Novel risk genes and mechanisms implicated by exome sequencing of 2,572 individuals with pulmonary arterial hypertension

Zhu, Na; Pauciulo, Michael W.; Welch, Carrie L.; Lutz, Katie A.; Coleman, Alan; Gonzaga‐Jauregui, Claudia; Wang, Jiayao; Grimes, Joseph M.; Martin, Lisa J.; He, Hua; Biobank, Pah; Shen, Yufeng; Chung, Wendy K.; Nichols, William C.

doi:10.1101/550327

Cited by 12 publications

(18 citation statements)

References 57 publications

(60 reference statements)

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“…Mutations in 12 established risk genes and 5 recently-validated risk genes predispose to PAH, with BMPR2 mutations as the most common genetic cause of HPAH and IPAH 7,18 . Here we identify an additional novel PAH gene and report that predicted deleterious germline and/or somatic variants of TET2 underlie 0.39% of PAH cases.…”

Section: Discussionmentioning

confidence: 99%

“…DNA was extracted from whole blood from participants in the National Biological Sample and Data Repository for PAH (PAH Biobank), and exome sequencing was carried out in collaboration with the Regeneron Genetics Center or at the Cincinnati Children's Hospital Medical Center DNA Sequencing and Genotyping Core, as described previously 17,18 . We used Burrows-Wheeler Aligner (BWA-MEM) 19 to map and align paired-end reads to human reference genome (GRCh38), Picard MarkDuplicates to identify and flag PCR duplicates and GATK 20 HaplotypeCaller to call genetic variants.…”

Section: Exome Sequencing Bioinformatics and Statistical Analyses Fomentioning

confidence: 99%

“…Detailed characterization of the PAH Biobank and gnomAD cohort are described in a separate report 18 and in Table-S1. The cohort includes 2572 total cases: 43% IPAH, 48% APAH 4% FPAH and 5% other (Table S1).…”

Section: Exome Sequencing Identifies Rare Deleterious Variants In Tet2mentioning

confidence: 99%

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Novel Mutations and Decreased Expression of the Epigenetic Regulator TET2 in Pulmonary Arterial Hypertension

et al. 2020

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Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy. Hereditary cases are associated with germline mutations in BMPR2 and 16 other genes. However, these mutations occur in under 25% of idiopathic PAH patients (IPAH) and are rare in PAH associated with connective tissue diseases (APAH). Preclinical studies suggest epigenetic dysregulation, including altered DNA methylation, promotes PAH. Somatic mutations of Tet-methylcytosine-dioxygenase-2 (TET2), a key enzyme in DNA demethylation, occur in cardiovascular disease and are associated with clonal hematopoiesis, inflammation and adverse vascular remodeling. The role of TET2 in PAH is unknown. Methods: To test for a role of TET2, we utilized a cohort of 2572 cases from the PAH Biobank. Within this cohort, gene-specific rare variant association tests were performed using 1832 unrelated European PAH patients and 7509 non-Finnish European gnomAD subjects as controls. In an independent cohort of 140 patients, we quantified TET2 expression in peripheral blood mononuclear cells. To assess causality, we investigated hemodynamic and histologic evidence of PAH in hematopoietic Tet2-knockout mice. Results: We observed an increased burden of rare, predicted deleterious, germline variants in TET2 in PAH patients of European ancestry (9/1832) compared to controls (6/7509; relative risk=6, p=0.00067). Assessing the whole cohort, 0.39% (10/2572) of patients had 12 TET2 mutations (75% predicted germline and 25% somatic). These patients had no mutations in other PAH-related genes. Patients with TET2 mutations were older (71±7 years versus 48±19 years, p<0.0001) unresponsive to vasodilator challenge (0/7 vs 140/1055 (13.2%)), had lower PVR (5.2±3.1 versus 10.5±7.0 Woods units, p=0.02) and had increased inflammation (including elevation of IL-1β). Circulating TET2 expression did not correlate with age and was decreased in >86% of PAH patients. Tet2-knockout mice spontaneously developed PAH, adverse pulmonary vascular remodeling and inflammation, with elevated levels of cytokines, including IL-1β. Chronic therapy with an antibody targeting IL-1β blockade regressed PAH. Conclusions: PAH is the first human disease related to potential TET2 germline mutations. Inherited and acquired abnormalities of TET2 occur in 0.39% of PAH cases. Decreased TET2 expression is ubiquitous and has potential as a PAH biomarker.

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Section: Discussionmentioning

confidence: 99%

Section: Exome Sequencing Bioinformatics and Statistical Analyses Fomentioning

confidence: 99%

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Novel Mutations and Decreased Expression of the Epigenetic Regulator TET2 in Pulmonary Arterial Hypertension

et al. 2020

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“…This set of patients with ABCC8 variants compose a 1.76% of our cohort and show a younger age of diagnosis when compared with other recent studies 9,31 . Also, they seem to show more severe forms of the disease with higher PAP values and FC, but this may be due to the small number of patients in our cohort referring variants in this gene.…”

Section: Discussionmentioning

confidence: 50%

Characterization of rare ABCC8 variants identified in Spanish pulmonary arterial hypertension patients

Lago-Docampo

Tenorio

Hernández-González

et al. 2020

Sci Rep

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Pulmonary Arterial Hypertension (PAH) is a rare and fatal disease where knowledge about its genetic basis continues to increase. In this study, we used targeted panel sequencing in a cohort of 624 adult and pediatric patients from the Spanish PAH registry. We identified 11 rare variants in the ATP-binding Cassette subfamily C member 8 (ABCC8) gene, most of them with splicing alteration predictions. One patient also carried another variant in SMAD1 gene (c.27delinsGTAAAG). We performed an ABCC8 in vitro biochemical analyses using hybrid minigenes to confirm the correct mRNA processing of 3 missense variants (c.211C > T p.His71Tyr, c.298G > A p.Glu100Lys and c.1429G > A p.Val477Met) and the skipping of exon 27 in the novel splicing variant c.3394G > A. Finally, we used structural protein information to further assess the pathogenicity of the variants. The results showed 11 novel changes in ABCC8 and 1 in SMAD1 present in PAH patients. After in silico and in vitro biochemical analyses, we classified 2 as pathogenic (c.3288_3289del and c.3394G > A), 6 as likely pathogenic (c.211C > T, c.1429G > A, c.1643C > T, c.2422C > A, c.2694 + 1G > A, c.3976G > A and SMAD1 c.27delinsGTAAAG) and 3 as Variants of Uncertain Significance (c.298G > A, c.2176G > A and c.3238G > A). In all, we show that coupling in silico tools with in vitro biochemical studies can improve the classification of genetic variants.

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“…Estimating the true penetrance of TBX4 disease remains a high priority and impacts on variant interpretation as well as genetic counseling of respective families. A characteristic example exhibiting inter-and intra-familial variability is that of splice variant c.1021+1G>A reported by 3 independent studies (supplementary data, xlsx); index cases had adult-onset lung disease with positive family history, including first-degree relatives with severe PAH resulting in death in infancy/childhood or absent patella only (21,35,36). Leaky splicing variants (reducing but not completely abolishing the production of normal transcripts) can result in reduced penetrance although this phenomenon would still not explain the variable phenotypes observed in association with other types of recurrent variants (supplementary data, xlsx).…”

Section: Gene-specific Variant Classification and Prognostic Valuementioning

confidence: 98%

First genotype-phenotype study in TBX4 syndrome: gain-of-function mutations causative for lung disease

Prapa

Lago-Docampo

Swietlik

et al. 2022

Preprint

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RationaleDespite the increasing frequency of TBX4-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights.MethodsWe assembled a multi-center cohort of 137 patients harboring monoallelic TBX4 variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype-phenotype correlations and undertook a comparative analysis with PAH patients with BMPR2 causal variants (n = 162) or no identified variants in PAH associated genes (n = 741) genotyped via the NIHR BioResource - Rare Diseases (NBR).ResultsFunctional assessment of TBX4 missense variants revealed gain-(n=8) or loss-of-function effects (n=23) with a similar wide phenotypic spectrum, ranging from early-onset developmental lung disease to adult-onset PAH. Variants located in the T-BOX and nuclear localization domains associated with earlier presentation (p = 0.002) and increased incidence of interstitial lung disease (p = 0.001). Event-free survival (death or transplantation) was marginally lower in the T-BOX group (p = 0.049) with adjustment for age and sex. Carriers of TBX4 variants were diagnosed at a younger age (p < 0.001) and had worse baseline lung function (FEV1, FVC) (p < 0.001) compared to the BMPR2 and no identified causal variant groups.ConclusionsWe demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain-of-function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains.

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Novel risk genes and mechanisms implicated by exome sequencing of 2,572 individuals with pulmonary arterial hypertension

Cited by 12 publications

References 57 publications

Novel Mutations and Decreased Expression of the Epigenetic Regulator TET2 in Pulmonary Arterial Hypertension

Novel Mutations and Decreased Expression of the Epigenetic Regulator TET2 in Pulmonary Arterial Hypertension

Characterization of rare ABCC8 variants identified in Spanish pulmonary arterial hypertension patients

First genotype-phenotype study in TBX4 syndrome: gain-of-function mutations causative for lung disease

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