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Europace. 2019 Aug 13. pii: euz215. doi: 10.1093/europace/euz215. [Epub ahead of print]

Type 8 long QT syndrome: pathogenic variants in CACNA1C-encoded Cav1.2 cluster in STAC protein binding site.

Author information

1
Division of Cardiology, University of British Columbia, 1033 Davie St., Rm 211, Vancouver, BC V6E 1M7, Canada.
2
Cardiology Department, Royal Papworth Hospital, Cambridge, UK.
3
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
4
Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada.
5
Division of Cardiology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.
6
Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada.
7
Heart Rhythm Service, Division of Cardiology, Queen's University, Kingston, ON, Canada.
8
Division of Heart Rhythm Services, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
9
Division of Pediatric Cardiology, Department of Pediatrics, Mayo Clinic, Rochester, MN, USA.
10
Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
11
Vanderbilt University Medical Center, Nashville, TN, USA.
12
Department of Medicine & Geriatrics, Princess Margaret Hospital, Kowloon, Hong Kong.
13
Labatt Family Heart Centre and Division of Cardiology, Department of Pediatrics, and Translational Medicine, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada.
14
MetroHealth Campus, Case Western Reserve University, Cleveland, OH, USA.
15
Division of Cardiology, Montefiore Medical Center, Bronx, NY, USA.
16
Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
17
School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
18
Division of Pediatric Cardiology, University of Virginia, Charlottesville, VA, USA.
19
Royal Jubilee Hospital, Victoria, BC, Canada.
20
Pediatric Cardiology, Children's Hospital & Medical Center/University of Nebraska Medical Center, Omaha, NA, USA.
21
Division of Cardiology, Department of Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA.
22
Cardiology Clinical Academic Group, St. George's, University of London, London, UK.
23
Heart Centre, Department of Clinical and Experimental Cardiology, Academic Medical Centre, Amsterdam, the Netherlands.
24
Children's Heart Center, BC Children's Hospital, Vancouver, BC, Canada.

Abstract

AIMS:

Pathogenic gain-of-function variants in CACAN1C cause type-8 long QT syndrome (LQT8). We sought to describe the electrocardiographic features in LQT8 and utilize molecular modelling to gain mechanistic insights into its genetic culprits.

METHODS AND RESULTS:

Rare variants in CACNA1C were identified from genetic testing laboratories. Treating physicians provided clinical information. Variant pathogenicity was independently assessed according to recent guidelines. Pathogenic (P) and likely pathogenic (LP) variants were mapped onto a 3D modelled structure of the Cav1.2 protein. Nine P/LP variants, identified in 23 patients from 19 families with non-syndromic LQTS were identified. Six variants, found in 79% of families, clustered to a 4-residue section in the cytosolic II-III loop region which forms a region capable of binding STAC SH3 domains. Therefore, variants may affect binding of SH3-domain containing proteins. Arrhythmic events occurred in similar proportions of patients with II-III loop variants and with other P/LP variants (53% vs. 48%, P = 0.41) despite shorter QTc intervals (477 ± 31 ms vs. 515 ± 37 ms, P = 0.03). A history of sudden death was reported only in families with II-III loop variants (60% vs. 0%, P = 0.03). The predominant T-wave morphology was a late peaking T wave with a steep descending limb. Exercise testing demonstrated QTc prolongation on standing and at 4 min recovery after exercise.

CONCLUSION:

The majority of P/LP variants in patients with CACNA1C-mediated LQT8 cluster in an SH3-binding domain of the cytosolic II-III loop. This represents a 'mutation hotspot' in LQT8. A late-peaking T wave with a steep descending limb and QT prolongation on exercise are commonly seen.

KEYWORDS:

3D crystal structure; CACNA1C; Electrocardiogram; Genetics; Long QT syndrome

PMID:
31408100
DOI:
10.1093/europace/euz215

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