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Mayo Clin Proc. 2016 Nov;91(11):1503-1514. doi: 10.1016/j.mayocp.2016.06.031. Epub 2016 Oct 1.

Does Sudden Unexplained Nocturnal Death Syndrome Remain the Autopsy-Negative Disorder: A Gross, Microscopic, and Molecular Autopsy Investigation in Southern China.

Author information

1
Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
2
Departments of Cardiovascular Diseases (Division of Heart Rhythm Services), Pediatrics (Division of Pediatric Cardiology), and Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN.
3
Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI.
4
Department of Cardiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
5
BGI-Shenzhen, Shenzhen, China.
6
Department of Pathology and Laboratory Medicine and Waisman Center, University of Wisconsin, Madison, WI.
7
Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. Electronic address: chengjd@mail.sysu.edu.cn.

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.

PMID:
27707468
PMCID:
PMC5097692
DOI:
10.1016/j.mayocp.2016.06.031
[Indexed for MEDLINE]
Free PMC Article

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