Abstract
Objective
To look for previously unrecognized cardiac structural abnormalities and address the
genetic cause for sudden unexplained nocturnal death syndrome (SUNDS).
Methods
Data for 148 SUNDS victims and 444 controls (matched 1:3 on sex, race, and age of
death within 1 year) were collected from Sun Yat-sen University from January 1, 1998,
to December 31, 2014, to search morphological changes. An additional 17 patients with
Brugada syndrome (BrS) collected from January 1, 2006, to December 31, 2014, served
as a comparative disease cohort. Target-captured next-generation sequencing for 80
genes associated with arrhythmia/cardiomyopathy was performed in 44 SUNDS victims
and 17 patients with BrS to characterize the molecular spectrum.
Results
The SUNDS victims had slight but statistically significant increased heart weight
and valve circumference compared with controls. Twelve of 44 SUNDS victims (SCN5A, SCN1B, CACNB2, CACNA1C, AKAP9, KCNQ1, KCNH2, KCNJ5, GATA4, NUP155, ABCC9) and 6 of 17 patients with BrS (SCN5A, CACNA1C; P>.05) carried rare variants in primary arrhythmia-susceptibility genes. Only 2 of
44 SUNDS cases compared with 5 of 17 patients with BrS hosted a rare variant in the
most common BrS-causing gene, SCN5A (P=.01). Using the strict American College of Medical Genetics guideline-based definition,
it was found that only 2 of 44 (KCNQ1) SUNDS and 3 of 17 (SCN5A) patients with BrS hosted a “(likely) pathogenic” variant. Fourteen of 44 SUNDS cases
with cardiomyopathy-related variants had a subtle but significantly decreased circumference
of cardiac valves, and tended to die on average 5 to 6 years younger compared with
the remaining 30 cases (P=.02).
Conclusion
We present the first comprehensive autopsy evidence that SUNDS victims may have concealed
cardiac morphological changes. SUNDS and BrS may result from different molecular pathological
underpinnings. The distinct association between cardiomyopathy-related rare variants
and SUNDS warrants further investigation.
Abbreviations and Acronyms:
ACMG (American College of Medical Genetics), AF (familial atrial fibrillation), BrS (Brugada syndrome), CCS (cardiac conduction system), CPVT (catecholaminergic polymorphic ventricular tachycardia), ECG (electrocardiogram), LQTS (long QT syndrome), SCD (sudden cardiac death), SUNDS (sudden unexplained nocturnal death syndrome)To read this article in full you will need to make a payment
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Article Info
Publication History
Published online: October 01, 2016
Footnotes
For editorial comment, see page 1489; for related articles, see pages 1493, 1606, and 1617
Grant Support: This work was supported by grant 81430046 from the Key Program (J.C.) and grant 81172901 from the General Program (J.C.) from the National Natural Science Foundation of China , by a grant from the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program (D.J.T. and M.J.A.), and by grants R56 HL71092 and R01HL128076-01 from the National Institutes of Health (J.C.M.).
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© 2016 Mayo Foundation for Medical Education and Research
