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Short QT Syndrome and its Genetics

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The Short QT Syndrome (SQTS) is a potentially life-threatening genetic heart disorder affecting the heart rhythm. It results from abnormal functioning of ion channel proteins in the heart tissue. An electrocardiogram (ECG) typically shows a consistent shortening of the QT interval, that may be accompanied by clinical symptoms related to atrial or ventricular arrhythmias (episodes of rapid heartbeats originating from the heart chambers). Electrophysiological studies of SQTS reveal significantly shortened atrial and ventricular refractory periods, with QT intervals of less than 320 milliseconds (ms). The normal range for the length of a QT segment is 360 to 450 ms.

SQTS is an autosomal dominant disorder that may be found in families with a history of sudden cardiac death. The disorder may manifest in any stage of life, sometimes as early as infancy. While some patients may have clinical symptoms, (atrial fibrillation, syncope), others may be asymptomatic but are at risk for sudden cardiac arrest.

Clinical presentation/course
Clinical manifestations of SQTS vary widely. SQTS patients may have a history of syncope or heart palpitations, both of which can be the first presenting symptoms, while others are completely asymptomatic. In some patients, sudden cardiac death is the first observable sign of SQTS. In addition to a shortened QT interval, the ECGs of SQTS patients show an improper adaptation of the heart rate during exercise (Zareba, 2008).  Because SQTS was only recently recognized as a distinct heart rhythm disorder and only a small number of cases have been published, the diagnostic criteria for SQTS are not well established. It has been suggested that the presence of a short QT interval on ECG alone is not sufficient to make a diagnosis of SQTS and that also  the morphology of the T wave and QT adaptation must be considered, together with personal and family history (Crotti, 2010).
 

Genetics of SQTS

SQTS is an autosomal dominant disorder due to gain-of-function mutations in three potassium ion channel genes (Table 1). Therefore, an individual carrying a disease-causing SQTS mutation has a 50% chance of transmitting the mutation to a child, regardless of its gender.
Table 1
Symbol Gene Name
KCNQ1 KQT-like voltage-gated potassium channel-1
KCNJ2 Inwardly rectifying potassium channel
KCNH2 Potassium channel, voltage gated, H2


Genetic testing for SQTS and its utility:
Diagnostic genetic testing can be considered for:

  • Patients who clinically manifest symptoms of SQTS or have a family history of sudden cardiac death.
  • Asymptomatic first-degree relatives of individuals who are known to have a disease-causing mutation associated with SQTS. Note, testing should be performed first in a family member who is symptomatic, i.e. has clinical manifestations of SQTS.  Preferably, the youngest or most severely affected family member should be tested first.  Identification of a disease-causing mutation in the family can lead to genetic identification of at-risk family members who are clinically asymptomatic and who may have normal ECGs.  Family members who test positive for the familial mutation should have regular cardiac evaluations.  Alternatively, a negative genetic test result for the familial mutation would obviate the need for repeated follow-up examinations.
  • Genetic testing can also be used for prenatal diagnosis. 

All patients who undergo genetic testing should receive pre-test and post-test genetic counseling to understand the implications of genetic testing and its possible outcomes. The three possible outcomes of genetic testing are: positive, negative, and variant of unknown clinical significance (VOUS).

Resources for Patients
 


References

  1. Giustetto, C et al. Short QT syndrome: clinical findings and diagnostic-therapeutic implications. European Heart Journal 27:2440-2447. 2006. PMID: 16926178
  2. Zareba W. and Cygankiewicz I. Long QT Syndrome and Short QT Syndrome. Progress in Cardiovascular Diseases. 51(3); pp. 264-278. 2008. PMID: 19026859
  3. Gallagher MM et al. Distribution and prognostic significance of QT intervals in the lowest half centile in 12,012 apparently healthy persons. American Journal of Cardiology 98(7): 933-935. 2006. PMID: 16996877
  4. Anttonen, O et al. Prevalence and prognostic significance of short QT interval in a middle-aged Finnish population. Circulation 116: 714-720. 2007. PMID: 17679619 
  5. Crotti L et al. Congenital Short QT Syndrome. Indian Pacing and Electrophysiology Journal. 10 (2); pp. 86-95. 2010. PMID: 20126594
  6. National Library of Medicine. Short QT Syndrome Genetics Home Reference. www.ghr.nlm.nih.gov. 2007.