What is the role of genetics in the etiology of long QT syndrome (LQTS)?

Updated: Nov 29, 2017
  • Author: Ali A Sovari, MD, FACP, FACC; Chief Editor: Mikhael F El-Chami, MD  more...
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Answer

LQTS is known to be caused by mutations of the genes for cardiac potassium, sodium, or calcium ion channels; at least 10 genes have been identified. Based on this genetic background, 6 types of Romano-Ward syndrome, 1 type of Andersen syndrome and 1 type of Timothy syndrome, and 2 types of JLN syndrome are characterized (see Table 1, below).

LQTS results from mutations of genes encoding for cardiac ion channel proteins, which cause abnormal ion channel kinetics. Shortened opening of the potassium channel in LQT1, LQT2, LQT5, LQT6, JLN1, and JLN2 and delayed closing of a sodium channel in LQT3 overcharges a myocardial cell with positive ions. At least 10 genes have been identified in LQTS.

Table 1. Genetic Background of Inherited Forms of LQTS (Romano-Ward Syndrome: LQT1-6, Anderson Syndrome: LQT7, Timothy Syndrome: LQT8, and Jervell and Lang-Nielsen Syndrome: JLN1-2) (Open Table in a new window)

Type of LQTS

Chromosomal Locus

Mutated Gene

Ion Current Affected

LQT1

11p15.5

KVLQT1 or KCNQ1 (heterozygotes)

Potassium (IKs)

LQT2

7q35-36

HERG, KCNH2

Potassium (IKr)

LQT3

3p21-24

SCN5A

Sodium (INa)

LQT4

4q25-27

ANK2, ANKB

Sodium, potassium and calcium

LQT5

21q22.1-22.2

KCNE1 (heterozygotes)

Potassium (IKs)

LQT6

21q22.1-22.2

MiRP1, KNCE2

Potassium (IKr)

LQT7 (Anderson syndrome)

17q23.1-q24.2

KCNJ2

Potassium (IK1)

LQT8 (Timothy syndrome)

12q13.3

CACNA1C

Calcium (ICa-Lalpha)

LQT9

3p25.3

CAV3

Sodium (INa)

LQT10

11q23.3

SCN4B

Sodium (INa)

LQT11

7q21-q22

AKAP9

Potassium (IKs)

LQT12

 

SNTAI

Sodium (INa)

JLN1

11p15.5

KVLQT1 or KCNQ1 (homozygotes)

Potassium (IKs)

JLN2

21q22.1-22.2

KCNE1 (homozygotes)

Potassium (IKs)

 

LQT1, LQT2, and LQT3 account for most cases of LQTS, with estimated prevalences of 45%, 45%, and 7%, respectively. In LQTS, QT prolongation is due to an overload of myocardial cells with positively charged ions during ventricular repolarization. In LQT1, LQT2, LQT5, LQT6, and LQT7, potassium ion channels are blocked, they open with a delay, or they are open for a shorter period than they are in normally functioning channels. These changes decrease the potassium outward current and prolong repolarization.


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