Lidia Hategan1, Beáta Csányi1, Balázs Ördög2, Kornél Kákonyi1, Annamária Tringer1, Orsolya Kiss1, Andrea Orosz2, László Sághy1, István Nagy3, Zoltán Hegedűs4, László Rudas5, Márta Széll6, András Varró2, Tamás Forster1, Róbert Sepp7. 1. 2nd Department of Internal Medicine and Cardiology Center, University of Szeged, Hungary. 2. Department of Pharmacology and Pharmacotherapy, University of Szeged, Hungary. 3. Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary; Seqomics Biotechnology Ltd., Mórahalom, Hungary. 4. Institute of Biophysics, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary; Department of Biochemistry and Medical Chemistry, University of Pécs, Hungary. 5. Department of Anesthesiology and Intensive Therapy, University of Szeged, Hungary. 6. Department of Medical Genetics, University of Szeged, Hungary. 7. 2nd Department of Internal Medicine and Cardiology Center, University of Szeged, Hungary. Electronic address: sepp.robert@med.u-szeged.hu.
Abstract
BACKGROUND: The most important molecular determinant of heart rate regulation in sino-atrial pacemaker cells includes hyperpolarization-activated, cyclic nucleotide-gated ion channels, the major isoform of which is encoded by the HCN4 gene. Mutations affecting the HCN4 gene are associated primarily with sick sinus syndrome. METHODS AND RESULTS: A novel c.1737+1 G>T 'splice-site' HCN4 mutation was identified in a large family with familial bradycardia which co-segregated with the disease providing a two-point LOD score of 4.87. Twelve out of the 22 investigated family members [4 males, 8 females average age 36 (SD 6) years] were considered as clinically affected (heart rate<60/min on resting ECG). Minimum [36 (SD 7) vs. 47 (SD 5) bpm, p=0.0087) and average heart rates [62 (SD 8) vs. 73 (SD 8) bpm, p=0.0168) were significantly lower in carriers on 24-hour Holter recordings. Under maximum exercise test carriers achieved significantly lower heart rates than non-carrier family members, and percent heart rate reserve and percent corrected heart rate reserve were significantly lower in carriers. Applying rigorous criteria for chronotropic incompetence a higher number of carriers exhibited chronotropic incompetence. Parameters, characterizing short-term variability of heart rate (i.e. rMSSD and pNN50%) were increased in carrier family members, even after normalization for heart rate, in the 24-hour ECG recordings with the same relative increase in 5-minute recordings. CONCLUSIONS: The identified novel 'splice site' HCN4 gene mutation, c.1737+1 G>T, causes familial bradycardia and leads to reduced heart rate response, impaired chronotropic competence and increased short-term heart rate variability in the mutation carriers.
BACKGROUND: The most important molecular determinant of heart rate regulation in sino-atrial pacemaker cells includes hyperpolarization-activated, cyclic nucleotide-gated ion channels, the major isoform of which is encoded by the HCN4 gene. Mutations affecting the HCN4 gene are associated primarily with sick sinus syndrome. METHODS AND RESULTS: A novel c.1737+1 G>T 'splice-site' HCN4 mutation was identified in a large family with familial bradycardia which co-segregated with the disease providing a two-point LOD score of 4.87. Twelve out of the 22 investigated family members [4 males, 8 females average age 36 (SD 6) years] were considered as clinically affected (heart rate<60/min on resting ECG). Minimum [36 (SD 7) vs. 47 (SD 5) bpm, p=0.0087) and average heart rates [62 (SD 8) vs. 73 (SD 8) bpm, p=0.0168) were significantly lower in carriers on 24-hour Holter recordings. Under maximum exercise test carriers achieved significantly lower heart rates than non-carrier family members, and percent heart rate reserve and percent corrected heart rate reserve were significantly lower in carriers. Applying rigorous criteria for chronotropic incompetence a higher number of carriers exhibited chronotropic incompetence. Parameters, characterizing short-term variability of heart rate (i.e. rMSSD and pNN50%) were increased in carrier family members, even after normalization for heart rate, in the 24-hour ECG recordings with the same relative increase in 5-minute recordings. CONCLUSIONS: The identified novel 'splice site' HCN4 gene mutation, c.1737+1 G>T, causes familial bradycardia and leads to reduced heart rate response, impaired chronotropic competence and increased short-term heart rate variability in the mutation carriers.
Authors: Michael J Wallace; Mona El Refaey; Pietro Mesirca; Thomas J Hund; Matteo E Mangoni; Peter J Mohler Journal: Front Genet Date: 2021-04-01 Impact factor: 4.599