Long QT Syndrome genetic studies

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

## Overview

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Either compressive testing for all variants of LQTs or for the LQTs 1-3 variants is recommended in any patient in whom there is a strong clinical suspicion based on the family history, symptoms, resting EKG, provoked findings on an exercise treadmill test or during catecholamine infusion. Genetic studies remain to be the gold standard in the diagnosis of long QT syndrome.

## Genetic studies

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### LQT 1 Genetics

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* The LQT1 gene is KCNQ1 which has been isolated to chromosome 11p15.5. KCNQ1 codes for the voltage-gated potassium channel KvLQT1 that is highly expressed in the heart.[1]
* It is believed that the product of the KCNQ1 gene produces an alpha subunit that interacts with other proteins (particularly the minK beta subunit) to create the IKs ion channel, which is responsible for the delayed potassium rectifier current of the cardiac action potential.[2]
* Mutations to the KCNQ1 gene can be inherited in an autosomal dominant or anautosomal recessive pattern in the same family.
* In the autosomal recessive mutation of this gene,homozygous mutations in KVLQT1 leads to severe prolongation of the QT interval (due to near-complete loss of the IKs ion channel), and is associated with increased risk of ventricular arrhythmias and congenital deafness.

### LQT 2 Genetics

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* The LQT2 form of long QT syndrome most likely involves mutations of the human ether-a-go-go related gene (HERG) on chromosome 7.[3]
* The HERG gene (also known as KCNH2) is part of the rapid component of the potassium rectifying current (IKr).
* (The IKr current is mainly responsible for the termination of the cardiac action potential, and therefore the length of the QT interval.) The normally functioning HERG gene allows protection against early after depolarizations (EADs).

### LQT 3 Genetics

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* This variant involves a mutation of the gene that encodes the alpha subunit of the Na+ ion channel.
* This gene is located on chromosome 3p21-24, and is known as SCN5A (also hH1 and NaV1.5).
* The mutations involved in LQT3 slow the inactivation of the Na+ channel, resulting in prolongation of the Na+ influx during depolarization.[4]
* A large number of mutations have been characterized as leading to or predisposing LQT3.

## References

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1. ↑ Chiang CE, Roden DM (July 2000). "The long QT syndromes: genetic basis and clinical implications". J. Am. Coll. Cardiol. 36 (1): 1–12. doi:10.1016/s0735-1097(00)00716-6. PMID 10898405.
2. ↑ Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean L, Stephens K, Amemiya A, Alders M, Bikker H, Christiaans I. PMID 20301308. Vancouver style error: initials (help); Missing or empty `|title=` (help)
3. ↑ Tester DJ, Ackerman MJ (2014). "Genetics of long QT syndrome". Methodist Debakey Cardiovasc J. 10 (1): 29–33. doi:10.14797/mdcj-10-1-29. PMC 4051331. PMID 24932360.
4. ↑ Wilde AA, Moss AJ, Kaufman ES, Shimizu W, Peterson DR, Benhorin J, Lopes C, Towbin JA, Spazzolini C, Crotti L, Zareba W, Goldenberg I, Kanters JK, Robinson JL, Qi M, Hofman N, Tester DJ, Bezzina CR, Alders M, Aiba T, Kamakura S, Miyamoto Y, Andrews ML, McNitt S, Polonsky B, Schwartz PJ, Ackerman MJ (September 2016). "Clinical Aspects of Type 3 Long-QT Syndrome: An International Multicenter Study". Circulation. 134 (12): 872–82. doi:10.1161/CIRCULATIONAHA.116.021823. PMC 5030177. PMID 27566755.