Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases

Neubauer, Jacqueline; Haas, Cordula; Bärtsch, Christine; Medeiros-Domingo, Argelia; Berger, Wolfgang

doi:10.1007/s00414-016-1317-4

Cited by 23 publications

(11 citation statements)

References 52 publications

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“…Our higher percentage may be due to a comprehensive genetic analysis including both genes associated with channelopathies and genes associated with cardiomyopathies, recently associated with arrhythmic pathologies without any structural alteration [52, 53]. In concordance with our results, recent studies performed in post-mortem samples using NGS technology showed percentages of rare variants potentially pathogenic in 30%-40% of samples analyzed [24–26, 54–58]. …”

Section: Discussionsupporting

confidence: 90%

Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation

et al. 2016

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BackgroundSudden unexplained death may be the first manifestation of an unknown inherited cardiac disease. Current genetic technologies may enable the unraveling of an etiology and the identification of relatives at risk. The aim of our study was to define the etiology of natural deaths, younger than 50 years of age, and to investigate whether genetic defects associated with cardiac diseases could provide a potential etiology for the unexplained cases.Methods and FindingsOur cohort included a total of 789 consecutive cases (77.19% males) <50 years old (average 38.6±12.2 years old) who died suddenly from non-violent causes. A comprehensive autopsy was performed according to current forensic guidelines. During autopsy a cause of death was identified in most cases (81.1%), mainly due to cardiac alterations (56.87%). In unexplained cases, genetic analysis of the main genes associated with sudden cardiac death was performed using Next Generation Sequencing technology. Genetic analysis was performed in suspected inherited diseases (cardiomyopathy) and in unexplained death, with identification of potentially pathogenic variants in nearly 50% and 40% of samples, respectively.ConclusionsCardiac disease is the most important cause of sudden death, especially after the age of 40. Close to 10% of cases may remain unexplained after a complete autopsy investigation. Molecular autopsy may provide an explanation for a significant part of these unexplained cases. Identification of genetic variations enables genetic counseling and undertaking of preventive measures in relatives at risk.

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Section: Discussionsupporting

confidence: 90%

Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation

et al. 2016

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“…Neubauer et al have studied five young sudden unexplained death cases by focusing on 184 genes associated with heart disease by the WES. They found that there were different variants of the DCHS1 gene in one of these individuals, which are involved in mitral valve prolapse [26]. Besides, in agreement with our result, Freed et al have examined five generations of a large family and found that at least 12 members had mitral valve prolapse without any manifestation of connective tissue abnormalities [27].…”

Section: Discussionsupporting

confidence: 90%

Secondary findings from whole-exome sequencing data in families with familial combined hyperlipidemia (FCHL)

Zakeri

Safaiee

Taheri

et al. 2021

Egypt J Med Hum Genet

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Background During the interpretation of genome sequencing data, some types of secondary findings are identified that are located in genes that do not appear to be related to the causes of the primary disease. Although these are not the primary targets for evaluation, they have a high risk for some diseases different from the primary disease. Therefore, they can be vital for preventing and intervention from such disease. Results Here, we analyzed secondary findings obtained from WES in 6 families with FCHL disease who had an autosomal-dominant pattern based on their pedigrees. These finding are found in CDKAL1, ITGA2, FAM111A, WNK4, PTGIS, SCN10, TBX20, DCHS1, ANK2 and ABCA1 genes. Conclusions Secondary findings are very important and must be considered different variants from sequencing results in a diagnostic setting. Although we have considered these variants as secondary findings, some of them may be related to the primary disease.

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“…Variants in TTN were not further evaluated due to reported difficulties in sequencing and variant interpretation. 27 We adapted our previously published filter strategy 28 as follows: (1) a global minor allele frequency value (MAF) of ≤ 0.01 based on NCBI dbSNP, 26 (2) focus on exonic and splice site variants and (3) the exclusion of synonymous variants ( Supplementary Figure 1). In addition, Human Gene Mutation Database (HGMD, Qiagen) 29 was consulted to check already reported variants in the literature.…”

Section: Discussionmentioning

confidence: 99%

Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases

et al. 2017

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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.

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Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases

Cited by 23 publications

References 52 publications

Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation

Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation

Secondary findings from whole-exome sequencing data in families with familial combined hyperlipidemia (FCHL)

Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases

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