Short QT Syndrome Panel

Short QT Syndrome (SQTS) is an inherited cardiac arrhythmogenic disorder characterized by marked shortened QT intervals, increased risk of atrial /ventricular fibrillation and sudden cardiac death (SCD) in individuals with a structurally normal heart (Gussak et al. 2000; Gaita et al. 2003). The clinical presentation of SQTS is diverse with a high penetrance, but a great variability of expression. Patients with SQTS may have cardiac arrest, palpitations, syncope, atrial fibrillation, but many patients are asymptomatic (Giustetto et al. 2006). Although it usually occurs in adults (median age 30 years), the age of presentation ranges from a few months to the sixth decade of life. SQTS diagnosis is based on the evaluation of symptoms, patient's family history and 12-lead ECG. Early diagnosis improves the prognosis of the disorder.

Short QT Syndrome is transmitted in an autosomal dominant pattern. Some cases of SQTS are sporadic and occur in people with no apparent family history of heart problems. SQTS is caused by genes encoding ion channels and is classified into 6 types (SQT1-6). Gain-of-function variants augment outward potassium currents in SQT1-3(KCNH2, KCNQ1 and KCNJ2), and loss-of-function variants reduces the current of calcium channels in SQT4-6 (CACNA1C, CACNB2 and CACNA2D1)(Patel et al. 2010; Templin et al. 2011). Many of the genes involved in SQTS are the same as those responsible for LQTS, but the effect of variants is opposite to those encountered in LQTS. The most common form of SQTS (SQT1) is caused by pathogenic variants in KCNH2, which contribute approximately 25 percent of cases (Giustetto et al. 2006). The precise prevalence of SQTS is unknown due to failure to identify risk factors and varying definitions of SQTS. However, it is estimated to be 2 percent or less when using a cutoff of 360 msec (Kobza et al. 2009; Miyamoto et al. 2012). A wide variety of causative variants (missense, nonsense, splicing, small deletions, insertions, large deletions /duplications) have been reported in all 6 genes, with the exception of no record of large deletions/duplications or complex genomic rearrangements in CACNA1C (Human Gene Mutation Database).

It is estimated that this NGS panel can detect a pathogenic variant in approximately 20% of patients with SQTS (Schimf et al. 2008).

Gross deletions or duplications not detectable by Sanger sequencing have been reported in CACNA2D1, CACNB2, KCNH2, KCNJ2, and KCNQ1, but no statistical data is available yet (Human Gene Mutation Database). No gross deletions or duplications have been reported in CACNA1C.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).