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

作者：Hategan Lidia; Csanyi Beata; Ordog Balazs; Kakonyi Kornel; Tringer Annamaria; Kiss Orsolya; Orosz Andrea; Saghy Laszlo; Nagy Istvan; Hegedus Zoltan; Rudas Laszlo; Szell Marta; Varro Andras; Forster Tamas; Sepp Robert^*

来源：International Journal of Cardiology, 2017, 241: 364-372.

DOI：10.1016/j.ijcard.2017.04.058

• Familial bradycardia
• HCN4 gene
• Sick sinus syndrome
• Chronotropic competence
• Heart rate response
• Heart rate variability

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 familymembers [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.

• 出版日期2017-8-15