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J Transl Med. 2017 Apr 20;15(1):78. doi: 10.1186/s12967-017-1180-1.

Novel trigenic CACNA1C/DES/MYPN mutations in a family of hypertrophic cardiomyopathy with early repolarization and short QT syndrome.

Author information

1
Department of Cardiology, Wuhan Asia Heart Hospital, Wuhan University, Wuhan, 430022, China.
2
Department of Cardiology, Nantong University, 3rd People's Hospital of Wuxi Affiliated To Nantong University, 585 Xingyuan Road, Wuxi, 214043, Jiangsu, China.
3
Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY, 13501, USA.
4
Department of Cardiology, Nantong University, 3rd People's Hospital of Wuxi Affiliated To Nantong University, 585 Xingyuan Road, Wuxi, 214043, Jiangsu, China. 1807250234@qq.com.
5
Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, 430060, China. dianah@mmrl.edu.
6
Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY, 13501, USA. dianah@mmrl.edu.
7
Molecular Genetics Department, SCRO Chair of Stem Cell Center, Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY, 13501, USA. dianah@mmrl.edu.

Abstract

BACKGROUND:

Hypertrophic cardiomyopathy (HCM) patients with early repolarization (ER) pattern are at higher risk of ventricular arrhythmia, yet the genetic background of this situation has not been well investigated. Here we report novel trigenic mutations detected in a Chinese family of obstructive HCM with ER and short QT syndrome (SQTS).

METHODS:

Proband and family members underwent detailed medical assessments. DNAs were extracted from peripheral blood leukocytes for genetic screening with next generation method. The functional characterization of the mutation was conducted in TSA201 cells with patch-clamp experiment.

RESULTS:

The proband was a 52-year-old male who had a ER pattern ECG in inferioral-lateral leads with atrioventricular block and QTc of 356 ms. He also suffered from severe left ventricular hypertrophy and dysfunction. Targeted sequencing revealed trigenic mutations: c.700G>A/p.E234K in DES, c.2966G>A/p.R989H in MYPN, and c.5918G>C/p.R1973P in CACNA1C. All mutations were also detected in his daughter with ER and mild myocardium hypertrophy. The CACNA1C-R1973P mutation caused significant reduction (68.4%) of ICa compared to CACNA1C-WT (n = 14 and 14, P < 0.05). The computer modeling showed that all 3 mutations were highly disease-causing. The proband received the CRT-D (cardiac resynchronizing therapy) implantation, which lowered the left ventricular outflow tract gradient (LVOTG, 124 mmHg pre vs. 27 mmHg post) and restored the LV function (LVEF 40% pre vs. 63% post).

CONCLUSIONS:

The study reveals a novel CACNA1C mutation underlying the unique ER pattern ECGs with SQTS. It also shows the rare trigenic mutations are the pathogenic substrates for the complicated clinical manifestation in HCM patients.

KEYWORDS:

Calcium channels; Cardiac resynchronization therapy (CRT); Early repolarization (ER); Genetics; Hypertrophic cardiomyopathy (HCM)

PMID:
28427417
PMCID:
PMC5399316
DOI:
10.1186/s12967-017-1180-1
[Indexed for MEDLINE]
Free PMC Article

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