Author + information
- Maen D. Abou Ziki,
- Sara Seidelmann,
- Emily Smith,
- Anand Narayanan,
- Gourg Atteya,
- Yuexin Jiang,
- Rodolfo Gil-Fernandez,
- Mark Marieb,
- Joseph Akar and
- Arya Mani
Background: Long QT syndrome (LQTS) is a pro-arrhythmogenic condition with life threatening complications. There have been 18 different subtypes of congenital LQTS attributed to mutations in genes involved in cardiac conduction. However, the genetic causes of LQTS are not known in about 20% of cases. Eighteen patients with prolonged QT were referred to the Yale Cardiovascular Genetics Clinic after excluding compounding risk factors such as structural heart disease, and medication induced LQTS.
Methods: All patients were recruited and underwent whole exome sequencing after obtaining informed consent. Sanger sequencing was used to confirm the mutation sites. In silico analysis, tissue-specific expression, and review of public genetic databases were performed in search for damaging mutations. 2,000 control exomes were also used for allele frequencies.
Results: Deleterious mutations in the SCN10A gene were identified in 5 patients (28%), which included 2 frameshifts (fs) and 3 missense mutations (R14L, G810fs, R1268Q, and P1877fs). All mutations were predicted to be damaging by PolyPhen or SIFT software. Only one patient (P1877fs) had additional mutations in LQTS genes, however those were common variants predicted to be benign. Three mutations were completely absent in public databases (G810fs, R1259Q, and P1877fs). The R14L mutation had been previously associated with atrial fibrillation (Afib). Afib was present in 3 of the 5 patients, and 4 of the patients had a family history of arrhythmias. SCN10A encodes the alpha subunit of a voltage gated sodium channel and has been linked to Brugada syndrome, Afib, and other conduction abnormalities but not LQTS. Interestingly, mutations in SCN5A the alpha subunit of another voltage gated sodium channel have been associated with LQTS type 3.
Conclusions: Our findings implicate SCN10A mutations as an underlying cause of LQTS. The presence of frameshift mutations, which result in premature stop codon and potentially non-sense mediated decay, suggest that the disease is due to loss of function of the encoded protein. In addition, the common association with Afib suggests that SCN10A may represent a unique subtype of LQTS genes.
Poster Hall, Hall C
Saturday, March 18, 2017, 3:45 p.m.-4:30 p.m.
Session Title: Arrhythmias and Clinical EP: Basic 4
Abstract Category: 4. Arrhythmias and Clinical EP: Basic
Presentation Number: 1238-116
- 2017 American College of Cardiology Foundation