# 613693

LONG QT SYNDROME 6; LQT6


Other entities represented in this entry:

LONG QT SYNDROME 6, ACQUIRED, SUSCEPTIBILITY TO, INCLUDED
LONG QT SYNDROME 3/6, DIGENIC, INCLUDED; LQT3/6, DIGENIC, INCLUDED

Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
21q22.11 Long QT syndrome 6 613693 AD 3 KCNE2 603796
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal dominant
CARDIOVASCULAR
Heart
- Prolonged QT interval on EKG
- Syncope
- Torsade de pointes
- Ventricular fibrillation
- Sudden cardiac death
MISCELLANEOUS
- Association of cardiac events with exercise
- Genetic heterogeneity (see LQT1 192500)
- Patients with more severe phenotype have been reported with mutations in more than 1 LQT-related gene
- GEI (gene-environment interaction) - association of cardiac events with drug administration
MOLECULAR BASIS
- Caused by mutation in the potassium voltage-gated channel, Isk-related family, member 2 gene (KCNE2, 603796.0001)

TEXT

A number sign (#) is used with this entry because of evidence that long QT syndrome-6 (LQT6) is caused by heterozygous mutation in the KCNE2 gene (603796) on chromosome 21q22.

Digenic inheritance has also been reported; see MOLECULAR GENETICS.


Description

Congenital long QT syndrome is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncope, seizure, or sudden death (Jongbloed et al., 1999).

For a discussion of genetic heterogeneity of long QT syndrome, see LQT1 (192500).


Clinical Features

Abbott et al. (1999) reported a healthy 38-year-old Caucasian female who had had ventricular fibrillation while jogging. Her resuscitation required defibrillation. The results from echocardiography and cardiac catheterization with electrophysiologic studies and right ventricular biopsy were normal. Subsequent electrocardiograms showed an atypical response to exercise with QTc intervals ranging from 390 to 500 ms.


Molecular Genetics

In 2 healthy females with LQT5, Abbott et al. (1999) identified heterozygosity for different missense mutations in the KCNE2 gene (603796.0002-603796.0003).

In a 76-year-old African American female with acquired long QT syndrome, Abbott et al. (1999) identified a heterozygous missense mutation in the KCNE2 gene (603796.0001).

Splawski et al. (2000) screened 262 unrelated individuals with LQT syndrome for mutations in the 5 defined genes (KCNQ1, 607542; KCNH2, 152427; SCN5A 600163; KCNE1, 176261; and KCNE2) and identified mutations in 177 individuals (68%). KCNQ1 and KCNH2 accounted for 87% of mutations (42% and 45%, respectively), and SCN5A, KCNE1, and KCNE2 for the remaining 13% (8%, 3%, and 2%, respectively).

Digenic Inheritance

Tester et al. (2005) analyzed 5 LQTS-associated cardiac channel genes in 541 consecutive unrelated patients with LQT syndrome (average QTc, 482 ms). In 272 (50%) patients, they identified 211 different pathogenic mutations, including 88 in KCNQ1, 89 in KCNH2, 32 in SCN5A, and 1 each in KCNE1 and KCNE2. Mutations considered pathogenic were absent in more than 1,400 reference alleles. Among the mutation-positive patients, 29 (11%) had 2 LQTS-causing mutations, of which 16 (8%) were in 2 different LQTS genes (biallelic digenic). Tester et al. (2005) noted that patients with multiple mutations were younger at diagnosis, but they did not discern any genotype/phenotype correlations associated with location or type of mutation.

In a 1-month-old male infant who had syncope, torsade de pointes, cardiac arrest, and a QTc of 460 ms, Millat et al. (2006) identified biallelic digenic mutations: an F60L mutation in the KCNE2 gene (603796.0005) and an R1623Q mutation in the SCN5A gene (600163.0007).


REFERENCES

  1. Abbott, G. W., Sesti, F., Splawsky, I., Buck, M. E., Lehmann, M. H., Timothy, K. W., Keating, M. T., Goldstein, S. A. N. MiRP1 forms I(kr) potassium channels with HERG and is associated with cardiac arrhythmia. Cell 97: 175-187, 1999. [PubMed: 10219239, related citations] [Full Text]

  2. Jongbloed, R. J. E., Wilde, A. A. M., Geelen, J. L. M. C., Doevendans, P., Schaap, C., Van Langen, I., van Tintelen, J. P., Cobben, J. M., Beaufort-Krol, G. C. M., Geraedts, J. P. M., Smeets, H. J. M. Novel KCNQ1 and HERG missense mutations in Dutch long-QT families. Hum. Mutat. 13: 301-310, 1999. [PubMed: 10220144, related citations] [Full Text]

  3. Millat, G., Chevalier, P., Restier-Miron, L., Da Costa, A., Bouvagnet, P., Kugener, B., Fayol, L., Gonzalez Armengod, C., Oddou, B., Chanavat, V., Froidefond, E., Perraudin, R., Rousson, R., Rodriguez-Lafrasse, C. Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome. Clin. Genet. 70: 214-227, 2006. [PubMed: 16922724, related citations] [Full Text]

  4. Splawski, I., Shen, J., Timothy, K. W., Lehmann, M. H., Priori, S., Robinson, J. L., Moss, A. J., Schwartz, P. J., Towbin, J. A., Vincent, G. M., Keating, M. T. Spectrum of mutations in long-QT syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 102: 1178-1185, 2000. [PubMed: 10973849, related citations] [Full Text]

  5. Tester, D. J., Will, M. L., Haglund, C. M., Ackerman, M. J. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm 2: 507-517, 2005. [PubMed: 15840476, related citations] [Full Text]


Creation Date:
Carol A. Bocchini : 1/14/2011
carol : 10/24/2016
carol : 10/21/2016
carol : 06/01/2016
carol : 9/18/2015
alopez : 6/12/2014
alopez : 2/3/2012
carol : 1/14/2011

# 613693

LONG QT SYNDROME 6; LQT6


Other entities represented in this entry:

LONG QT SYNDROME 6, ACQUIRED, SUSCEPTIBILITY TO, INCLUDED
LONG QT SYNDROME 3/6, DIGENIC, INCLUDED; LQT3/6, DIGENIC, INCLUDED

ORPHA: 101016, 768;   DO: 0110648;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
21q22.11 Long QT syndrome 6 613693 Autosomal dominant 3 KCNE2 603796

TEXT

A number sign (#) is used with this entry because of evidence that long QT syndrome-6 (LQT6) is caused by heterozygous mutation in the KCNE2 gene (603796) on chromosome 21q22.

Digenic inheritance has also been reported; see MOLECULAR GENETICS.


Description

Congenital long QT syndrome is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncope, seizure, or sudden death (Jongbloed et al., 1999).

For a discussion of genetic heterogeneity of long QT syndrome, see LQT1 (192500).


Clinical Features

Abbott et al. (1999) reported a healthy 38-year-old Caucasian female who had had ventricular fibrillation while jogging. Her resuscitation required defibrillation. The results from echocardiography and cardiac catheterization with electrophysiologic studies and right ventricular biopsy were normal. Subsequent electrocardiograms showed an atypical response to exercise with QTc intervals ranging from 390 to 500 ms.


Molecular Genetics

In 2 healthy females with LQT5, Abbott et al. (1999) identified heterozygosity for different missense mutations in the KCNE2 gene (603796.0002-603796.0003).

In a 76-year-old African American female with acquired long QT syndrome, Abbott et al. (1999) identified a heterozygous missense mutation in the KCNE2 gene (603796.0001).

Splawski et al. (2000) screened 262 unrelated individuals with LQT syndrome for mutations in the 5 defined genes (KCNQ1, 607542; KCNH2, 152427; SCN5A 600163; KCNE1, 176261; and KCNE2) and identified mutations in 177 individuals (68%). KCNQ1 and KCNH2 accounted for 87% of mutations (42% and 45%, respectively), and SCN5A, KCNE1, and KCNE2 for the remaining 13% (8%, 3%, and 2%, respectively).

Digenic Inheritance

Tester et al. (2005) analyzed 5 LQTS-associated cardiac channel genes in 541 consecutive unrelated patients with LQT syndrome (average QTc, 482 ms). In 272 (50%) patients, they identified 211 different pathogenic mutations, including 88 in KCNQ1, 89 in KCNH2, 32 in SCN5A, and 1 each in KCNE1 and KCNE2. Mutations considered pathogenic were absent in more than 1,400 reference alleles. Among the mutation-positive patients, 29 (11%) had 2 LQTS-causing mutations, of which 16 (8%) were in 2 different LQTS genes (biallelic digenic). Tester et al. (2005) noted that patients with multiple mutations were younger at diagnosis, but they did not discern any genotype/phenotype correlations associated with location or type of mutation.

In a 1-month-old male infant who had syncope, torsade de pointes, cardiac arrest, and a QTc of 460 ms, Millat et al. (2006) identified biallelic digenic mutations: an F60L mutation in the KCNE2 gene (603796.0005) and an R1623Q mutation in the SCN5A gene (600163.0007).


REFERENCES

  1. Abbott, G. W., Sesti, F., Splawsky, I., Buck, M. E., Lehmann, M. H., Timothy, K. W., Keating, M. T., Goldstein, S. A. N. MiRP1 forms I(kr) potassium channels with HERG and is associated with cardiac arrhythmia. Cell 97: 175-187, 1999. [PubMed: 10219239] [Full Text: https://doi.org/10.1016/s0092-8674(00)80728-x]

  2. Jongbloed, R. J. E., Wilde, A. A. M., Geelen, J. L. M. C., Doevendans, P., Schaap, C., Van Langen, I., van Tintelen, J. P., Cobben, J. M., Beaufort-Krol, G. C. M., Geraedts, J. P. M., Smeets, H. J. M. Novel KCNQ1 and HERG missense mutations in Dutch long-QT families. Hum. Mutat. 13: 301-310, 1999. [PubMed: 10220144] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1999)13:4<301::AID-HUMU7>3.0.CO;2-V]

  3. Millat, G., Chevalier, P., Restier-Miron, L., Da Costa, A., Bouvagnet, P., Kugener, B., Fayol, L., Gonzalez Armengod, C., Oddou, B., Chanavat, V., Froidefond, E., Perraudin, R., Rousson, R., Rodriguez-Lafrasse, C. Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome. Clin. Genet. 70: 214-227, 2006. [PubMed: 16922724] [Full Text: https://doi.org/10.1111/j.1399-0004.2006.00671.x]

  4. Splawski, I., Shen, J., Timothy, K. W., Lehmann, M. H., Priori, S., Robinson, J. L., Moss, A. J., Schwartz, P. J., Towbin, J. A., Vincent, G. M., Keating, M. T. Spectrum of mutations in long-QT syndrome genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 102: 1178-1185, 2000. [PubMed: 10973849] [Full Text: https://doi.org/10.1161/01.cir.102.10.1178]

  5. Tester, D. J., Will, M. L., Haglund, C. M., Ackerman, M. J. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm 2: 507-517, 2005. [PubMed: 15840476] [Full Text: https://doi.org/10.1016/j.hrthm.2005.01.020]


Creation Date:
Carol A. Bocchini : 1/14/2011

Edit History:
carol : 10/24/2016
carol : 10/21/2016
carol : 06/01/2016
carol : 9/18/2015
alopez : 6/12/2014
alopez : 2/3/2012
carol : 1/14/2011