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J Am Coll Cardiol. 2018 Mar 20;71(11):1217-1227. doi: 10.1016/j.jacc.2018.01.030.

Cardiac Genetic Predisposition in Sudden Infant Death Syndrome.

Author information

1
Departments of Cardiovascular Medicine (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, Minnesota.
2
Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, United Kingdom; Cardiology Clinical Academic Group, St. George's University Hospitals' NHS Foundation Trust, London, United Kingdom.
3
Medical and Molecular Genetics, Guy's Hospital, King's College London, London, United Kingdom.
4
MRC Human Genetics Unit, University of Edinburgh, Edinburgh, United Kingdom.
5
Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.
6
Centre for Child and Adolescent Health, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
7
Department of Cellular Pathology, St George's, University of London, London, United Kingdom; Department of Cellular Pathology', St. George's University Hospitals' NHS Foundation Trust, London, United Kingdom.
8
Histopathology Department, Sheffield Children's Hospital, Sheffield, United Kingdom; Honorary Senior Lecturer, University of Sheffield, Sheffield, United Kingdom.
9
Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
10
Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, United Kingdom; Cardiology Clinical Academic Group, St. George's University Hospitals' NHS Foundation Trust, London, United Kingdom. Electronic address: ebehr@sgul.ac.uk.
11
Departments of Cardiovascular Medicine (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, Minnesota. Electronic address: ackerman.michael@mayo.edu.

Abstract

BACKGROUND:

Sudden infant death syndrome (SIDS) is a leading cause of postneonatal mortality. Genetic heart diseases (GHDs) underlie some cases of SIDS.

OBJECTIVES:

This study aimed to determine the spectrum and prevalence of GHD-associated mutations as a potential monogenic basis for SIDS.

METHODS:

A cohort of 419 unrelated SIDS cases (257 male; average age 2.7 ± 1.9 months) underwent whole exome sequencing and a targeted analysis of 90 GHD-susceptibility genes. The yield of "potentially informative," ultra-rare variants (minor allele frequency <0.00005) in GHD-associated genes was assessed.

RESULTS:

Overall, 53 of 419 (12.6%) SIDS cases had ≥1 "potentially informative," GHD-associated variant. The yield was 14.9% (21 of 141) for mixed-European ancestry cases and 11.5% (32 of 278) for European ancestry SIDS cases. Infants older than 4 months were more likely to host a "potentially informative" GHD-associated variant. There was significant overrepresentation of ultra-rare nonsynonymous variants in European SIDS cases (18 of 278 [6.5%]) versus European control subjects (30 of 973 [3.1%]; p = 0.013) when combining all 4 major cardiac channelopathy genes (KCNQ1, KCNH2, SCN5A, and RYR2). According to the American College of Medical Genetics guidelines, only 18 of 419 (4.3%) SIDS cases hosted a "pathogenic" or "likely pathogenic" variant.

CONCLUSIONS:

Less than 15% of more than 400 SIDS cases had a "potentially informative" variant in a GHD-susceptibility gene, predominantly in the 4- to 12-month age group. Only 4.3% of cases possessed immediately clinically actionable variants. Consistent with previous studies, ultra-rare, nonsynonymous variants within the major cardiac channelopathy-associated genes were overrepresented in SIDS cases in infants of European ethnicity. These findings have major implications for the investigation of SIDS cases and families.

KEYWORDS:

genetic heart diseases; molecular autopsy; sudden infant death syndrome; whole exome sequencing

PMID:
29544605
DOI:
10.1016/j.jacc.2018.01.030

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