New approach for genetic screening for syndrome linked to cardiac irregularities and sudden death

December 20, 2005

Italian researchers have developed a novel approach for genetic screening for long QT syndrome (LQTS), an inherited disease that predisposes young individuals to cardiac arrhythmias and sudden death, according to a study in the December 21 issue of JAMA.

The clinical value of genetic testing has been demonstrated by the evidence that carriers of LQTS mutations lacking QT interval prolongation (certain measurement on an electrocardiogram), who therefore escape clinical diagnosis, have a 10 percent risk of major cardiac events by age 40 years whenever left untreated, according to background information in the article. In LQTS, disease severity and response to therapy vary according to the genetic mutation involved. There exists a critical need to devise more efficient genetic testing for LQTS.

Carlo Napolitano, M.D., Ph.D., of the S. Maugeri Foundation, Pavia, Italy, and colleagues performed genetic screening in patients with LQTS to determine the yield of genetic testing, as well as the type and the prevalence of mutations. The study involved genetic testing of 430 patients with LQTS and 1,115 family members between June 1996 and June 2004. The researchers confirmed their findings by testing for the identified mutations in a separate cohort of 75 patients.

The researchers identified 235 different mutations, 138 of which were new, in 310 (72 percent) of 430 patients. "The clinical value of molecular screening is influenced by the percentage of successfully genotyped individuals. Our data show that 70 percent of Romano Ward [a genetic mutation of LQTS] probands [an individual or member of a family being studied in a genetic investigation] can be successfully genotyped by standard methods based on the current knowledge about the molecular substrate of LQTS. This number, obtained in a population of consecutively genotyped patients, is high enough to support the introduction of genotyping into clinical medicine," the authors write.

"We have developed an approach to improve the efficiency of genetic screening for LQTS," the researchers write. "The novel strategy for LQTS genotyping may facilitate the access to genetic testing to a broader group of individuals, such as patients receiving drugs that ... prolong QT interval; family members of individuals with idiopathic ventricular fibrillation; and depending on results of further investigation, members of the general population to define the prevalence of known genetic variants of LQTS."
(JAMA.2005; 294:2975-2980. Available pre-embargo to the media at

Editor's Note: This work was supported by grants from the National Institutes of Health. Co-author Dr. Priori has a patent pending for the proposed screening algorithm. Otherwise, none were reported.

Editorial: Efficient Genotyping for Congenital Long QT Syndrome

In an accompanying editorial, Elizabeth S. Kaufman, M.D., of Metro Health Medical Center and Case Western Reserve University, Cleveland, comments on the study on LQTS.

"Napolitano et al have provided important new information about the yield of genetic testing and about the distribution of mutations, and their proposed efficient genotyping strategy could make genetic testing accessible to more families with LQTS but at the cost of some accuracy. As the authors note, 'the more complete the screening process the higher the accuracy of the results of genetic analysis. ... [T]he ideal screening should include the evaluation of the entire coding region of each disease-related gene of each patient. However, this comprehensive approach may be neither possible nor cost-effective' everywhere based on current technology. Novel technologies for rapid and efficient DNA sequencing are on the horizon. Until these technologies are developed further, the medical community will have to decide how much accuracy is reasonable to sacrifice to make genetic testing more accessible."

(JAMA.2005; 294:3027-3028. Available pre-embargo to the media at

The JAMA Network Journals

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