SQTS is a genetically heterogeneous disease. In the long-term follow-up study from 2011 of patients with SQTS by Giustetto et al, the yield of genetic screening in SQTS was 23 % of the investigated index patients in their study. So far a genetic mutation has been found in at least 22 patients from 13 families with SQTS and in 15 patients from 5 families with a short QT interval and ST-segment changes. Patients in the latter group have ST changes in precordial leads somewhat similar to Brugada Syndrome patients either spontaneously or by provocation, and since there is no clear basis on which to select one syndrome over another, they are best looked upon as a distinct clinical entity. With QTc’s ranging from 330 to 360 msec the QT interval in these patients has generally not been as short as reported for patients with only SQTS. Initially mutations in patients with SQTS were found in 3 genes (KCNH2, KCNQ1 and KCNJ2) encoding for potassium channels and the respective syndromes were called SQT1, SQT2 and SQT3 based upon the chronology of their discovery.
In the first two families from Europe with SQT1 reported in 2004 by Gaita et al. two different missense mutations (C1764A and C1764G) were later discovered and found to result in the same amino acid change (N588K) in the S5-P loop region of the cardiac IKr channel KCNH2 (HERG). Within the same year the first patient with SQT2 was reported, when a mutation (V307L) in the KCNQ1 gene encoding the IKs channel KvLQT1 was found by Bellocq C et al. in a 70 year old male with idiopathic ventricular fibrillation and a short QT interval. Another KCNQ1 mutation was later found by Hong K, et al. in two unrelated patients with bradycardia in utero and born with atrial fibrillation and high degree atrio-ventricular block in addition to a very short QT interval. Genetic testing showed a missense mutation, G to A substitution at nucleotide 421 (g421a). This mutation results in substitution of valine by methionine at position 141 (V141M) adjacent to a previously described S140G mutation for familial AF . Finally, in 2008 a third gain-of-function mutation (I274V) was found by Rhodes et al. in KCNQ1 in a patient with SIDS.
In 2005 in an Italian family a KCNJ2 gene mutation was found in a 5-year old girl with a short QT interval (SQT3). Genetic analysis by Priori et al. led to the identification of a single base pair substitution (G514A) in KCNJ2, resulting in an amino acid change from aspartic acid to asparagine at position 172 in the Kir2.1 potassium channel (IK1). From these initial findings an interesting concept emerged, that LQTS and SQTS had closely related genetic basis. Since then additional mutations responsible for shortening of the QT interval have been found in the same 3 genes bringing the number of mutations up to a total of 5 KCNH2 (N588K, R1135H, T618I, E50D, p.Pro872fs), 3 KCNQ1 (V307L, V141M, I274V) and 4 KCNJ2 (D172N, K364T, E299V.
M310K). In patients with Brugada Syndrome and a short QT interval mutations have been found in 4 different genes (CACNA1C, CACNB2, CACNA2D1 and SCN5A).