title: Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases.
abstract: Sudden infant death syndrome (SIDS) is described as the sudden and unexplained death of an apparently healthy infant younger than one year of age. Genetic studies indicate that up to 35% of SIDS cases might be explained by familial or genetic diseases such as cardiomyopathies, ion channelopathies or metabolic disorders that remained undetected during conventional forensic autopsy procedures. Post-mortem genetic testing by using massive parallel sequencing (MPS) approaches represents an efficient and rapid tool to further investigate unexplained death cases and might help to elucidate pathogenic genetic variants and mechanisms in cases without a conclusive cause of death. In this study, we performed whole-exome sequencing (WES) in 161 European SIDS infants with focus on 192 genes associated with cardiovascular and metabolic diseases. Potentially causative variants were detected in 20% of the SIDS cases. The majority of infants had variants with likely functional effects in genes associated with channelopathies (9%), followed by cardiomyopathies (7%) and metabolic diseases (1%). Although lethal arrhythmia represents the most plausible and likely cause of death, the majority of SIDS cases still remains elusive and might be explained by a multifactorial etiology, triggered by a combination of different genetic and environmental risk factors. As WES is not substantially more expensive than a targeted sequencing approach, it represents an unbiased screening of the exome, which could help to investigate different pathogenic mechanisms within the genetically heterogeneous SIDS cohort. Additionally, re-analysis of the datasets provides the basis to identify new candidate genes in sudden infant death.
authors.affiliation: Zurich Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Neubauer
authors.affiliation: Functional Genomics Center Zurich (FGCZ), University of Zurich/ETH Zurich, Zurich, Switzerland.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Lecca
authors.affiliation: Functional Genomics Center Zurich (FGCZ), University of Zurich/ETH Zurich, Zurich, Switzerland.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Russo
authors.affiliation: University of Zurich, Zurich, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Bartsch
authors.affiliation: Department of Cardiology, Inselspital, University Hospital Bern, Bern, Switzerland.
authors.forename: Argelia
authors.initials: A
authors.lastname: Medeiros-Domingo
authors.affiliation: Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland.|Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.|Neuroscience Center (ZNZ), University and ETH Zurich, Zurich, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Berger
authors.affiliation: Zurich Institute of Forensic Medicine, University of Zurich, Zurich, Switzerland.
authors.forename: Cordula
authors.initials: C
authors.lastname: Haas
mesh_terms: D002318:Cardiovascular Diseases / Q000175:diagnosis / Q000235:genetics*; D053447:Channelopathies / Q000175:diagnosis / Q000235:genetics*; D059472:Exome; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008661:Metabolism, Inborn Errors / Q000175:diagnosis / Q000235:genetics*; D013398:Sudden Infant Death / Q000175:diagnosis / Q000235:genetics*