A NOVEL MUTATION IN KVLQT1 IS THE MOLECULAR-BASIS OF INHERITED LONG QT SYNDROME IN A NEAR-DROWNING PATIENTS FAMILY

After identifying a 10-year-old boy with inherited long QT syndrome (L QTS) after a near-drowning that required defibrillation from torsades de pointes, evaluation of first degree relatives revealed a four-gener ation kindred comprising 26 individuals with four additional symptomat ic and eight asymptomatic members harboring an abnormally prolonged QT c (defined as greater than or equal to 0.46 s(1/2)). We set out to det ermine the molecular basis of their LOTS. The inherited LQTS represent s a collection of genetically distinct ion channelopathies with over 4 0 mutations in four fundamental cardiac ion channels identified. Molec ular studies, including linkage analysis and identification of the dis ease-associated mutation, were performed on genomic DNA isolated from peripheral blood samples from 29 available family members. Genetic lin kage analysis excluded the regions for LQT2, LQT3, and LQT5. However, the chromosome 11p15.5 region (LQT1) showed evidence of linkage with, a maximum lod score of 3.36. Examination of the KVLQT1 gene revealed a novel 3-bp deletion resulting in an in-frame Delta F339 (phenylalanin e) deletion in the proband. This Delta F339 mutation was confirmed in nine additional family members who shared both an assigned affected ph enotype and the disease-associated linked haplotype. Importantly, thre e asymptomatic family members, with a tentative clinical diagnosis bas ed on their QTc, did not have this mutation and could be reclassified as unaffected. It is noteworthy that the proband's ECG suggested the s odium channel-based LQT3 genotype. These findings show the potential i mportance of establishing a molecular diagnosis rather than initiating genotype-specific interventions based upon inspection of a patient's ECG.