Long, longer, long QT syndrome: what makes the difference?

Listen to the podcast associated with this article, which can also be found at ESC CardioTalk https://www.escardio.org/The-ESC/Whatwe-do/news/ESC-Cardio-Talk This editorial refers to ‘MTMR4 SNPs modulate ion channel degradation and clinical severity in congenital long QT syndrome: insights in the mechanism of action of protective modifier genes’ by Y.-K. Lee et al., pp. 767–779. Long QT syndrome (LQTS; also: Romano–Ward syndrome) in its primary and genetic form resembles an outstanding example of a rare, but quite relevant inherited arrhythmia in which excellent translational research over >2 decades led to an in-depth understanding of underlying mechanisms of physiological and impaired myocellular repolarization. By unravelling its genetic components, 70–80% of congenital LQTS can be deciphered (mutation detection rate) (Table 1) and within these, the subform LQT1, resulting from pathogenic variants in the cardiac potassium Kv7.1 channel gene KCNQ1, is the major one. To date, more than 600 disease-causing variants are known in this gene (HGMD, January 2021) and the spectrum of genetic variation includes nearly all genetic types of nucleotide variation (∼400 missense/non-sense; 50 splicing; 110 small deletions and insertions; 25 gross deletions and insertions; 5 indels; 5 complex rearrangements) with a random distribution over the entire coding region. In addition, copy number variation (CNV) and recessive traits are known. The functional characterization of non-synonymous and truncating variants in KCNQ1 was in line with a concordant loss-of-function of the encoded I(Ks) potassium channel as the key mechanism. In addition, many in vitro studies of non-synonymous variants allowed a detailed structure-function understanding of I(Ks) channel domains1 and its regulatory and auxiliary components. Moreover, these studies also paved the way for patient-derived disease modelling by the generation of hiPSC-derived myocellular cells from LQT1 patients2 and for subsequent component testing for physiological reconstitution of repolarization.