Clinical characterization of type 1 long QT syndrome caused by C-terminus Kv7.1 variants.

Variants in the KCNQ1 gene, encoding the α-subunit of the slow component of delayed rectifier K⁺ channel Kv7.1, cause long QT syndrome (LQTS) type 1. The location of variants may be one of the factors in determining prognosis. However, detailed genotype-phenotype relationships associated with C-terminus variants remain unelucidated. We investigated the clinical characteristics and variant-specific arrhythmic risks in patients with LQTS carrying Kv7.1 C-terminus variants. The study comprises 202 consecutive patients with LQTS (98 probands and 104 family members) who carry a rare heterozygous variant in the Kv7.1 C-terminus. Their clinical characteristics and arrhythmic events were investigated. We identified 36 unique C-terminus variants (25 missense and 11 non-missense). The p.R366W variant was identified in 8 families, and p.T587M was identified in 21 families in large numbers from northwestern Japan. As for the location of the variant, we found that the variants in highly conserved regions and nonhelical domains were associated with longer QTc intervals compared with the variants in other regions. Both p.R366W and p.T587M variants are located in the highly conserved and functionally pivotal regions close to helices A and D, which are associated with calmodulin binding and channel assembly (tetramerization), respectively. The probands carrying p.T587M and p.R366W variants had worse arrhythmia outcomes compared with those with other C-terminus variants. The haplotype analysis of p.T587M families was suggestive of a founder effect. The arrhythmic risk of C-terminus variants in Kv7.1 in LQTS is not homogeneous, and locations of variants can be a determining factor for prognosis. [Display omitted] [ABSTRACT FROM AUTHOR]