UMMS Affiliation

Department of Population and Quantitative Health Sciences

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Computational Biology | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Environmental Public Health | Genetic Phenomena | Genomics | Maternal and Child Health | Pulmonology | Respiratory Tract Diseases


AIMS: Persistent 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 RESULTS: In 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.

CONCLUSIONS: Our 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.


Hypoxia tolerance, Persistent pulmonary hypertension of the newborn, Target region sequencing, Whole exome sequencing

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© The Author(s). 2020 Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

DOI of Published Version



Wang M, Zhuang D, Mei M, Ma H, Li Z, He F, Cheng G, Lin G, Zhou W. Frequent mutation of hypoxia-related genes in persistent pulmonary hypertension of the newborn. Respir Res. 2020 Feb 13;21(1):53. doi: 10.1186/s12931-020-1314-5. PMID: 32054482; PMCID: PMC7020588. Link to article on publisher's site

Journal/Book/Conference Title

Respiratory research

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Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.