.9 per thousand live births and is one of the important factors leading to neonatal mortality [1], the main feature of patients with PPHN is that pulmonary vascular resistance cannot be rapidly reduced to increase pulmonary blood flow and oxygen levels and to adapt to the postnatal environment [2]
We previously used target region sequencing (TRS) of genes associated with vascular activity in PPHN patients, and we found a significant association between the disease and a variant of the EDN1 endothelin 1-coding gene [9], recently, we screened clinically relevant mutations in children with PPHN patients through a target panel containing more than 2700 rare disease-related genes [10]
In a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we identified eight pathways enriched in genes with PPHN-associated variants (Q < 0.05, Table 1)
Summary
Persistent pulmonary hypertension of the newborn (PPHN) affects 1.9 per thousand live births and is one of the important factors leading to neonatal mortality [1], the main feature of patients with PPHN is that pulmonary vascular resistance cannot be rapidly reduced to increase pulmonary blood flow and oxygen levels and to adapt to the postnatal environment [2]. PPHN can be rapidly diagnosed and treated with vasodilators and life support, the mortality rate remains high, at 8–10%. Epidemiological data support the association between PPHN and the development of lung disease [5, 6]. A selective pulmonary vasodilator, is widely used in PPHN therapy; 30–40% of treated patients, those with pulmonary parenchymal lesions and pulmonary hypoplasia, fail to achieve sustained improvement in oxygenation [7]. These findings suggest that there may be a genetic basis for the disease in some PPHN patients
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