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Development and Validation of an Efficient Approach to Genotyping in Clinical Practice

Carlo Napolitano, MD, PhD; Silvia G. Priori, MD, PhD; Peter J. Schwartz, MD; Raffaella Bloise, MD; Elena Ronchetti, PhD; Janni Nastoli, BS; Georgia Bottelli, BS; Marina Cerrone, MD; Sergio Leonardi, MD

JAMA. 2005;294:2975-2980.

Context  In long QT syndrome (LQTS), disease severity and response to therapy vary according to the genetic loci. There exists a critical need to devise strategies to expedite genetic analysis.

Objective  To perform genetic screening in patients with LQTS to determine the yield of genetic testing, as well as the type and the prevalence of mutations.

Design, Patients, and Setting  We investigated whether the detection of a set of frequently mutated codons in the KCNQ1, KCNH2, and SCN5A genes may translate in a novel strategy for rapid efficient genetic testing of 430 consecutive patients referred to our center between June 1996 and June 2004. The entire coding regions of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 were screened by denaturing high-performance liquid chromatography and DNA sequencing. The frequency and the type of mutations were defined to identify a set of recurring mutations. A separate cohort of 75 consecutive probands was used as a validation group to quantify prospectively the prevalence of the recurring mutations identified in the primary LQTS population.

Main Outcome Measures  Development of a novel approach to LQTS genotyping.

Results  We identified 235 different mutations, 138 of which were novel, in 310 (72%) of 430 probands (49% KCNQ1, 39% KCNH2, 10% SCN5A, 1.7% KCNE1, and 0.7% KCNE2). Fifty-eight percent of probands carried nonprivate mutations in 64 codons of KCNQ1, KCNH2, and SCN5A genes. A similar occurrence of mutations at these codons (52%) was confirmed in the prospective cohort of 75 probands and in previously published LQTS cohorts.

Conclusions  We have developed an approach to improve the efficiency of genetic screening for LQTS. This novel method may facilitate wider access to genotyping resulting in better risk stratification and treatment of LQTS patients.

Author Affiliations: Molecular Cardiology, IRCCS Fondazione S. Maugeri Foundation (Drs Napolitano, Priori, Bloise, Ronchetti, Cerrone, and Leonardi and Mss Nastoli and Bottelli); Department of Cardiology, University of Pavia (Drs Priori and Schwartz); and IRCCS Policlinico S. Matteo (Dr Schwartz), Pavia, Italy.

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