HCN4-sinus node dysfunction with or without hypertrabeculation phenotype-autosomal dominant
HCN4 encodes hyperpolarization-activated cyclic nucleotide channel 4 subunits, which form an ion channel that plays a key role in cardiac rhythmicity as a major constituent of the hyperpolarisation-activated “funny” current (If) in the sinoatrial node, also known as the spontaneous cardiac pacemaker. Genetic variation in HCN4 was first described by Schulze-Bahr (PMID 12750403) in 2003 in a patient with sinus node dysfunction (SND). In 2014 Schweizer et al. (PMID 25145518) and Milano et al (PMID 25145517) separately reported families in which genetic variation within HCN4 segregated with the combined SND and ventricular hypertrabeculation phenotype.
At least 25 unique variants have been reported to cause SND, primarily sinus bradycardia (PMIDs 12750403, 25145518, 25145517, 16407510, 35257104, 26688388, 23178648, 34088380, 31731876, 32600061, 28104484, 20662977, 16407510, 26206080, 32577394, 17646576, 35328031, 30471092, 33082984, 29440115, 15123648, 36244448). Fifteen publications report variants as the likely aetiology of both SND and ventricular hypertrabeculation (PMIDs 25145518, 25145517, 33008772, 35257104, 26688388, 34088380, 31731876, 32600061, 28104484, 26206080, 32577394, 35328031, 30471092, 33082984, 29440115).
The phenotypes of SND and ventricular hypertrabeculation were lumped as per criteria outlined by the ClinGen Lumping and Splitting Working Group (no differences in molecular mechanism, or inheritance pattern were identified). The mechanism of pathogenicity appears to be primarily one of loss of function (PMID 25145518). Segregation data support an autosomal dominant inheritance pattern (PMID 16407510). Genetic variants resulting in SND, and ventricular hypertrabeculation are predominately non-truncating, and reside within the transmembrane region (residues 267-517). The significance of genetic variation located outside of the transmembrane region remains unclear (PMID 33500567). Genetic hotspots exist within the conserved pore-forming region (nucleotide residues 465-486).
The association between HCN4 and SND with or without ventricular hypertrabeculation, is supported by both genetic and experimental evidence. The maximum score for genetic evidence (12 points) has been reached through review of case-level data, extensive family segregation and case-control data (variant burden analysis PMID 33500567; GWAS highlighting HCN4 as a modulator of heart rate PMID 23583979; case level and segregation data listed in publications above).
Experimental evidence supporting the disease-gene association includes functional alteration data (PMIDs 33008772, 28104484, 25145517, 17646576, 25145517, 25145518, 12750403, 15123648, 23178648, 24607718, 16407510, 36244448), pharmacological targets (ivabradine-induced bradycardia), protein interaction data (STRING database) and multiple animal models demonstrating sinus node dysfunction with HCN4 knockout (PMID 17914461; PMID 18219271).
Studies of individuals with specific variants located within the HCN4 pore-forming domain (p.Tyr481His, p.Gly482Arg, and p.Arg483_Val487del) support an association between HCN4 and thoracic aortic aneurysms (PMIDs 27173043, 31731876, 33185997, 35257104, 32577394). Additionally, genetic variation in HCN4 has also been associated with early onset atrial fibrillation (PMID 24607718s, 23178648, 28104484, 12750403), left atrial dilatation (PMID 33008772), mitral valve prolapse (PMIDs 26206080, 27173043, 25145518), atrioventricular block (PMID 36381173), ventricular tachycardia (PMID 36244448), ventricular fibrillation (PMIDs 36381173, 29440115), and tachycardia-induced cardiomyopathy (PMID 29987112). Further data is required to assess the strength of these gene-disease-gene associations.
In summary, HCN4 is definitively associated with autosomal dominant sinus node dysfunction with or without ventricular hypertrabeculation. This classification was approved by the ClinGen Hereditary Cardiovascular Disease GCEP on 22/10/24 (SOP version 11).
HCN4-sinus node dysfunction with or without hypertrabeculation phenotype-autosomal dominant
HCN4 encodes hyperpolarization-activated cyclic nucleotide channel 4 subunits, which form an ion channel that plays a key role in cardiac rhythmicity as a major constituent of the hyperpolarisation-activated “funny” current (If) in the sinoatrial node, also known as the spontaneous cardiac pacemaker. Genetic variation in HCN4 was first described by Schulze-Bahr (PMID 12750403) in 2003 in a patient with sinus node dysfunction (SND). In 2014 Schweizer et al. (PMID 25145518) and Milano et al (PMID 25145517) separately reported families in which genetic variation within HCN4 segregated with the combined SND and ventricular hypertrabeculation phenotype.
At least 25 unique variants have been reported to cause SND, primarily sinus bradycardia (PMIDs 12750403, 25145518, 25145517, 16407510, 35257104, 26688388, 23178648, 34088380, 31731876, 32600061, 28104484, 20662977, 16407510, 26206080, 32577394, 17646576, 35328031, 30471092, 33082984, 29440115, 15123648, 36244448). Fifteen publications report variants as the likely aetiology of both SND and ventricular hypertrabeculation (PMIDs 25145518, 25145517, 33008772, 35257104, 26688388, 34088380, 31731876, 32600061, 28104484, 26206080, 32577394, 35328031, 30471092, 33082984, 29440115).
The phenotypes of SND and ventricular hypertrabeculation were lumped as per criteria outlined by the ClinGen Lumping and Splitting Working Group (no differences in molecular mechanism, or inheritance pattern were identified). The mechanism of pathogenicity appears to be primarily one of loss of function (PMID 25145518). Segregation data support an autosomal dominant inheritance pattern (PMID 16407510). Genetic variants resulting in SND, and ventricular hypertrabeculation are predominately non-truncating, and reside within the transmembrane region (residues 267-517). The significance of genetic variation located outside of the transmembrane region remains unclear (PMID 33500567). Genetic hotspots exist within the conserved pore-forming region (amino acid residues 465-486).
The association between HCN4 and SND with or without ventricular hypertrabeculation, is supported by both genetic and experimental evidence. The maximum score for genetic evidence (12 points) has been reached through review of case-level data, extensive family segregation and case-control data (variant burden analysis PMID 33500567; GWAS highlighting HCN4 as a modulator of heart rate PMID 23583979; case level and segregation data listed in publications above).
Experimental evidence supporting the disease-gene association includes functional alteration data (PMIDs 33008772, 28104484, 25145517, 17646576, 25145517, 25145518, 12750403, 15123648, 23178648, 24607718, 16407510, 36244448), pharmacological targets (ivabradine-induced bradycardia), protein interaction data (STRING database) and multiple animal models demonstrating sinus node dysfunction with HCN4 knockout (PMID 17914461; PMID 18219271).
Studies of individuals with specific variants located within the HCN4 pore-forming domain (p.Tyr481His, p.Gly482Arg, and p.Arg483_Val487del) support an association between HCN4 and thoracic aortic aneurysms (PMIDs 27173043, 31731876, 33185997, 35257104, 32577394). Additionally, genetic variation in HCN4 has also been associated with early onset atrial fibrillation (PMID 24607718s, 23178648, 28104484, 12750403), left atrial dilatation (PMID 33008772), mitral valve prolapse (PMIDs 26206080, 27173043, 25145518), atrioventricular block (PMID 36381173), ventricular tachycardia (PMID 36244448), ventricular fibrillation (PMIDs 36381173, 29440115), and tachycardia-induced cardiomyopathy (PMID 29987112). Further data is required to assess the strength of these gene-disease-gene associations.
In summary, HCN4 is definitively associated with autosomal dominant sinus node dysfunction with or without ventricular hypertrabeculation. This classification was approved by the ClinGen Hereditary Cardiovascular Disease GCEP on 22/10/24 (SOP version 11).
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