TY - JOUR
T1 - Does Sudden Unexplained Nocturnal Death Syndrome Remain the Autopsy-Negative Disorder
T2 - A Gross, Microscopic, and Molecular Autopsy Investigation in Southern China
AU - Zhang, Liyong
AU - Tester, David J.
AU - Lang, Di
AU - Chen, Yili
AU - Zheng, Jinxiang
AU - Gao, Rui
AU - Corliss, Robert F.
AU - Tang, Shuangbo
AU - Kyle, John W.
AU - Liu, Chao
AU - Ackerman, Michael J.
AU - Makielski, Jonathan C.
AU - Cheng, Jianding
N1 - Funding Information:
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.).
Publisher Copyright:
© 2016 Mayo Foundation for Medical Education and Research
PY - 2016/11/1
Y1 - 2016/11/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.mayocp.2016.06.031
DO - 10.1016/j.mayocp.2016.06.031
M3 - Article
C2 - 27707468
AN - SCOPUS:84995551053
SN - 0025-6196
VL - 91
SP - 1503
EP - 1514
JO - Mayo Clinic proceedings
JF - Mayo Clinic proceedings
IS - 11
ER -