Cost-Effectiveness of the ‘Molecular Autopsy’ in Sudden Unexplained Death in the Young

Abstract Background Molecular autopsy represents an efficient tool to save the diagnosis in up to one-third of sudden unexplained death (SUD). A defined gene panel is usually used for the examination. Alternatively, it is possible to carry out a comprehensive genetic assessment (whole exome sequencing, WES), which also identifies rare, previously unknown variants. The disadvantage is that a dramatic number of variants must be assessed to identify the causal variant. To improve the evaluation of WES, the human phenotype ontology (HPO) annotation is used internationally for deep phenotyping in the field of rare disease. However, a HPO-based evaluation of WES in SUD has not been described before. Methods We performed WES in tissue samples from 16 people after SUD. Instead of a fixed gene panel, we defined a set of HPO terms and thus created a flexible “virtual gene panel”, with the advantage, that recently identified genes are automatically associated by HPO terms in the HPO database. Results We obtained a mean value of 68,947 variants per sample. Stringent filtering ended up in a mean value of 276 variants per sample. Using the HPO-driven virtual gene panel we developed an algorithm that prioritized 1.4% of the variants. Variant interpretation resulted in eleven potentially causative variants in 16 individuals. Conclusion Our data introduce an effective diagnostic procedure in molecular autopsy of SUD with a non-specific clinical phenotype.

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Broad-based molecular autopsy: a potential tool to investigate the involvement of subtle cardiac conditions in sudden unexpected death in infancy and early childhood

Archives of Disease in Childhood ◽

10.1136/archdischild-2015-308200 ◽

2015 ◽

Vol 100 (10) ◽

pp. 952-956 ◽

Cited By ~ 16

Author(s):

Montserrat Santori ◽

Alejandro Blanco-Verea ◽

Rocio Gil ◽

Judith Cortis ◽

Katrin Becker ◽

...

Keyword(s):

Sudden Cardiac Death ◽

Genetic Variants ◽

Early Onset ◽

Cardiac Death ◽

Sudden Unexpected Death ◽

Unexpected Death ◽

Molecular Autopsy ◽

Sudden Unexplained Death ◽

Unexplained Death ◽

In Infants And Children

ObjectivesSudden unexplained death in children is a tragic and traumatic event, often worsened when the cause of death cannot be determined. This work aimed to investigate the presence of putative pathogenic genetic variants in a broad spectrum of cardiomyopathy, channelopathy and aortic disease associated genes that may have increased these children's vulnerability to sudden cardiac death.DesignWe performed molecular autopsy of 41 cases of sudden unexplained death in infants and children through massive parallel sequencing of up to 86 sudden cardiac death-related genes. Multiple in silico analyses were conducted together with a thorough review of the literature in order to prioritise the putative pathogenic variants.ResultsA total of 63 variants in 35 cases were validated. The largest proportion of these variants is located within cardiomyopathy genes although this would have been more expected of channelopathy gene variants. Subtle microscopic features of heart tissue may indicate the presence of an early onset cardiomyopathy as a predisposing condition to sudden unexpected death in some individuals.ConclusionsNext-generation sequencing technologies reveal the existence of a wide spectrum of rare and novel genetic variants in sarcomere genes, compared with that of cardiac ion channels, in sudden unexplained death in infants and children. Our findings encourage further investigation of the role of early onset inherited cardiomyopathies and other diseases involving myocardial dysfunction in these deaths. Early detection of variants in these individuals could help to unmask subtle forms of disease within their relatives, who would eventually benefit from better counselling about their genetic history.

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Sudden Unexplained Death – Treating the Family

Arrhythmia & Electrophysiology Review ◽

10.15420/aer.2014.3.3.156 ◽

2014 ◽

Vol 3 (3) ◽

pp. 156 ◽

Cited By ~ 5

Author(s):

Greg Mellor ◽

Elijah R Behr ◽

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Keyword(s):

Genetic Diagnosis ◽

Post Mortem ◽

Molecular Autopsy ◽

Arrhythmic Death ◽

Sudden Unexplained Death ◽

Unexplained Death ◽

Provocation Tests ◽

The Family ◽

Sudden Arrhythmic Death Syndrome ◽

Erroneous Interpretation

Sudden unexplained death in the context of a normal heart at post-mortem and negative toxicological analysis is termed sudden arrhythmic death syndrome (SADS). SADS is often due to cardiac genetic disease, particularly channelopathies. Assessment of family members of SADS victims will reveal at least one affected individual in up to half of families. Specialist evaluation begins with an expert cardiac autopsy that improves diagnostic accuracy and minimises erroneous interpretation of minor pathological findings. Retention of appropriate material for post-mortem genetic testing, ‘the molecular autopsy’, is recommended as this may provide a genetic diagnosis in up to a third of cases. Clinical assessment of families initially comprises 12-lead ECG with high right ventricular leads, echocardiogram and exercise testing. Additional investigations include sodium channel blocker and epinephrine provocation tests. Families with a diagnosis should be managed as per guidelines. Those with negative investigations can generally be discharged unless they are young and/or symptomatic.

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