Short QT Syndrome Patients

Individual Short QT Syndrome patients

CLINICAL DATA ON INDIVIDUAL PATIENTS IN THE SQTS LITERATURE 2000-2018

(49 publications with 219 patients from 144 families)

First Author
Journal Year		 Gene/Mut Age & gender Presentation QT/QTc HR

P = Proband | Fx = Family history
Gussak I.
Cardiology
2000		 KCNH2/N588K 17 YO F(P) AF at young age 280/300 69
  Same 21 YO M Fx of SQTS 272/267 57
  Same 51 YO F Fx of SQTS 260/289 75
  Not Done 37 YO F(P) SCD 266/248 52
 
Gaita F.
Circulation
2003		 KCNH2/N588K 35 YO M(P) Sync/Fx SCD 240/280 82
  Same 31 YO F Fx SCD 240/290 88
  Same 6 YO M Ab SCD 260/270 65
 
Brugada R.
Circulation
2004		 KCNH2/N588K 62 YO F(P) SCD 210/250 85
  Same 67 YO F Fx SCD 270/295 72
  Same 15 YO M Sync/Fx SCD 260/300 80
  Same 40 YO F Fx SCD 240/268 75
  negative 51 YO M (P) Ab SCD 280/288 81
  negative 20 YO M Fx SCD 290/293 61
 
Bellocq C.
Circulation
2004		 KCNQ1/V307L 70 YO M (P) Ab SCD 290/302 65
 
Riera A.R.P
A.N.E.
2005		 Not Done 27 YO M (P) Incidental finding 302/315 65
 
Maury P.
Heart Rhythm
2005		 negative 15 YO M(P) Ab SCD 300/335 67
  Episodes of nocturnal seizure-like activity with SOB and fast heart rate.
 
Priori S.G.
Circ Res.
2005		 (INCOMPLETE DATA (NO HR OR QT INTERVAL REGISTERED IN 2 PATIENTS)
  KCNJ2/D172N 5 YO F(P) Incidental finding ?/315  
  KCNJ2/D172N 35 YO M Fx of SQTS ?/320  
 
Kirilmax A.
Jelectrocard.
2005		 not done 20 YO M(P) AF at young age 308/257 42
 
Hong K
Cardiores
2005		 KCNQ1-V141M Newborn F(P) AF at young age 280/AF  
 
Giustetto C.
Eur Heart J
2006		 MULTICENTER study of 29 patients, but only 10 new families and 22 new patients
  neg 49 YO M(P) Fx of SCD 275/303 73
    39 YO M Fx of SCD/sync 290/311 69
    50 YO M Fx of SCD/sync 280/313 75
    21 YO M Fx of SCD 300/310 64
  neg 18 YO M(P) Ab SCD 270/308 78
    80 YO M Fx of SCD 280/302 70
    53 YO M Fx of SCD 300/315 66
  neg 35 YO F (P) Fx of SCD 320/317 59
    14 YO M Fx of SCD, sync. 240/282 83
    16 YO F Fx of SCD 300/333 74
  neg 17 YO M (P) Ab SCD 210/291 114  
    43 YO M Fx of SCD 290/338 82
  neg 16 YO M(P) Ab SCD 280/317 77
    19 YO M Fx of SCD 294/324 73
    21 YO M Fx of SCD 320/333  
  not done 30 YO M(P) SCD during sleep 315/302  
    52 YO F Fx of SCD 310/327  
    25 YO M Fx of SCD 315/323  
  neg 19 YO M(P) Ab SCD/Fx SCD 300/317  
  neg 4 MONTH F(P) Ab SCD/Fx SCD 210/307  
  neg 69 YO M(P) Sync/Fx SCD 240/294  
  not done 28 YO M(P) SCD 300/312  
 
Lu L.X.
Resuscitation
2006		 not done 30 YO F(P) Ab SCD 270/292  
    7 YO F Fx of SCD 290/308  
    53 YO F Fx of SCD 290/300  
Antzelevitch C.
Circulation
2007		 6 new patients with INCOMPLETE DATA (IN 6 no HR AND QT and IN 5 no age)
  CACNB2b-S481L 25 YO M(P) Ab SCD ?/320 -
  Same ? YO F Fx SCD ?/370 -
  Same ? YO F Fx SCD ?/368 -
  Same ? YO F Fx SCD ?/340 -
  Same 23 YO M Fx SCD ?/340 -
  Same ? YO M Fx SCD ?/345 -
  SQTS defined as QTc </= 360 ms in males and </= 370 ms in females.
  CACNA1C-G490R 41 YO M(P) Fx SCD 300/346 80
  INCOMPLETE DATA (QT AND HR MISSING IN 1 PATIENT):
  CACNA1C-A39V 44 YO M(P) Fx SCD ?/360 -
 
Mizobucgi M.
Pace
2008		 Neg. 24 YO M(P) Fx of SCD 313/308 58
 
Sawicki S.
Kardiol Pol.
2008		 KCNH2-T618I 23 YO M(P) Fx of SCD 250/264 67
  INCOMPLETE DATA (QT AND HR MISSING IN 1 PATIENT
  Same 42 YO F Fx of SCD ?/320  
 
Fichet J.
A.J.E.M.
2008		 Not Done 21 YO F(P) Ab SCD 280/215 35
 
Redpath CJ.
Can J Cardiol
2009		 KCNH2-E50D 22 YO M(P) Syncope 364/381 66
 
Villafane J.
Pediatr. Cardiol.
2009		 INTERNATIONAL MULTICENTER CASE SERIES INVOLVING 8 CENTERS with 10 pediatric patients, 7-19 years old (four 16-19), all male, only presented in the discussion section of the article entitled:
"Short QT Syndrome in a Pediatric Patient": Most (9?) patients published previously.
  Not Done 13 YO M(P) Ab SCD 300/310 64
 
Itoh H.
Int J Cardiol
2009		 KCNH2-R1135H 34 YO M(P) SQT/Routine ECG 315/329 65
 
Liu G.
2009		 Chinese publication in Chinese of a family with hx of 4 members with SCD. Four other members were diagnosed with Short QT and QTc less than 320 msec. One received an ICD. [Chinese publication in Chinese of a family with hx of 4 members with SCD. Four other members were diagnosed with Short QT and QTc less than 320 msec. One received an ICD. http://www.ncbi.nlm.nih.gov/pubmed/19781151
 
Efremidis M.
Clin Res Cardiol
2009		 INCOMPLETE DATA: 1 new patient with unknown gender:
  Negative 17 YO ?(P) Recurrent syncope 320/283 47
 
Watanabe H.
Heart Rhythm
2010		 MULTICENTER STUDY with INCOMPLETE DATA.
(12 patients with SQTS either referred to their institution or from previous reports) SQTS defined as QTc </= 330 ms or QTc </ = 360 ms when positive SQTS mutation is present.
 
Sun Y.
JMCC
2011		 KCNH2-T618I 45 YO M(P Ab SCD 276/298 69
  NEW PATIENTS WITH INCOMPLETE DATA (No age):
  Same ? YO F Fx SQTS/CA 320/346 70
  Same ? YO F Fx SQTS/CA 308/308 60
  Same ? YO F Fx SQTS/CA 295/315 68
 
Giustetto C. JACC 2011 MULTICENTER STUDY - THE EUROPEAN SQTS REGISTRY
  20 new patients with INCOMPLETE DATA and NOT CHARACTERIZED INDIVIDUALLY: 33 of the 53 patients in this paper have all been published previously: They are most likely the 29 patients from 11Giu06 and the last 4 patients from 22Sun11 even though this later study is not a European and not among the list of authors/hospitals mentioned?. The 20 NEW patients are not characterized individually, but CONSISTS OF 18 MALES AND 2 FEMALES. 53 patients (75% males) from 29 proband-identified families. Median age (males and females): 26 years (interquartile range: 17-39 years)
  Cardiac arrest was similar in males and females (35% vs. 30%; p = o.15) In males more than 90% of CA events occurred between 14 and 40 years of age, whereas in females the events were spread across the entire lifespan, but included very few events. The distribution in males corresponds to the age with the highest testosterone plasma (saliva?) levels (Ref 20). These hormonal influences have been considered protective in post-puberal boys and men in the context of the long QT syndrome (Ref 22). The role of testosterone in SQTS has not been studied. Syncope was observed only in males. Most events occurred in males. FU data on mixed treatments ICD/antiarrhythmics. Very few events (Fig 5). Patients with a HERG mutation constituted a subgroup with specific characteristics such as a greater proportion of affected females and a higher prevalence of AF compared to non-HERG patients. Morover, HERG patients exhibited shorter QT intervals and ERPs then non-HERG.
  Genetic: 5 mutations in 22 out of 30 index patients who were gene-analysed. SQTS defined as QTc < /= 340msec and < /= 360 ms associated with SCD, aborted SCD or syncope of arrhythmic origin.
 
Templin C. Eur Heart J 2011 CACNA2D1-S755T 17 YO F(P) Ab SCD 317/329 65
 
Chinushi M. J. Cardiovasc. Electrophysiol 2012 KCNH2-N588K 38 YO F(P) Syncope 260/300 80
  same 11 YO M Fx of SQTS 272/311 79
 
Hattori T. Cardiovasc. Res. 2012 KCNJ2-M301K 8 YO F(P) Incidental finding 172/194 76
  Mental retardation, abnormal proliferation of oesophageal blod vessels, Epilepsy, Kawasaki disease and AF. VF induced by placing Swan-Ganz catheter in
 
BUN S.-S.
J. Cardiovasc. Electrophysiol. 2012		 negative 26 YO M(P) Ab SCD 320/320 60
  Mother was found to have short QT, but no further data reported about her.
 
Hong K.
Eur. J. Human Genetics 2012		 SCN5A-R689H 40YO M(P) Fx SCD 320/348 71
  In addition to SQT the ECG showed Brugada-like changes.
 
Babaoglu K.
Anadolu Kardiyol Derg 2012		 Not done 13 YO M (P) Incidental finding 280/300 69
 
Villafane J.
JACC 2013		 MULTICENTER REVIEW ARTICLE - International case series involving 15 centers INCOMPLETE DATA , NO INDIVIDUAL DATA:
25 pts. (21 M, 4 F) 21 yo or younger from 21 families with 5.9 years follow-up. Most patients published previously
"Our cohort was predominantly male (84%), reflecting a sex-specific prevalence 20% of cases were identified to have disease-causing mutations." Mutation was detected in 24 of index patients who underwent genetic testing.
 
Deo M.
PNAS 2013		 KCNJ2-E299V 11 YO M(P) AF at young age 200/200 60
 
Maltret A
Int. J. Cardiol 2013		 KCNQ1-V141M Newborn F(P) SB at birth 260/279 69
  Newborn with inner ear abnormality.
 
Villafane J.
Cardiology 2014		 KCNQ1-V141M F(P) young age 200/292 128
  KCNQ1-V141M 9 YO F(P) AF at young age 260/317 90
  not done 3 WK O M(P) AF at young age 290/270 52
  not done 9 YO M(P) AF at young age 280  
  not done 3 YO F(P) AF at young age 290/?  
  One patient published earlier is excluded)
 
Sadeghian S.Europace 2014 not done 26 yo M(P) VT/palpitations 280/300 69
 
Portugal G.
Rev. Port. Cardiol. 2014		 negative 52 YO M(P) Ab SCD 270/327 88
 
Ambrosini E.Human Mol Gen. 2014 KCNJ2-K346T 9 YO M(P)(Twin 1) Autism-epilepsy 275/331 87
  INCOMPLETE DATA (QT/QTc AND HR MISSING IN 1 PATIENT)
  same 9 YO M (Twin 2) Autism-epilepsy ? /?  
 
Suzuki H.
Pediatr. Int. 2014		 KCNH2-N588K 10 YO M(P) Incidental finding 260/283 71
  Health screening at school including ECG showing very short QT
INCOMLETE DATA (AGE IS MISSING IN 1 PATIENT)
  same ? YO F Fx SQTS 260/283 71
 
Mazzanti A. JACC 2014

INHERITED ARRHYTHMIAS DATABASE, PAVIA, ITALY (Silvia G. Priori)

None of these patients have been previously published.

(Page 1301, line 6: “Here we present for the first time data pertaining to 73 SQTS patients identified in 47 families”from Italy, Poland and USA

INCOMPLETE DATA IN FORM OF MISSING INFORMATION ABOUT THE INDIVIDUAL PATIENTS

73 new patients (61 male, 12 female) from 47 proband-identified families. When the diagnosis is established based upon clinical parameters excluding the contribution of genetic testing the predominance of male patients is overwhelming (91%), suggesting that SQTS has, like BrS, a sex-dependent penetrance.

None of the genes related to SQTS identified a disease causing mutation in > 5% of clinically affected probands. All mutations found in this study showed a complete penetrance in carriers. A pathogenic mutation in K-channels was identified in 5 of 45 (11%): 2 in KCNJ2 gene (D172N, E299V), 2 in KCNH2 (N588K, T618I) and 1 in KCNQ1 (R259H). One in a CACNA1C gene(R1977Q).

A significant shorter QTc interval was found in mutation carriers versus noncarriers.

In familial cases, half of the first-degree relatives screened were clinically affected, consistent with a autosomal dominant pattern of inheritance.

Median age: 26 years +/- 15 (NO SEPERATION IN MALES AND FEMALES)

Life threatening arrhythmias were similar in males and females (30% vs 15 %, p=0.49).

There data identified a peak incidence of CA in the first year of life (4% per year). A quiescent phase encompassing adolescence, followed by an annual CA event rate of 1.3% between 20 and 40 years of age. “We should not consider affected female patients at lower risk of CA” (?)

Neither the presence of a very short QT interval nor the history of syncope alone identifies patients at higher risk of CA. The only predictor of malignant arrhythmias at follow-up is having experienced a first CA.

The majority (83%) of CAs occurred under resting condition or during sleep.

19 presented with SCD, 9 with syncope, 2 with Fx SCD and 17 SQTS as an incidental finding.

SQTS defined as QTc </= 340 msec or </= 360 msec combined with history of CA or syncope, a family history of unexplained CA at age </= 40 of age or a family history of SQTS
 
Harrell D.T.
Int. C. Cardiol. 2015		 KCNH2-I560T 64 YO M(P) Incidental finding 287/319 71
  KCNH2-T618I 39 YO F(P) Ab SCD 357/322 48
  INCOMPLETE DATA IN 2 PATIENTS):
  same 42 YO M Fx of Ab SCD ?/330
  same 14 YO M Fx of Ab SCD ?/330
  KCNQ1-V141M 10 YO F(P) Fetal brady/SB at birth 270/280 65
  INCOMPLETE DATA IN 1 PATIENT):
  same 3 YO M AF/brady at 3 years of age ?/?  
  negative 17 YO F(P) Ab SCD 280/330 83
  KCNQ1-F279I 23 YO M(P) Fx of SCD 330/356 70
 
Ergul Y.
Anat. J. Cardiol. 2015		 not done 14 YU M(P) Fx SCD/syncope 310/320 64
 
Righi D.
Cardiology in the Young 2016		 KCNQ1-V141M 1 YO M(P) Bradycardia in infancy 300/286 55
 
Sarquella-Brugada G.
Heart Rhythm 2016		 KCNQ1-V141M 0 YO F(P) Brady/AF in infancy 230/270 82
  INCOMPLETE DATA (QT AND HR MISSING IN 1 PATIENT):
  KCNQ1-V141M 0 YO M(P) Brady/AF in infancy ?/290  
  KCNQ1-V141M 0 YO F(P) Fetal brady/AF in infancy 250/290 81
 
Giustetto C.
Heart Rhythm 2015		 KCNH2-T618I 16 YO M(P) Fx of SCD 260/300 80
  same 21 YO F Fx OF SCD 280/340 88
  same 47 YO F Ab SCD 300/344 79
  not done 34 YO F SCD 270/300 74
 
Rothenberg I.
Heart Rhythm 2016		 KCNQ1-A287T 16 YO F(P) Ab SCD 380/333 46
 
Hu D.
JACC 2017		 KCNH2-T618I 30 YO M(P) Fx of SCD 260/260 60
  KCNH2-T618I 9 YO F(P) Fx of SCD 270/300 74
  (INCOMPLETE DATA (QT, HR AND GENDER MISSING IN 2 PATIENTS)
  same ? YO M Fam hx of SCD ? /328  
  same ? YO M Fam hx of SCD ?/299  
  KCNH2-T618I 46 YO F(P) FX of SCD 260/315 88
  (INCOMPLETE DATA (QT, HR AND GENDER MISSING IN 1 PATIENT):
  same ? YO M Fam hx of SCD ?/320  
 
Thorsen K.
Nature Com. 2017		 This is the first report in two unrelated families of a mutation in the SLCAA3 gene which encodes the cardiac chloride-bicarbonate exchanger AE3 being associated with SQTS. The mutation causes reduced surface expression of AE3 and reduced bicarbonate transport. Sic4a3 knockdown in zebrafish causes increased cardiac pHi and short QT.
  Family 1
  SLCAA3 39 YO M(P) Abort SCD 320/320 60
  same 74 YO F Fx of SCD 320/348 70
  same 66 yo F Fx of SCD 300/355 85
  same 64 yo M Fx of SCD 360/332 51
  same 63 yo F Fx of SCD 300/300 60
  same 56 YO F Fx of SCD 280/346 92
  same 55 YO F Fx of SCD 320/335 82
  same 50 YO M Fx of SCD 360/360 60
  same 43 YO M Syncope/Fx of SCD 300/337 76
  same 56 YO M Fx of SCD 300/335 75
  same 40 YO F Fx of SCD 320/345 70
  same 43 YO F Fx of SCD 360/345 70
  same 36 YO M Syncope /Fx of SCD 320/320 60
  same 39 YO M Fx of SCD 320/320 60
  same 37 YO F Fx of SCD 280/323 80
  same 32 YO F Fx of SCD 300/333 72
  same 34 YO M Fx of SCD 300/320 68
  same 26 YO F Fx of SCD 300/355 85
  same 32 YO M Fx of SCD 340/370 65
  same 30 YO M DCM/Fx of SCD 320/367 79
  same 16 YO M Fx of SCD 340/362 68
  same 20 YO M Fx of SCD 320/367 92
  (13 males, 10 females. Five with symptoms all male 30-43 years of age)
  Family 2
  not done 22 YO M(P) SCD/Fx of SQTS not available  
  SL4A3 61 YO F Fx of SCD 300/355 84
  same 64 YO F Fx of SCD 360/360 60
  same 65 YO M Fx of SCD 340/354 65
  same 25 YO M Fx of SCD 320/345 70
 
Wakatsuki D.
IJC Heart & Vasculature 2018		 KCNH2-W927G 22 YO M(P) Ab SCD 360/340 53
  This mutation has previously been described in patients with Brugada Syndrome and some of them had a QTc < 360 msec. Family not examined.
 
Akdis D.
Europace 2018		 INCOMPLETE DATA (QT AND HR MISSING IN 3 PATIENTS)
  KCNH2-c1891T>G 6 YO F(P) Fx SCD/SYNC ?/323  
  same 54 YO M Fx of SCD ?/324  
  same 12 YO F Fx of SCD ?/340  
  The missense mutation in this family in the KCNH2-gene has not previously been associated with SQTS. Some family members had in addition a missense variant in SCN10A c.5605C>T (p.Ser631Ala) which was not considered to have any clinical significance.

HOW TO DEFINE SQTS?

Based upon these data my suggested definition of SQTS 2021 is:

QTc </= 340 msec at heart rates between 50 and 70 beats/min, or

QTc </= 370 msec at heart rates between 50 and 70 beats/min, when associated with a pathogenic mutation, family history of SCD at age </= 40 years old, survival of VT/VF episode in the absence of heart disease, atrial fibrillation at very young age and syncopal episode that strongly suggests a cardiac arrhythmia.

SPECIAL FEATURES OF PATIENTS WITH SQTS PRESENTED SCHEMATICALLY

REASON FOR REFERRAL OF 117 PROBANDS (FAMILIES with SQTS):

  Males Females MAZ14 Total # Pts
SCD/Ab SCD 17 10 19 46
Incidental finding 6 2 17 25
Fx SCD 9 3 2 14
Syncope 1 1 9 11
Syncope in a family with a hx of SCD 3 1 0 4
Palpitations/VT 1 0 0 1
AF/Severe bradycardia at young age 8 8   16
TOTAL (Including 47 from 38Maz14) 45(64%) 25(36%) 47 117

Giustetto11 does not specify reason for referral of 20 new patients and therefore not include.

Percent distribution of 129 patients by sex and age at 10 year increments.

Age Groups Males Females
0-10 6 (27%) 16 (73%)
11-20 19(73%) 7 (27%)
21-30 20 (83% 4 (17%)
31-40 9 (45%) 11 (55%)
41-50 9 (69%) 4 (31%)
51-60 5 (50%) 5 (50%)
60+ 7 (50%) 7 (50%)
 
TOTAL 75 (58%) 54 (42%)
 
11-50 57 (69%) 26 (31%
Total number of articles describing new patients with SQTS: 49
Articles with a single case report (Often no attempt to examine family members) 24
Articles with a single family 10
Total number of patients in articles about SQTS 320
Previously published 40
Remaining 280
Not indicated whether new or previously published 46
Remaining SQTS population 234
Patients presented in review articles without individual data 93
Remaining (118 single center pts, 23 pts from multicenter studies) 141
Individual patients without individual age (11) or gender data(1) 12
Remaining SQTS patients with complete information 129 (75 M, 54 F)
No. of pts with individual data from multicenter studies (Giu-06 (22), Vil-09 (1)) 23
No. of pts with individual data from small single center studies often single patients 118
Total number of patients with individual data 141
No. of new patients without individual data (Mazzanti-14 (73) +Giustetto-11 (20)) 93
PROBANDS
Total number of probands with SQTS and reason for referral mentioned 117
Total number of probands with clinical data incl. Age, gender, QT, QTc and/or HR: 109
Number of probands with individual clinical data incl. Age, gender, QT, QTc and/or HR: 71