Do
 HCN4
 Variants Predispose to Thoracic Aortic Aneurysms and Dissections?

Hanania, Hannah L.; Regalado, Ellen S.; Guo, Dongchuan; Xu, Lili; Demo, Erin; Sallee, Denver; Milewicz, Dianna M.

doi:10.1161/circgen.119.002626

Cited by 9 publications

(7 citation statements)

References 5 publications

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“…She transmitted the HCN4 variant to her son, who at the age of 35 years also presented with sinus bradycardia 38 bpm, LVNC ( Figure 1D, 1E) and mild ascending aortic dilation of 42 mm ( Figure 1F). Our novel variant in the HCN4 gene (p.Arg483_Val487del) is directly adjacent ( Figure 1G, 1H) to the variants published by Vermeer et al [3] and Hanania et al [4], so this further confirms an existence of HCN4 mutation hot-spot site specific for the combined phenotype of sinus bradycardia/LVNC/TAA, as suggested previously [4].…”

supporting

confidence: 88%

“…Another group of researchers found the HCN4 p.Gly482Arg variant in a proband with sinus bradycardia, ascending aortic dilation with moderate aortic regurgitation and LVNC [4]. In turn, we identified a novel in-frame deletion in the HCN4 gene (p.Arg483_Val487del) in a 56 years old female patient with sinus bradycardia and a history of paroxysmal atrial fibrillation, who was treated with DDDR pacemaker and diagnosed with LVNC at the age of 47 years.…”

mentioning

confidence: 71%

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A novel HCN4 variant related to familial sinus bradycardia, left ventricular noncompaction and thoracic aortic aneurysm

Ponińska¹,

Michalak²,

Śpiewak³

et al. 2020

Polish Archives of Internal Medicine

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supporting

confidence: 88%

mentioning

confidence: 71%

A novel HCN4 variant related to familial sinus bradycardia, left ventricular noncompaction and thoracic aortic aneurysm

Ponińska¹,

Michalak²,

Śpiewak³

et al. 2020

Polish Archives of Internal Medicine

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“… 1 , 2 Hence, as a result of the I f channel malfunction, mutations in the HCN4 gene had been primarily associated with sinus bradycardia and sick sinus syndrome and, more recently, with a wide spectrum of phenotypes including a few cases of HCN4 mutations linked with NCC and aortic dilatation. 2 , 3 , 4 , 5 , 7 , 8 …”

Section: Discussionmentioning

confidence: 99%

“…Similarly, we observed significant aortic dilatation in the proband and borderline aortic dilatation in his sister, but we could not demonstrate the age-dependent penetrance of the aortic dilatation as it was already present in the younger members of this family and absent in the mother. 4 In addition, in 2019, Hanania et al 7 described a family with p.Gly482Arg variant and thoracic aortic disease, bradycardia, and NCC ( Table 1 [Family F]).…”

Section: Discussionmentioning

confidence: 99%

Noncompaction Cardiomyopathy, Sick Sinus Disease, and Aortic Dilatation

et al. 2022

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“…Vermeer et al 45 Missense p.Tyr481His detected in nine members of a family with sinus bradycardia, LVNC and aortic dilation. Hanania et al 46 Missense p.Gly482Arg detected in three members of a family with aortic dilation, bradycardia and LVNC.…”

Section: Hcn4mentioning

confidence: 99%

The genetic architecture of left ventricular non-compaction reveals both substantial overlap with other cardiomyopathies and a distinct aetiology in a subset of cases

Mazzarotto

Hawley

Beltrami

et al. 2020

Preprint

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Background: Left ventricular non-compaction (LVNC) is a condition characterised by trabeculations in the myocardial wall and is the subject of considerable conjecture as to whether it represents a distinct pathology or a secondary phenotype associated with other cardiac diseases, particularly cardiomyopathies. We sought to investigate the genetic architecture of LVNC by identifying genes and variant classes robustly associated with disease and comparing these to other genetically characterised cardiomyopathies. Methods: We performed rare variant association analysis using six different LVNC cohorts comprising 840 cases together with 125,748 gnomAD population controls and compared results to similar analyses with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) cases. Results: We observed substantial overlap in genes and variant classes enriched in LVNC and DCM/HCM, indicating that in many cases LVNC belongs to a spectrum of more established cardiomyopathies, with non-compaction representing a phenotypic variation in patients with DCM- or HCM-causing variants. In contrast, five variant classes were uniquely enriched in LVNC cases, of which truncating variants in MYH7, ACTN2 and PRDM16 may represent a distinct LVNC aetiology. MYH7 truncating variants are generally considered as non-pathogenic but were detected in 2% of LVNC cases compared to 0.1% of controls, including a cluster of variants around a single splice region. Individuals with MYH7 truncating variants identified in the UK Biobank and cohorts of healthy volunteers also displayed significantly greater non-compaction compared to matched controls, with 50% meeting the diagnostic criteria for LVNC. Additionally, structural variants (exon deletions) in RYR2 and missense variants in the transmembrane region of HCN4 were enriched in LVNC cases, confirming prior reports regarding the association of these variant classes with combined LVNC and arrhythmia phenotypes. Conclusions: We demonstrated that genetic association analysis can clarify the relationship between LVNC and established cardiomyopathies, highlighted substantial overlap with DCM/HCM but also identified variant classes associated with distinct LVNC and with joint LVNC/arrhythmia phenotypes. These results underline the complex genetic landscape of LVNC and inform how genetic testing in LVNC cases should be pursued and interpreted.

show abstract

Do HCN4 Variants Predispose to Thoracic Aortic Aneurysms and Dissections?

Cited by 9 publications

References 5 publications

A novel <i>HCN4</i> variant related to familial sinus bradycardia, left ventricular noncompaction and thoracic aortic aneurysm

A novel <i>HCN4</i> variant related to familial sinus bradycardia, left ventricular noncompaction and thoracic aortic aneurysm

Noncompaction Cardiomyopathy, Sick Sinus Disease, and Aortic Dilatation

The genetic architecture of left ventricular non-compaction reveals both substantial overlap with other cardiomyopathies and a distinct aetiology in a subset of cases

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