Clinical and genetic characteristics of pulmonary arterial hypertension in Lebanon

Hassan, Ossama K. Abou; Haidar, Wiam; Nemer, Georges; Skouri, Hadi; Haddad, Fadi; Akl, Imad Bou

doi:10.1186/s12881-018-0608-7

Cited by 19 publications

(24 citation statements)

References 36 publications

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“…Additionally, the group of Yuxin Fan described a severe early-onset PAH individual that had two variants probably contributing to the disease, one in BMPR2 and one in KCNA5 [ 19 ]. This was also reported in two families from Lebanon in a combination of variants in BMPR2-GDF2 and BMPR2-TBX4 , respectively [ 20 ]. Taking this into account and based on the low penetrance of BMPR2 -associated PAH, the co-occurrence of more than one variant associated with the disease might explain why some individuals with only BMPR2 mutations do not develop PAH.…”

Section: Introductionsupporting

confidence: 60%

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: Introductionsupporting

confidence: 60%

Customized Massive Parallel Sequencing Panel for Diagnosis of Pulmonary Arterial Hypertension

Tenorio

Hernández-González

Gallego

et al. 2020

Genes

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“…Genetic analyses of larger cohorts using gene panels, exome sequencing (ES), or genome sequencing (GS) have further defined the frequency of individuals with deleterious variants in PAH risk genes and have identified novel candidate risk genes. BMPR2 mutations are observed in the majority of FPAH cases across genetic ancestries [ 7 – 11 ]. BMPR2 carriers have younger mean age-of-onset and are less responsive to vasodilators compared to non-carriers [ 7 , 12 , 13 ], with an enrichment of predicted deleterious missense (D-Mis) variants with younger age-of-onset [ 7 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH

et al. 2021

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Background Pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. PAH can be associated with other diseases (APAH: connective tissue diseases, congenital heart disease, and others) but often the etiology is idiopathic (IPAH). Mutations in bone morphogenetic protein receptor 2 (BMPR2) are the cause of most heritable cases but the vast majority of other cases are genetically undefined. Methods To identify new risk genes, we utilized an international consortium of 4241 PAH cases with exome or genome sequencing data from the National Biological Sample and Data Repository for PAH, Columbia University Irving Medical Center, and the UK NIHR BioResource – Rare Diseases Study. The strength of this combined cohort is a doubling of the number of IPAH cases compared to either national cohort alone. We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 1647 IPAH cases and 18,819 controls. We also analyzed de novo variants in 124 pediatric trios enriched for IPAH and APAH-CHD. Results Seven genes with rare deleterious variants were associated with IPAH with false discovery rate smaller than 0.1: three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (fibulin 2, FBLN2; platelet-derived growth factor D, PDGFD). The new genes were identified based solely on rare deleterious missense variants, a variant type that could not be adequately assessed in either cohort alone. The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most variants occur in conserved protein domains. For pediatric PAH, predicted deleterious de novo variants exhibited a significant burden compared to the background mutation rate (2.45×, p = 2.5e−5). At least eight novel pediatric candidate genes carrying de novo variants have plausible roles in lung/heart development. Conclusions Rare variant analysis of a large international consortium identified two new candidate genes—FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling. Trio analysis predicted that ~ 15% of pediatric IPAH may be explained by de novo variants.

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“…Analysis was performed based on a filtering panel consisting of genes (Additional file 4: Table S1) implicated in PAH as previously described [14]. Only non-synonymous, insertion/deletions variants in the coding regions, and splicing variants with allele frequencies inferior to 1% were filtered in according to their evolutionary conservation, and location within the encoded protein.…”

Section: Methodsmentioning

confidence: 99%

Novel EIF2AK4 mutations in histologically proven pulmonary capillary hemangiomatosis and hereditary pulmonary arterial hypertension

Hassan¹,

Haidar²,

Arabi³

et al. 2019

BMC Med Genet

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BackgroundPulmonary hypertension (PH) remains one of the rarest and deadliest diseases. Pulmonary Capillary Hemangiomatosis (PCH) is one of the sub-classes of PH. It was identified using histological and molecular tools and is characterized by the proliferation of capillaries into the alveolar septae. Mutations in the gene encoding the eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) have recently been linked to this particular subgroup of PH.MethodsIn our effort to unveil the genetic basis of idiopathic and familial cases of PH in Lebanon, we have used whole exome sequencing to document known and/or novel mutations in genes that could explain the underlying phenotype.ResultsWe showed bi-allelic mutations in EIF2AK4 in two non-consanguineous families: a novel non-sense mutation c.1672C > T (p.Q558*) and a previously documented deletion c.560_564drlAAGAA (p.K187Rfs9*). Our histological analysis coupled with the CT-scan results showed that the two patients with the p.Q558* mutation have PH. In contrast, only one of the individuals harboring the p.K187Rfs9* variant has a documented PCH while his older brother remains asymtomatic. Differential analysis of the variants in the genes of the neighboring network of EIF2AK4 between the two siblings identified a couple of interesting missense mutations that could account for this discrepancy.ConclusionThese findings represent a novel documentation of the involvement of EIF2AK4 in the different aspects of pulmonary hypertension. The absence of a molecular mechanism that relates the abrogated function of the protein to the phenotype is still a major hurdle in our understanding of the disease.

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Clinical and genetic characteristics of pulmonary arterial hypertension in Lebanon

Cited by 19 publications

References 36 publications

Customized Massive Parallel Sequencing Panel for Diagnosis of Pulmonary Arterial Hypertension

Customized Massive Parallel Sequencing Panel for Diagnosis of Pulmonary Arterial Hypertension

Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH

Novel EIF2AK4 mutations in histologically proven pulmonary capillary hemangiomatosis and hereditary pulmonary arterial hypertension

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