P1584A HCN4 previously undescribed variant in a large kindred with familial atrial fibrillation

Abstract

BACKGROUND: Genetic background can be difficult to relate to accepted mechanisms of atrial fibrillation (AF). Mutation of genes encoding ionic channels can result in early onset, familial AF while other variants can be associated to AF risk without clear definition of mechanisms. Mutations in hyperpolarization-activated cyclic nucleotide- gated channel 4 (HCN4 - 15q24.1) belong to the second category. OBJECTIVE(S): Genetic and clinical study of three generations (G) of a large kindred with high incidence of AF (Figure). First G (G-I), both parents dead, no clinical information. Second G (G-II) made of 15 siblings, 4 with clinical AF. Third generation (G-III) made of 43 subjects. METHOD(S): Long-term ECG monitoring (average 12 days / 282 655 h / 22 61.5 h per day) in subjects without clinical AF by means of full time recording of 1 ECG lead supported by a new type of textile electrodes mounted on a wearable band, with good tolerance. Full visual review of continuous recordings by 2 cardiologists, supported by analysis software, blinded to genetic testing. Doubtful findings resolved by wider consensus. Genetic study: The 4 affected siblings were genotyped by next generation sequencing by means of a Haloplex Custom panel including coding regions and untranslated (UTR) boundaries of 82 genes encoding cardiac ion channels, proteins of cardiac channelosomes, and other proteins that modulate ion channel activity. Variants found were confirmed by the Sanger method. RESULT(S): Fifty % of subjects were women (33% in G-II, 53% in G-III, P =0.65). Average age 38+/-14 y/o G-II subjects were older (63+/-7 y/o vs 32+/-8, P<0.001), had more hypertension (50% vs 0%, P=0.004), dislipidemia in (50% vs 24%, P=0.3), smoking habit (50% vs 7.7%, P=1), overweight (80% vs 38%, P=1) and sleep apnea (50% vs 24%,P=0.034). Genetic testing and Holter were performed in 7 of 13 living G-II and 26 of 43 G-III subjects (Figure). All 4 G-II subjects with clinical AF shared a heterozygous variant (NM-005477.2:c.3488C>A) at the HCN4 gene, leading to substitution of Pro1163 residue, located at the end of the C-terminus of the channel, to His (p.P1163H hcn4). This variant was also indentified by Sanger in 2 other G-II subjects, of whom 1 had frequent atrial extrasystoles and a 6 min run of atrial tachycardia in Holter. Five G-III subjects had the same heterozygous HCN4 mutation but no AF clinically or in Holter. Sinus node dysfunction was not evident in any of the subjects clinically or by Holter. CONCLUSION(S): This large family with a new HCN4 variant and a high clinical incidence of AF shows a complex genotype/phenotype relationship. The incidence of AF was not related to sinus node dysfunction. The relationship of the HCN4 variant with the incidence of AF remains obscure, suggesting a multi-factorial mechanism, including age, and the possible effect on ionic currents other than If. Follow-up of relatives without AF should help clarify the issue. (Figure Presented).