Atypical long QT syndrome phenotype in heterozygous/homozygous KCNQ1 Ala590Thr

Long QT syndrome (LQTS) is a cardiac arrhythmia that frequently presents in childhood and is characterized by a prolonged QT interval on electrocardiogram (ECG) in combination with syncope or cardiac arrest; these findings often occur in the setting of physical or emotional stress or abrupt auditory stimuli. The genetics of LQTS have been well documented over the past decade, with the identification of Z15 genes corresponding to different disease subtypes. Typically, LQTS type 1 presents as 1 of 2 clinical syndromes: 1 with a severe arrhythmia phenotype and often congenital deafness due to homozygous or compound heterozygous mutation of KNCQ1 (including the Jervell and Lange-Nielsen syndrome) and the other with isolated arrhythmias of variable severity due to heterozygous KCNQ1 mutation (originally known as the Romano-Ward syndrome). This complex inheritance pattern relates partly to the multimeric nature of the Kv7.1 channel, where a single aberrant subunit can disrupt the function of an entire channel, resulting in a dominant-negative effect by which a heterozygous mutation can impair physiological function by 450%. However, the dominant-negative effect is not universal among KCNQ1 mutations, and other mutation patterns are recognized (such as nonsense mutations, which can manifest as disease-causing in the heterozygous state, albeit often with a milder phenotype). Here we present a case of a patient with severe LQTS phenotype due to homozygous nondominant-negative mutation in the KCNQ1 gene, whose heterozygous family members are unaffected.