Characterization of the cardiac and non-cardiac phenotype associated with genetic variants in KCNJ2

Abstract Introduction Sequence variants in KCNJ2 are associated with Andersen-Tawil syndrome (ATS), a rare, multisystem disorder characterized by a triad of cardiac arrhythmia, periodic paralysis, and craniofacial-skeletal developmental anomalies. Purpose To define the cardiac and non-cardiac features of ATS associated with KCNJ2 variants. Methods Patients with KCNJ2 variants and features within the spectrum of ATS were identified from a detailed literature search between 2001 and 2020. Demographic, clinical and genetic data were collected. To avoid double counting the same proband, publications from the same authors or institutions were cross referenced and only included once unless it was evident that cases were not previously reported based on age, sex and specific KCNJ2. Minor allelic frequency was assessed in the Genome Aggregation Database (gnomAD). Results 296 patients (aged 25.5 ± 15.6 years) were identified from 66 publications. 136 (44%) were male and 162 (55%) probands. Age of symptom onset (reported in 100) was 10.7 ± 6.4 years. There were 162 probands. A family history of sudden death was reported for 23 probands. There were 69 different variants (fig 1a): missense (n=57), inframe deletion (n=5) and insertion (n=2), truncating (n=3), frameshift (n=1), copy number variant (n=1). Overall, penetrant disease was reported in 288 (96%), and only 2 (Arg312Cys, Pro415Leu) were seen in gnomAD. Variants at 2 residues (Arg67 and Arg218) were seen in 43 (26%) probands and 120 (41%) of all patients. Clinical data for all 3 major phenotypes was available for 289 individuals, with the full triad reported in 99 (34%) (fig 1b). A cardiac phenotype seen in 244 (84%), which was an isolated finding in 37 (13%). There was no difference in the phenotypic spectrum in those with variants Arg67 and Arg218 (fig 1c). An isolated cardiac phenotype was seen in 13/120 (11%) at these residues. Cardiac symptoms included palpitations (34/91; 37%), syncope (44/131; 34%). Cardiac arrest was reported in 20 (6.7%). ECG features included ventricular premature beats (VPB) (214/243; 90%), U wave (123/141; 87.2%), bidirectional (82/119; 68.9%), polymorphic (68/118; 57.6%) and monomorphic (7/35; 20.0%) ventricular tachycardia (VT). Arrhythmia-mediated cardiomyopathy was reported in 8. In 37 patients with an isolated cardiac phenotype, features included VPB (29/36; 81%), U waves (21/24; 88%), bidirectional (6/13; 43%), polymorphic (11/17; 65%) and monomorphic (2/7; 29%) VT. Cardiac arrest occurred in 5 (10%) cases. Conclusion The cardiac phenotype associated with KCNJ2 is highly varied. U-waves and VPB are prevalent features, and there is significant arrhythmic burden and morbidity. Identified KCNJ2 variants are highly penetrant and very rarely observed in the population. DIsease-associated variants are especially prevalent at the key functional residues 67 and 218. Improved recognition of this rare disorder will help further define the cardiac features and associated risk.