-
Abstract: The proband, a 31-years-old female, was admitted for dizzy. Twenty-four-hour electrocardiogram(ECG) monitoring showed sinus bradycardia with an average heart rate of 40 beats per minute, which supported the diagnosis of sick sinus syndrome(SSS). Echocardiography demonstrated ventricular noncompaction locating at basal anterolateral, mid lateral, mid inferolateral, mid anterolateral, and apical segments of left ventricle within an ejection fraction of 67%. Her father died suddenly at age of 50 years. Her asymptomatic son(4-year-old) was also diagnosed SSS with left ventricular noncompaction(LVNC) in a pedigree investigation. To explore the genetic etiology of the overlapping cardiac disorder in the family, whole exome sequencing(WES) was performed on the proband. WES detected a heterozygous variant, c. 1438 G>C/p. Gly480 Arg is located in the HCN4 gene, which was reported to be associated with familial SSS before. Her 4-years-old son carried the same variant. The HCN4 gene encodes hyperpolarization-activated cyclic nucleotide-gated channel 4(HCN4), which conducts the hyperpolarization-activated If current in the sinoatrial node(SAN) pacemaker activity. The identified variant is located in the evolutionarily conserved region of the HCN4 gene. And the p. Gly480 residue affected by the variant is located in the pore domain of the HCN4 channel. Previous work has found that the variant in the pore domain could reduce the pacemaker current, and suppress diastolic depolarization and automaticity in SAN. Half of the patients with HCN4 variant-causing SSS displayed the cardiomyopathy phenotype of LVNC. However, the mechanism underlying the overlapping disorder is few understood. To our knowledge, this is the first case of the overlapping SSS and LVNC associated with variant c. 1438 G>C/p. Gly480 Arg in the HCN4 gene. Therefore, the HCN4 gene should be listed as genetic screening for familial SSS with or without LVNC.
-
Key words:
- sick sinus syndrome /
- left ventricular noncompaction /
- HCN4
-
-
[1] Sedaghat-Hamedani F,Haas J,Zhu F,et al.Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy[J].Eur Heart J,2017,38(46):3449-3460.
[2] Milanesi R,Baruscotti M,Gnecchi-Ruscone T,et al.Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel[J].N Engl J Med,2006,354(2):151-7.
[3] Nof E,Luria D,Brass D,et al.Point mutation in the HCN4 cardiac ion channel pore affecting synthesis,trafficking,and functional expression is associated with familial asymptomatic sinus bradycardia[J].Circulation,2007,116(5):463-70.
[4] DiFrancesco D.HCN4,sinus bradycardia and atrial fibrillation[J].Arrhythm Electrophysiol Rev,2015,4(1):9-13.
[5] Milano A,Vermeer AM,Lodder EM,et al.HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy[J].J Am Coll Cardiol,2014,64(8):745-56.
[6] Verkerk AO,Wilders R.Pacemaker activity of the human sinoatrial node:effects of HCN4 mutations on the hyperpolarization-activated current[J].Europace,2014,16(3):384-95.
[7] Campostrini G,DiFrancesco JC,Castellotti B,et al.A loss-of-function HCN4 mutation associated with familial benign myoclonic epilepsy in infancy causes increased neuronal excitability[J].Front Mol Neurosci,2018,11:269.
[8] Hategan L,Csányi B,Ördög B,et al.A novel 'splice site' HCN4 Gene mutation,c.1737+1 G>T,causes familial bradycardia,reduced heart rate response,impaired chronotropic competence and increased short-term heart rate variability[J].Int J Cardiol,2017,241:364-372.
[9] Ishikawa T,Ohno S,Murakami T,et al.Sick sinus syndrome with HCN4 mutations shows early onset and frequent association with atrial fibrillation and left ventricular noncompaction[J].Heart Rhythm,2017,14(5):717-724.
[10] Li W,Yin L,ShenC,et al.SCN5A variants:association with cardiac disorders[J].Front Physiol,2018,9:1372.
[11] Wilde AAM,Amin AS.Clinical spectrum of SCN5A mutations:long QT syndrome,brugada syndrome,and cardiomyopathy[J].JACC Clin Electrophysiol,2018,4(5):569-579.
-
计量
- 文章访问数: 266
- PDF下载数: 194
- 施引文献: 0
下载: