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Alterations in the long QT syndrome genes KVLQT1 and SCN5A and methods for detecting same

a technology of kvlqt1 and scn5a, which is applied in the field of alterations in the long qt syndrome, can solve the problems of increasing the risk of arrhythmia, prolonging the cardiac action potential, and prolonging the qt interval

Inactive Publication Date: 2005-01-06
UNIV OF UTAH RES FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the heart, reduced IKs or IKr or increased INa leads to prolongation of the cardiac action potential, lengthening of the QT interval and increased risk of arrhythmia.
Genetic studies, however, have shown that diagnosis based solely on electrocardiogram is neither sensitive nor specific (Vincent et al., 1992; Priori et al., 1999).
However, a comprehensive study identifying and cataloging all LQTS-associated mutations in all five genes has not been achieved.

Method used

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  • Alterations in the long QT syndrome genes KVLQT1 and SCN5A and methods for detecting same
  • Alterations in the long QT syndrome genes KVLQT1 and SCN5A and methods for detecting same
  • Alterations in the long QT syndrome genes KVLQT1 and SCN5A and methods for detecting same

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example 1

Ascertainment and Phenotyping

[0061] Individuals were ascertained in clinics from North America and Europe. Individuals were evaluated for LQTS based on QTc (the QT interval corrected for heart rate) and for the presence of symptoms. In this study, we focused on the probands. Individuals show prolongation of the QT interval (QTc≧460 ms) and / or documented torsade de pointes, ventricular fibrillation, cardiac arrest or aborted sudden death. Informed consent was obtained in accordance with local institutional review board guidelines. Phenotypic data were interpreted without knowledge of genotype. Sequence changes altering coding regions or predicted to affect splicing that were not detected in at least 400 control chromosomes were defined as mutations. No changes except known polymorphisms were detected ina ny of the genes in the control population. This does not exclude the possibility that some mutations are rare variants not associated with disease.

example 2

Mutational Analyses

[0062] To determine the spectrum of LQTS mutations, we used SSCP (Single Stand Conformation Polymorphism) and DNA sequence analyses to screen 262 unrelated individuals with LQTS. Seventeen primer pairs were used to screen KVLQT1 (Splawski et al., 1998), twenty-one primer pairs were used for HERG (Splawski et al., 1998) and three primer pairs were used for KCNE1 (Splawski et al., 1997a) and KCNE2 (Abbott et al., 1999). Thirty-three primer pairs (Wang Q. et al., 1996b) were used in SSCP analysis to screen all SCN5A exons in 50 individuals with suspected abnormalities in INa. Exons 23-28, in which mutations were previously identified, were screened in all 262 individuals.

[0063] Gender, age, QTc and presence of symptoms are summarized in Table 1. The average age at ascertainment was 29 with a corrected QT interval of 492 ms. Seventy-five percent had a history of symptoms and females predominated with an˜2:1 ratio. Although the numbers were small, corrected QT interv...

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Abstract

Long QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on electrocardiogram and presence of syncope, seizures and sudden death. Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS. These genes are KVLQT1, HERG, SCN5A, KCNE1 and KCNE2. Mutations in KVLQT1 and KCNE1 also cause the Jervell and Lange-Nielsen syndrome, a form of LQTS associated with deafness, a phenotypic abnormality inherited in an autosomal recessive fashion. Mutational analyses were used to screen 262 unrelated individuals with LQTS for mutations in the five defined genes. A total of 134 mutations were observed of which eighty were novel.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] The present invention is a division of U.S. patent application Ser. No. 09 / 840,125 filed 24 Apr. 2001 which in turn is a division of U.S. patent application Ser. No. 09 / 634,920 filed 9 Aug. 2000. Ser. No. 09 / 634,920 is related and claims priority under 35 U.S.C. § 119(e) to provisional patent application Ser. No. 60 / 190,057 filed 17 Mar. 2000 and to provisional patent application Ser. No. 60 / 147,488 filed 9 Aug. 1999. Each application is incorporated herein by reference.[0002] This application was made with Government support from NHLBI under Grant Nos. RO1-HL46401, RO1-HL33843, RO1-HL51618, P50-HL52338 and MO1-RR000064. The federal government may have certain rights in this invention.BACKGROUND OF THE INVENTION [0003] Long QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on electrocardiogram and presence of syncope, seizures and sudden death, usually in young, otherwise healthy individual...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61P9/02C07C209/84G01N33/483C07C211/42C07K14/47C07K16/18C12N15/09C12P21/08C12Q1/42C12Q1/68G01N33/15G01N33/50G01N33/53G01N33/566
CPCC07C209/84C07C211/42C12Q2600/156C12Q1/6883C12Q2565/131C07C2102/10C07C2602/10A61P9/02
Inventor SPLAWSKI, IGORKEATING, MARK
Owner UNIV OF UTAH RES FOUND
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