Homozygous <i>GDF2</i> nonsense mutations result in a loss of circulating BMP9 and BMP10 and are associated with either PAH or an “HHT‐like” syndrome in children

Hodgson, Joshua; Ruiz, Lı́dia; McDonald, Jamie; Quarrell, Oliver; Ugonna, Kelechi; Bentham, James R.; Mason, Rebecca; Martin, Jennifer; Moore, D. J.; Bergstrom, Katie; Bayrak-Toydemir, Pınar; Wooderchak-Donahue, Whitney; Morrell, Nicholas W.; Condliffe, Robin; Bernabéu, Carmelo; Upton, Paul D.

doi:10.1002/mgg3.1685

Cited by 26 publications

(39 citation statements)

References 47 publications

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“…Previous studies have measured BMP9 and pBMP10 plasma levels along with the serum-derived endothelial BMP activity in patients with homozygous nonsense GDF2 mutations, PAH patient and a patient with "HHT-like" phenotype. They confirmed that it results in reduced plasma BMP9 and pBMP10 levels, even in asymptomatic heterozygous parents [33]. Furthermore, the variant specifically detected in patient 1 in this study has been previously described in heterozygosis by Hodson et al [32] in a female patient diagnosed at 46 years with PAH.…”

Section: Discussionsupporting

confidence: 89%

Expanding the Evidence of a Semi-Dominant Inheritance in GDF2 Associated with Pulmonary Arterial Hypertension

Gallego

Cruz‐Utrilla

Guillén

et al. 2021

Cells

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Pulmonary arterial hypertension (PAH) sometimes co-exists with hereditary hemorrhagic telangiectasia (HHT). Despite being clinically diagnosable according to Curaçao criteria, HHT can be difficult to diagnose due to its clinically heterogenicity and highly overlapping with PAH. Genetic analysis of the associated genes ACVRL1, ENG, SMAD4 and GDF2 can help to confirm or discard the presumptive diagnosis. As part of the clinical routine and to establish a genetic diagnosis, we have analyzed a cohort of patients with PAH and overlapping HHT features through a customized Next Generation Sequencing (NGS) panel of 21 genes, designed and validated in-house. We detected a homozygous missense variant in GDF2 in a pediatric patient diagnosed with PAH associated with HHT and a missense variant along with a heterozygous deletion in another idiopathic PAH patient (compound heterozygous inheritance). In order to establish variant segregation, we analyzed all available family members. In both cases, parents were carriers for the variants, but neither was affected. Our results expand the clinical spectrum and the inheritance pattern associated with GDF2 pathogenic variants suggesting incomplete penetrance and/or variability of expressivity with a semi-dominant pattern of inheritance.

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Section: Discussionsupporting

confidence: 89%

Expanding the Evidence of a Semi-Dominant Inheritance in GDF2 Associated with Pulmonary Arterial Hypertension

Gallego

Cruz‐Utrilla

Guillén

et al. 2021

Cells

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“…However, three other children under the age of ten years with homozygous truncating variants showed no evidence of PAH (confirmed by right heart catheterization in one) (49,50), suggesting that homozygosity does not necessarily lead to early age of onset or more severe disease, and thus GDF2 variants may act as a dominant gene in PAH susceptibility. There is also an emerging picture of overlap with HHT-like phenotypes, notably pulmonary arteriovenous malformations, that is beyond the scope of this manuscript (49)(50)(51).…”

Section: The Identification Of Homozygous Gdf2mentioning

confidence: 97%

Defining the Clinical Validity of Genes Reported to Cause Pulmonary Arterial Hypertension

Welch

Aldred

Balachandar

et al. 2022

Preprint

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BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare, progressive vasculopathy with significant cardiopulmonary morbidity and mortality. The disease is caused by both genetic and environmental factors, with genetic variants in at least 27 genes displaying putative evidence for disease causality. Genetic testing is currently recommended for adults diagnosed with heritable or idiopathic PAH, and all children diagnosed with PAH. However, testing panels vary in the number and list of genes included, and exome/genome sequencing data may reveal variants in genes with varying levels of evidence for a relationship with PAH. METHODS: An international panel of clinical and scientific experts in PAH was formed to perform an evidence-based review of heritable and idiopathic PAH gene-disease relationships. The panel performed literature searches and applied a semi-quantitative scoring system developed by the NIH Clinical Genome Resource to classify the relative strength of PAH gene-disease relationships based on genetic and experimental evidence. RESULTS: Of twenty-seven genes curated, twelve genes (BMPR2, ACVRL1, ATP13A3, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17, and TBX4) were classified as having definitive evidence for causal effects of variants. Three genes, ABCC8, GGCX, and TET2, were classified as having moderate evidence. Six genes (AQP1, BMP10, FBLN2, KLF2, KLK1, and PDGFD) were classified as having limited evidence, and TOPBP1 was classified as having no known PAH relationship. Some of the recently identified genes with moderate or limited evidence may move to a higher classification as new evidence emerges. Five genes (BMPR1A, BMPR1B, NOTCH3, SMAD1, and SMAD4) were disputed due to a paucity of genetic evidence over time. CONCLUSIONS: Evidence-based classification of PAH gene-disease relationships indicates that twelve genes have definitive evidence for causal effects of variants. We recommend that genetic testing panels include all genes with definitive evidence and that caution be taken in the interpretation of variants identified in genes with moderate or limited evidence. Genes with no known evidence for PAH or disputed genes should not be included in testing panels.

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“…Along with the genetic lesion in a predisposed (heterozygous) background, an environmental disturbance that causes increased angiogenesis and/or inflammation in the context of altered shear stress and blood flow patterns is necessary to generate an AVM [ 187 ]. Mutations in ENG, ALK1 , SMAD4 and GDF2 (Bmp9) are linked to human diseases involving AVM formation [ 9 , 11 , 27 , 188 , 189 ]. Such diseases include Hereditary Hemorrhagic Telangiectasia (HHT), where the resulting AVMs are prone to vessel wall fragility; this fragility leads to hemorrhage, which can be fatal if located in the brain, liver, or lungs [ 190 ].…”

Section: Chapter 22: Bmp Signaling In Vascular Patterningmentioning

confidence: 99%

The versatility and paradox of BMP signaling in endothelial cell behaviors and blood vessel function

Kulikauskas

Shaka

Bautch

2022

Cell. Mol. Life Sci.

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Blood vessels expand via sprouting angiogenesis, and this process involves numerous endothelial cell behaviors, such as collective migration, proliferation, cell–cell junction rearrangements, and anastomosis and lumen formation. Subsequently, blood vessels remodel to form a hierarchical network that circulates blood and delivers oxygen and nutrients to tissue. During this time, endothelial cells become quiescent and form a barrier between blood and tissues that regulates transport of liquids and solutes. Bone morphogenetic protein (BMP) signaling regulates both proangiogenic and homeostatic endothelial cell behaviors as blood vessels form and mature. Almost 30 years ago, human pedigrees linked BMP signaling to diseases associated with blood vessel hemorrhage and shunts, and recent work greatly expanded our knowledge of the players and the effects of vascular BMP signaling. Despite these gains, there remain paradoxes and questions, especially with respect to how and where the different and opposing BMP signaling outputs are regulated. This review examines endothelial cell BMP signaling in vitro and in vivo and discusses the paradox of BMP signals that both destabilize and stabilize endothelial cell behaviors.

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Homozygous GDF2 nonsense mutations result in a loss of circulating BMP9 and BMP10 and are associated with either PAH or an “HHT‐like” syndrome in children

Cited by 26 publications

References 47 publications

Expanding the Evidence of a Semi-Dominant Inheritance in GDF2 Associated with Pulmonary Arterial Hypertension

Expanding the Evidence of a Semi-Dominant Inheritance in GDF2 Associated with Pulmonary Arterial Hypertension

Defining the Clinical Validity of Genes Reported to Cause Pulmonary Arterial Hypertension

The versatility and paradox of BMP signaling in endothelial cell behaviors and blood vessel function

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