Genotypes and Phenotypes of Chinese Pediatric Patients With Idiopathic and Heritable Pulmonary Arterial Hypertension—A Single-Center Study

Zhang, Hongsheng; Liu, Qian; Piao, Chunmei; Zhu, Yan; Li, Qiang‐Qiang; Du, Jie; Gu, Heng

doi:10.1016/j.cjca.2019.07.628

Cited by 18 publications

(30 citation statements)

References 31 publications

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“…BMPR1B , CAV1 , GDF2 , KCNK3 and KDR/BMP9 were identified in one to four cases each, accounting for <1% for each gene. In addition to autosomal dominant inheritance, recessively inherited EIF2AK4 variants have been identified in 1–3% of children in European and Chinese cohorts [ 31 , 45 , 46 ]. In addition, a rare occurrence of recessively inherited GDF2 variants has been reported for a 3-year-old boy with right heart failure [ 47 ].…”

Section: Genetics Of Pediatric Pah—current Knowledgementioning

confidence: 99%

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Welch

Chung

2020

Genes

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Pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. The disease is caused by both genetic and environmental factors and likely gene–environment interactions. While PAH can manifest across the lifespan, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung/heart developmental anomalies. In light of these differences, it is perhaps not surprising that emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to ~42% of pediatric-onset PAH compared to ~12.5% of adult-onset PAH. De novo variants are frequently associated with PAH in children and contribute to at least 15% of all pediatric cases. The standard of medical care for pediatric PAH patients is based on extrapolations from adult data. However, increased etiologic heterogeneity, poorer prognosis, and increased genetic burden for pediatric-onset PAH calls for a dedicated pediatric research agenda to improve molecular diagnosis and clinical management. A genomics-first approach will improve the understanding of pediatric PAH and how it is related to other rare pediatric genetic disorders.

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Section: Genetics Of Pediatric Pah—current Knowledgementioning

confidence: 99%

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Welch

Chung

2020

Genes

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“…A total of 53.41% (47/88) of these variants were classified as pathogenic or likely pathogenic, and the remaining 31.82% (38/88) VUS, meaning that we have a relatively high number of variants without clear effect. The majority of the VUS have been found in NOTCH3 , a gene from which mutations have been recently associated with IPAH [ 9 , 28 , 29 ]. It has been suggested that NOTCH3 mutations are involved in proliferation and cell viability and impairs the NOTCH3-HES5 signaling pathway, a crucial pathway in the development of PAH [ 30 ].…”

Section: Discussionmentioning

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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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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“… Topological analysis of the human KCNK3/TASK-1 channel. Positions indicate the mutations identified by Ma et al [ 50 ], Navas et al [ 51 ], Zhang [ 53 ], and Haarman [ 54 ]. …”

Section: Figurementioning

confidence: 99%

“…One of the mutations (p.Gly106Arg) in a homozygous state is associated with an early and aggressive form of PAH [ 51 ]. Best et al identified two additional mutations [ 52 ], and one additional mutation has been identified in Chinese pediatric PAH patients [ 53 ]. In 2020, a new mutation in KCNK3 was identified in a Dutch national cohort of children with PAH [ 54 ].…”

Section: Introductionmentioning

confidence: 99%

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Implication of Potassium Channels in the Pathophysiology of Pulmonary Arterial Hypertension

et al. 2020

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Pulmonary arterial hypertension (PAH) is a rare and severe cardiopulmonary disease without curative treatments. PAH is a multifactorial disease that involves genetic predisposition, epigenetic factors, and environmental factors (drugs, toxins, viruses, hypoxia, and inflammation), which contribute to the initiation or development of irreversible remodeling of the pulmonary vessels. The recent identification of loss-of-function mutations in KCNK3 (KCNK3 or TASK-1) and ABCC8 (SUR1), or gain-of-function mutations in ABCC9 (SUR2), as well as polymorphisms in KCNA5 (Kv1.5), which encode two potassium (K+) channels and two K+ channel regulatory subunits, has revived the interest of ion channels in PAH. This review focuses on KCNK3, SUR1, SUR2, and Kv1.5 channels in pulmonary vasculature and discusses their pathophysiological contribution to and therapeutic potential in PAH.

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Genotypes and Phenotypes of Chinese Pediatric Patients With Idiopathic and Heritable Pulmonary Arterial Hypertension—A Single-Center Study

Cited by 18 publications

References 31 publications

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Customized Massive Parallel Sequencing Panel for Diagnosis of Pulmonary Arterial Hypertension

Implication of Potassium Channels in the Pathophysiology of Pulmonary Arterial Hypertension

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