Response by Crotti et al to Letter Regarding Article, “Genetic Modifiers for the Long-QT Syndrome: How Important Is the Role of Variants in the 3′ Untranslated Region of KCNQ1?”
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We welcome the opportunity to respond to the expected comments by Amin et al regarding our article on the modifying role of 3′ untranslated region (3′UTR) single-nucleotide polymorphisms (SNPs) in type 1 long-QT syndrome patients.1
In the original cohort studied by Amin et al,2 the analysis of 3 small families supported the modifying role of 3′UTR SNPs. Amin et al now propose, as a possible reason for the different results, the predominance of haploinsufficient type 1 long-QT syndrome–causative mutations in our population. However, in our 3 founder families, 2 (KCNQ1 A341V and also KCNQ1 IVS7-2A>G) of the 3 mutations have a dominant-negative effect,3,4 and only 1 (KCNQ1-G589D) reduces the ability of the mutated proteins to form functional tetramers leading to haploinsufficiency.5 This is exactly the same pattern of their 3 families: 2 have a dominant-negative effect …