Mutation in KCNQ1 that has both recessive and dominant characteristics.

Inherited forms of long QT syndrome (LQTS) are characterised by an extended QT interval and clinical manifestations that include syncope and sudden death. The known genes in which mutations give rise to LQTS all produce components of cardiac ion channels. The two genes mutated in the majority of cases are KCNQ1 or HERG. The proteins produced from these genes are subunits which form tetrameric transmembrane voltage gated potassium channels. KCNQ1 interacts with IsK (also called minK), the product of the KCNE1 gene, to produce ion channels that are responsible for the cardiac Iks current, which is one of the major delayed rectifying potassium currents responsible for phase 3 repolarisation of the heart. LQTS has been subdivided clinically into the dominantly inherited Romano-Ward syndrome (RWS) 8 and recessively inherited Jervell-Lange-Nielsen syndrome (JLNS). Although the cardiac abnormalities are similar in the two conditions, JLNS also presents with bilateral deafness. Mutations in KCNQ1 produce JLNS as well as RWS, although in the latter case there appears to be a strongly dominant negative effect exerted by the mutant protein, while this is very weak or absent in mutant proteins which produce JLNS. Three reports have shown that RWS can be inherited in a recessive manner. One of these families was a compound heterozygote, where there were extended QT intervals seen for both heterozygotes, but the other two families had no heterozygotes with QTc above 450 ms. 16 These were therefore recessive both for the effect on QT interval and for clinical manifestations. None of these families showed deafness. The family described in the present report was first reported by Reardon et al in 1993, the proband having had a cardiac arrest at 4 years, and she and her brother were then found to have a QTc of 490 ms. The parents of the proband were first cousins and there were hearing abnormalities reported in several family members. It was therefore difficult to determine whether the diagnosis should be RWS or JLNS. We looked for mutations in KCNQ1 to see if we could explain these diagnostic problems.