Cardiac arrhythmias - additional genes

Gene: STS

Red List (low evidence)

Four independent and converging lines of evidence currently support inclusion of STS (Xp22.31) as a novel candidate gene for arrhythmias (particularly in males):

1. Deletion Copy Number Variants encompassing STS are associated with increased risk of a variety of heart rhythm abnormalities:

• Middle-aged male deletion carriers are at ~4x risk of being diagnosed with atrial fibrillation compared to age/sex-matched non-carriers, and self-report higher levels of arrhythmia/atrial flutter (PMID: 32139392)
• Paroxysmal supraventricular tachycardia in 2 year old male deletion carrier (PMID: 29569268)
• Diagnoses of brady- and tachycardia and atrial fibrillation self-reported by male and female deletion carriers (PMID: 36379544)
• Exercise-induced atrial fibrillation presenting at 16 and 23 years in 25 year old male deletion carrier with ongoing sinus bradycardia (PMIDs: 39158681 and 39150468)
• 16 year old male deletion carrier presenting with history of sinus bradycardia from 5 years, shortened QT interval and polymorphic ventricular extrasystole (up to 9% of heartbeats); 2.5 year old male deletion carrier with supraventricular pacemaker migration, mild bradycardia with shortened QT interval, and significant arrhythmia with a heart rate ranging from 76–118 bpm (PMID: 40688208)
• Sudden cardiac arrest with ventricular fibrillation in 17 year old male deletion carrier. ECG showed a wandering atrial pacemaker, ST-segment elevation, and T-wave inversion, frequent polymorphic ventricular extrasystoles (VES), ventricular couplet, 1 3-beat 160/min ventricular tachycardia, and 131 ventricular bigeminies (PMID: 40062371)
• Three adult male deletion carriers with a history of (paroxysmal) atrial fibrillation and supraventricular ectopic beats; two presented with ongoing frequent ventricular ectopic beats (PMID: 39912958)

2. Genetic association analysis across Xp22.31 highlights an excess of common risk variants for idiopathic atrial fibrillation within STS in a large middle-aged male sample of 4556 cases and 163,499 controls (PMID: 36379544)

3. Systemic inhibition of the STS enzyme in a cohort of 10 patients with early breast cancer pre-screened to exclude a history of cardiac arrhythmia resulted in three Grade 2 adverse events (two related to abnormal ECG and one to tachycardia) and one Grade 1 adverse event (prolonged QT)(PMID: 28795252).

4. In ex vivo ECG, the hearts of mice with a small Sts-specific genetic deletion and >95% loss of enzyme activity show evidence for an increased frequency of abnormal rhythms (notably ventricular ectopics) and for longer runs of abnormal beats (doi:10.64898/2026.07.22.739997v1)
Sources: Research, Literature

Created: 13 Aug 2026, 1:17 p.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Atrial fibrillation/flutter; supraventricular tachycardia; bradycardia; ventricular ectopic beats; QT interval alteration

Publications

• PMIDs: 32139392
• 36379544
• 39158681
• 39150468
• 40688208
• 40062371
• 39912958
• 28795252 and doi: 10.64898/2026.07.22.739997v1

Mode of pathogenicity
Other