title: Does Sudden Unexplained Nocturnal Death Syndrome Remain the Autopsy-Negative Disorder: A Gross, Microscopic, and Molecular Autopsy Investigation in Southern China.
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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Liyong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI.
authors.forename: Di
authors.initials: D
authors.lastname: Lang
authors.affiliation: Department of Cardiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Yili
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jinxiang
authors.initials: J
authors.lastname: Zheng
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Gao
authors.affiliation: Department of Pathology and Laboratory Medicine and Waisman Center, University of Wisconsin, Madison, WI.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Corliss
authors.affiliation: Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Shuangbo
authors.initials: S
authors.lastname: Tang
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI.
authors.forename: John W
authors.initials: JW
authors.lastname: Kyle
authors.affiliation: BGI-Shenzhen, Shenzhen, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, Madison, WI.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Makielski
authors.affiliation: Department of Forensic Pathology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. Electronic address: chengjd@mail.sysu.edu.cn.
authors.forename: Jianding
authors.initials: J
authors.lastname: Cheng
mesh_terms: D000328:Adult; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D001344:Autopsy; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002681:China / Q000453:epidemiology; D003645:Death, Sudden / Q000453:epidemiology* / Q000209:etiology; D005260:Female; D020022:Genetic Predisposition to Disease; D006351:Heart Valves / Q000473:pathology; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D009206:Myocardium / Q000473:pathology*; D009929:Organ Size
chemical_list: D026901:Membrane Transport Proteins