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Protective effect of KCNH2 single nucleotide polymorphism K897T in LQTS families and identification of novel KCNQ1 and KCNH2 mutations.

Zhang X, Chen S, Zhang L, Liu M, Redfearn S, Bryant RM, Oberti C, Vincent GM, Wang QK - BMC Med. Genet. (2008)

Bottom Line: Notably, we have found that SNP K897T interacts with mutation A490T in cis orientation.Our family-based approach provides support that KCNH2 SNP K897T confers a protective effect on LQTS patients.Our study is the first to investigate the effect of SNP K897T on another KCNH2 mutation located in cis orientation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China. zhangx3@ccf.org

ABSTRACT

Background: KCNQ1 and KCNH2 are the two most common potassium channel genes causing long QT syndrome (LQTS), an inherited cardiac arrhythmia featured by QT prolongation and increased risks of developing torsade de pointes and sudden death. To investigate the disease expressivity, this study aimed to identify mutations and common variants that can modify LQTS phenotype.

Methods: In this study, a cohort of 112 LQTS families were investigated. Among them two large LQTS families linkage analysis with markers spanning known LQTS genes was carried out to identify the specific gene for mutational analysis. All exons and exon-intron boundaries of KCNH2 and KCNQ1 were sequenced for mutational analysis.

Results: LQTS-associated mutations were identified in eight of 112 families. Two novel mutations, L187P in KCNQ1 and 2020insAG in KCNH2, were identified. Furthermore, in another LQTS family we found that KCNH2 mutation A490T co-segregated with a common SNP K897T in KCNH2. KCNH2 SNP K897T was reported to exert a modifying effect on QTc, but it remains controversial whether it confers a risk or protective effect. Notably, we have found that SNP K897T interacts with mutation A490T in cis orientation. Seven carriers for A490T and the minor allele T of SNP K897T showed shorter QTc and fewer symptoms than carriers with A490T or A490P (P < 0.0001).

Conclusion: Our family-based approach provides support that KCNH2 SNP K897T confers a protective effect on LQTS patients. Our study is the first to investigate the effect of SNP K897T on another KCNH2 mutation located in cis orientation. Together, our results expand the mutational and clinical spectrum of LQTS and provide insights into the factors that determine QT prolongation associated with increased risk of ventricular tachycardia and sudden death.

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(A) Reduced penetrance of LQTS phenotype and effect of exercise on QTc. Mean QTc for carriers with mutation L187P and 11 non-carriers (left) and mean QTc for mutation carriers before (resting state) and during exercise (right). (B, C) Example of reduced penetrance of LQTS phenotype at baseline. Initial ECG (B) and ECG after 15-min exercise (C) are shown for a 29 year old, male, asymptomatic mutation L187P carrier.
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Figure 3: (A) Reduced penetrance of LQTS phenotype and effect of exercise on QTc. Mean QTc for carriers with mutation L187P and 11 non-carriers (left) and mean QTc for mutation carriers before (resting state) and during exercise (right). (B, C) Example of reduced penetrance of LQTS phenotype at baseline. Initial ECG (B) and ECG after 15-min exercise (C) are shown for a 29 year old, male, asymptomatic mutation L187P carrier.

Mentions: Detailed clinical analysis revealed that the penetrance of the L187P mutation was not 100%. In the family, 31 of 42 family members genetically characterized here were identified as mutation carriers (age 33 ± 21 years, 13 females and 18 males) with mean QTc of 0.468 ± 0.022 sec and 11 of 42 members as non-carriers (age 30 ± 22 years, 4 females and 7 males) with mean QTc of 0.426 ± 0.019 sec (Fig. 3). Typical LQT1 T wave patterns were present in 84% of affected members. Only 16% were symptomatic. Among mutation carriers, 58% (18/31) had normal to borderline prolonged QTc (≤0.46 sec) on their initial ECGs, which overlapped with non-carriers (Fig. 3). A bicycle exercise test was performed for 24 mutation carriers and 4 non-carriers. Mean QTc was significantly prolonged during exercise in mutation carriers, whereas it remained in the normal range in non-carriers (Fig. 3). All mutation carriers with a normal or borderline prolonged QT interval reached QTc of 0.48 sec or greater during exercise tests.


Protective effect of KCNH2 single nucleotide polymorphism K897T in LQTS families and identification of novel KCNQ1 and KCNH2 mutations.

Zhang X, Chen S, Zhang L, Liu M, Redfearn S, Bryant RM, Oberti C, Vincent GM, Wang QK - BMC Med. Genet. (2008)

(A) Reduced penetrance of LQTS phenotype and effect of exercise on QTc. Mean QTc for carriers with mutation L187P and 11 non-carriers (left) and mean QTc for mutation carriers before (resting state) and during exercise (right). (B, C) Example of reduced penetrance of LQTS phenotype at baseline. Initial ECG (B) and ECG after 15-min exercise (C) are shown for a 29 year old, male, asymptomatic mutation L187P carrier.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2570672&req=5

Figure 3: (A) Reduced penetrance of LQTS phenotype and effect of exercise on QTc. Mean QTc for carriers with mutation L187P and 11 non-carriers (left) and mean QTc for mutation carriers before (resting state) and during exercise (right). (B, C) Example of reduced penetrance of LQTS phenotype at baseline. Initial ECG (B) and ECG after 15-min exercise (C) are shown for a 29 year old, male, asymptomatic mutation L187P carrier.
Mentions: Detailed clinical analysis revealed that the penetrance of the L187P mutation was not 100%. In the family, 31 of 42 family members genetically characterized here were identified as mutation carriers (age 33 ± 21 years, 13 females and 18 males) with mean QTc of 0.468 ± 0.022 sec and 11 of 42 members as non-carriers (age 30 ± 22 years, 4 females and 7 males) with mean QTc of 0.426 ± 0.019 sec (Fig. 3). Typical LQT1 T wave patterns were present in 84% of affected members. Only 16% were symptomatic. Among mutation carriers, 58% (18/31) had normal to borderline prolonged QTc (≤0.46 sec) on their initial ECGs, which overlapped with non-carriers (Fig. 3). A bicycle exercise test was performed for 24 mutation carriers and 4 non-carriers. Mean QTc was significantly prolonged during exercise in mutation carriers, whereas it remained in the normal range in non-carriers (Fig. 3). All mutation carriers with a normal or borderline prolonged QT interval reached QTc of 0.48 sec or greater during exercise tests.

Bottom Line: Notably, we have found that SNP K897T interacts with mutation A490T in cis orientation.Our family-based approach provides support that KCNH2 SNP K897T confers a protective effect on LQTS patients.Our study is the first to investigate the effect of SNP K897T on another KCNH2 mutation located in cis orientation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China. zhangx3@ccf.org

ABSTRACT

Background: KCNQ1 and KCNH2 are the two most common potassium channel genes causing long QT syndrome (LQTS), an inherited cardiac arrhythmia featured by QT prolongation and increased risks of developing torsade de pointes and sudden death. To investigate the disease expressivity, this study aimed to identify mutations and common variants that can modify LQTS phenotype.

Methods: In this study, a cohort of 112 LQTS families were investigated. Among them two large LQTS families linkage analysis with markers spanning known LQTS genes was carried out to identify the specific gene for mutational analysis. All exons and exon-intron boundaries of KCNH2 and KCNQ1 were sequenced for mutational analysis.

Results: LQTS-associated mutations were identified in eight of 112 families. Two novel mutations, L187P in KCNQ1 and 2020insAG in KCNH2, were identified. Furthermore, in another LQTS family we found that KCNH2 mutation A490T co-segregated with a common SNP K897T in KCNH2. KCNH2 SNP K897T was reported to exert a modifying effect on QTc, but it remains controversial whether it confers a risk or protective effect. Notably, we have found that SNP K897T interacts with mutation A490T in cis orientation. Seven carriers for A490T and the minor allele T of SNP K897T showed shorter QTc and fewer symptoms than carriers with A490T or A490P (P < 0.0001).

Conclusion: Our family-based approach provides support that KCNH2 SNP K897T confers a protective effect on LQTS patients. Our study is the first to investigate the effect of SNP K897T on another KCNH2 mutation located in cis orientation. Together, our results expand the mutational and clinical spectrum of LQTS and provide insights into the factors that determine QT prolongation associated with increased risk of ventricular tachycardia and sudden death.

Show MeSH
Related in: MedlinePlus