Clinical heterogeneity of Pulmonary Arterial Hypertension associated with variants in TBX4

Hernández-González, Ignacio; Tenorio, Jair; Palomino-Doza, Julián; Meñaca, Amaya Martínez; Ruiz, Rafael Morales; Lago-Docampo, Mauro; Gómez, Mónica; Gómez-Román, Javier; Valls, Ana Belén Enguita; Pérez‐Olivares, Carmen; Valverde, Diana; Carbonell, Joan Gil; Rodríguez-Monte, Elvira Garrido-Lestache; Cerro, María Jesús del; Lapunzina, Pablo; Escribano, Pilar

doi:10.1371/journal.pone.0232216

Cited by 23 publications

(26 citation statements)

References 40 publications

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“…We have found five patients from five unrelated families carrying a pathogenic or likely pathogenic variant in TBX4 [ 24 ]. All patients had a variable clinical expressivity with a moderate to severe reduction in diffusion capacity (DLCO).…”

Section: Resultsmentioning

confidence: 99%

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Customized Massive Parallel Sequencing Panel for Diagnosis of Pulmonary Arterial Hypertension

Tenorio

Hernández-González

Gallego

et al. 2020

Genes

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Pulmonary arterial hypertension is a very infrequent disease, with a variable etiology and clinical expressivity, making sometimes the clinical diagnosis a challenge. Current classification based on clinical features does not reflect the underlying molecular profiling of these groups. The advance in massive parallel sequencing in PAH has allowed for the describing of several new causative and susceptibility genes related to PAH, improving overall patient diagnosis. In order to address the molecular diagnosis of patients with PAH we designed, validated, and routinely applied a custom panel including 21 genes. Three hundred patients from the National Spanish PAH Registry (REHAP) were included in the analysis. A custom script was developed to annotate and filter the variants. Variant classification was performed according to the ACMG guidelines. Pathogenic and likely pathogenic variants have been found in 15% of the patients with 12% of variants of unknown significance (VUS). We have found variants in patients with connective tissue disease (CTD) and congenital heart disease (CHD). In addition, in a small proportion of patients (1.75%), we observed a possible digenic mode of inheritance. These results stand out the importance of the genetic testing of patients with associated forms of PAH (i.e., CHD and CTD) additionally to the classical IPAH and HPAH forms. Molecular confirmation of the clinical presumptive diagnosis is required in cases with a high clinical overlapping to carry out proper management and follow up of the individuals with the disease.

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Section: Resultsmentioning

confidence: 99%

“…Finally, variants were classified according to the ACMG guidelines [ 23 ]. A custom script developed in-house called “LACONv” has also been developed by INGEMM in order to analyze large genomic DNA gain and losses or copy number variation (CNVs) which can be found in the following repository ( ) [ 24 ].…”

Section: Methodsmentioning

confidence: 99%

Customized Massive Parallel Sequencing Panel for Diagnosis of Pulmonary Arterial Hypertension

Tenorio

Hernández-González

Gallego

et al. 2020

Genes

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“…PAH is a devastating disease if it is not treated. During the last decade the application of high throughput sequencing has increased the knowledge on the genetic basis of PAH, becoming a strong tool with high potential to find out novel treatments 30 .…”

Section: Discussionmentioning

confidence: 99%

“…Since November 2011, genetic studies have been offered to all patients included in the Spanish Registry of Pulmonary Arterial Hypertension (REHAP) with idiopathic and hereditable forms of PAH, and PVOD 2 , 30 . All the methods were performed in accordance with the ethical principles of the European Board of Medical Genetics and the 2015 ERS/ESC guidelines for the diagnosis and treatment of pulmonary hypertension to provide accurate information on the range of options available to make informed decisions and allow equal access to genetic counseling and testing 1 .…”

Section: Methodsmentioning

confidence: 99%

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

Lago-Docampo

Tenorio

Hernández-González

et al. 2020

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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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“…We previously described the clinical characteristics of our TBX4 patients indicating a female predominance, bronchial diverticulosis, distinct skeletal anomalies, and a history of asthma in all [ 32 ]. PAH associated with variants in TBX4 is clinically highly variable [ 33 ]. In addition to TBX4 , we identified LP/P variants in GDF2 , resulting in loss of BMP9 function [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic Evaluation in a Cohort of 126 Dutch Pulmonary Arterial Hypertension Patients

Heuvel

Jansen

Alsters

et al. 2020

Genes

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Pulmonary arterial hypertension (PAH) is a severe, life-threatening disease, and in some cases is caused by genetic defects. This study sought to assess the diagnostic yield of genetic testing in a Dutch cohort of 126 PAH patients. Historically, genetic testing in the Netherlands consisted of the analysis of BMPR2 and SMAD9. These genes were analyzed in 70 of the 126 patients. A (likely) pathogenic (LP/P) variant was detected in 22 (31%) of them. After the identification of additional PAH associated genes, a next generation sequencing (NGS) panel consisting of 19 genes was developed in 2018. Additional genetic testing was offered to the 48 BMPR2 and SMAD9 negative patients, out of which 28 opted for NGS analysis. In addition, this gene panel was analyzed in 56 newly identified idiopathic (IPAH) or pulmonary veno occlusive disease (PVOD) patients. In these 84 patients, NGS panel testing revealed LP/P variants in BMPR2 (N = 4), GDF2 (N = 2), EIF2AK4 (N = 1), and TBX4 (N = 3). Furthermore, 134 relatives of 32 probands with a LP/P variant were tested, yielding 41 carriers. NGS panel screening offered to IPAH/PVOD patients led to the identification of LP/P variants in GDF2, EIF2AK4, and TBX4 in six additional patients. The identification of LP/P variants in patients allows for screening of at-risk relatives, enabling the early identification of PAH.

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Clinical heterogeneity of Pulmonary Arterial Hypertension associated with variants in TBX4

Cited by 23 publications

References 40 publications

Customized Massive Parallel Sequencing Panel for Diagnosis of Pulmonary Arterial Hypertension

Customized Massive Parallel Sequencing Panel for Diagnosis of Pulmonary Arterial Hypertension

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

Genetic Evaluation in a Cohort of 126 Dutch Pulmonary Arterial Hypertension Patients

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