A systematic review of genetic mutations in pulmonary arterial hypertension

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Gene	Abstracts	Lvl	Category	Notes
BMPR2	242	9.9	Experimental evidence of mutations	PMID 10973254 By comparison with in vitro studies, identified defects of BMPR-II in FPPH are predicted to disrupt ligand binding, kinase activity and heteromeric dimer formation. Our data demonstrate the molecular basis of FPPH and underscore the importance in vivo of the TGF-beta signalling pathway in the maintenance of blood vessel integrity SEVERAL REPORTS (vt)
ACVRL1	42	9.9	Experimental evidence of mutations	Id. 16540754 "Molecular analysis identified mutations in the ACVRL1 gene in 7 of these 9 subjects. Even on exclusion of relatives of the single case with known pulmonary hypertension, 5 of 37 patients (13.5%) still showed values higher than those of controls" Each proband with the ALK1 mutation developed PAH. (vt)
BMP1:BMP(52)	39	9.9
ENG	33	9.9	Experimental evidence of mutations	14684682,15687131,21378382 (mosaicism),26167679 (vt)
EDN1	18	9.9	Experimental evidence of mutations	Polymorphisms.- 21537392, 22754222, 24529882, 26252367 Review: 24570333 Mutacion en ERA: 25226600 A significant association of EDN1 3A/4A polymorphism (+138 A; rs10478694) (OR-3.485; CI-1.254, 9.999; p=0.013) and EDN1 Lys198Asn polymorphism (G/T, rs5370) (OR-3.378, CI-1.104, 10.582; p=0.03) with IPAH was observed. The genotype analysis of the EDN1 gene polymorphism shows statistically significant differences in patients with PAH compared to healthy individuals. Individuals carrying at least one T allele exhibit a higher relative significant risk to develop HAP. (vt)
EIF2AK4	18	9.9	Experimental evidence of mutations	24292273 Mutations in this gene associated with other diseases. PVOD 25512148 we sequenced EIF2AK4 and found a homozygous mutation in all five families: c.3344C>T(p.P1115L). The majority of our patients required early lung transplantation. Hence, this mutation appeared with a more severe phenotype than previously reported for other EIF2AK4 mutations. The finding of this novel mutation is important for genetic counseling and calculation of population recurrence risks. 26699722 Bi-allelic mutations in EIF2AK4 were identified in all patients with a family history of PVOD (n=19) and in seven patients (8.6%) presenting as sporadic PVOD. Pre-symptomatic genetic diagnosis was offered to 272 relatives of heritable PAH patients, identifying mutations in 36.4% of them * Other disease ? * It has been found also in heritable PAH patients. (vt)
KCNK3	16	9.9	Experimental evidence of mutations	Mutated in PAH. 24037626 Recent advancements in gene sequencing methods have facilitated the discovery of additional genes with mutations among those with and without familial PAH (CAV1, KCNK3). HPAH is an autosomal dominant disease characterized by reduced penetrance, variable expressivity, and female predominance. These characteristics suggest that genetic and nongenetic factors modify disease expression, highlighting areas of active investigation. The reduced penetrance makes genetic counseling complex, as the majority of carriers of PAH-related mutations will never be diagnosed with the disease. Our study identified the association of a novel gene, KCNK3, with familial and idiopathic pulmonary arterial hypertension. Mutations in this gene produced reduced potassium-channel current, which was successfully remedied by pharmacologic manipulation. (vt)
TGFB1	16	5.3	Related but not mutated	Related but not mutated in PAH
BMP4	15	9.9	Related but not mutated	Related but not mutated.
CAV1	15	9.9	Experimental evidence of mutations	PMID 23250901 The study highlights the utility of sequencing in identifying 2 novel mutations in CAV1 in human PAH and without involvement in transforming growth factor-_ signaling. Based upon the similarities in the clinical features of these two patients, previous reports of CAV1 mutations in patients with lipodystrophies and pulmonary hypertension, and similar features seen in CAV1 null mice, we conclude that these variants are the most likely cause of one subtype of neonatal onset generalized lipodystrophy syndrome (vt)

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The data shown here is supplementary for the research publication A systematic review of genetic mutations in pulmonary arterial hypertension. Gerardo Garcia-Rivas, Carlos Jerjes-Sánchez, David Rodriguez, José Garcia-Pelaez and Victor Trevino. PMID:28768485.

Abstract

Background: Pulmonary arterial hypertension (PAH) is a group of vascular diseases that produce right ventricular dysfunction, heart failure syndrome, and death. Although the majority of patients appear idiopathic, accumulated research work combined with current sequencing technology show that many gene variants could be an important component of the disease. However, current guidelines, clinical practices, and available gene panels focus the diagnosis of PAH on a relatively low number of genes and variants associated with the bone morphogenic proteins and transforming Growth Factor-β pathways, such as the BMPR2, ACVRL1, CAV1, ENG, and SMAD9.
Methods: To provide an expanded view of the genes and variants associated with PAH, we performed a systematic literature review. Facilitated by a web tool, we classified, curated, and annotated most of the genes and PubMed abstracts related to PAH, in which many of the mutations and variants were not annotated in public databases such as ClinVar from NCBI. The gene list generated was compared with other available tests. Results: Our results reveal that there is genetic evidence for at least 30 genes, of which 21 genes shown specific mutations. Most of the genes are not covered by current available genetic panels. Many of these variants were not annotated in the ClinVar database and a mapping of these mutations suggest that next generation sequencing is needed to cover all mutations found in PAH or related diseases. A pathway analysis of these genes indicated that, in addition to the BMP and TGFβ pathways, there was connections with the nitric oxide, prostaglandin, and calcium homeostasis signalling, which may be important components in PAH.
Conclusion: Our systematic review proposes an expanded gene panel for more accurate characterization of the genetic incidence and risk in PAH. Their usage would increase the knowledge of PAH in terms of genetic counseling, early diagnosis, and potential prognosis of the disease.
Keywords: Genetic panel, Germ-line mutation, Heterozygote detection, Systematic review