Frequent mutation of hypoxia-related genes in persistent pulmonary hypertension of the newborn

Abstract

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 hypoxiarelated 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 highaltitude 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.

Genome-wide association study identifies WWC2 as a possible locus associated with persistent pulmonary hypertension of the newborn in the Thai population

“…They found that 3 SNPs (rs192759073, rs1047883 and rs2229589) in CPS1 and one SNP (rs1044008) in NOTCH3 were significantly associated with PPHN (P<0.05). Wang et al ( 14 ) found that the p.E317K and p.P777S variants in the tubulin tyrosine ligase-like family member 3 ( TTLL3 ) gene and the p.E1071D variant in the integrin subunit alpha M ( ITGAM ) gene were associated with PPHN in high altitude areas (Tibet and Han in China). Recently, we found that the rs17034984 variant in the EPAS1 gene, which encodes either the endothelial PAS domain-containing protein 1 or the HIF-2α protein was a possible genetic susceptibility locus associated with PPHN ( 16 ).…”

Identifying Rare Genetic Variants of Immune Mediators as Risk Factors for Autism Spectrum Disorder

“…The correlation analysis of point mutations and gene levels was completed with reference to a previously published study [ 61 ]. In short, We first calculated the groups carrying rare variants, including heterozygous or homozygous mutations, referring to the gnomAD database [ 62 ] containing large-scale, whole exomes (123,136 samples, including 8624 people of East Asian ethnicity) and whole-genome sequencing samples.…”

Molecular genetics of pulmonary hypertension in children

“…The most common cause of transient PAH in neonates is persistent pulmonary hypertension of the newborn (PPHN), a failure of immediate postnatal cardiopulmonary transition with an annual incidence of 30.1 cases/million 1 , 35 . The genetic aetiology of PPHN is unclear; although potential susceptibility variants have been recently reported in CPS1 , NOTCH3 , SMAD9 and the hypoxia-related genes TTLL3 and ITGAM , these remain to be independently validated 36 , 37 .…”