Sodium channel abnormalities are infrequent in patients with long QT syndrome: Identification of two novel SCN5A mutations

Long QT syndrome (LQTS) is a heterogeneous disorder caused by mutations of at least five different loci, Three of these, LQT1, LQT2, and LQT5, encode potassium channel subunits, LQT3 encodes the cardiac-specific sodium channe l, SCN5A, Previously reported LQTS-associated mutations of SCN5A include a recurring three amino acid deletion (Delta KPQ1505-1507) in four different families, and four different missense mutations, We have examined the SCN5A gene in 88 index cases with LQTS, including four with Jervell and Lange-Ni elsen syndrome and the remainder with Romano-Ward syndrome. Screening porti ons of DIII-DIV, where mutations have previously been found, showed that no ne of these patients has the three amino acid deletion, Delta KPQ1505-1507, or the other four known mutations. We identified a novel missense mutation , T1645M, in the DIV; S4 voltage sensor immediately adjacent to the previou sly reported mutation R1644H. We also examined all of the additional pore-f orming regions and voltage-sensing regions and discovered another novel mut ation, T1304M, at the voltage-sensing region DIII; S4, Neither T1645M nor T 1304M were seen in a panel of unaffected control individuals. Five of six T 1304M gene carriers were symptomatic. In contrast to previous studies, QT(o nset-c) was not a sensitive indicator of SCN5A-associated LQTS, at least in this family. These data suggest that mutations of SCN5A are responsible fo r only a small proportion of LQTS cases. (C) 1999 Wiley-Liss, Inc.