Abstract
BackgroundMolecular autopsy refers to DNA-based identification of the cause of death. Despite recent attempts to broaden its scope, the term remains typically reserved to sudden unexplained death in young adults. In this study, we aim to showcase the utility of molecular autopsy in defining lethal variants in humans.MethodsWe describe our experience with a cohort of 481 cases in whom the cause of premature death was investigated using DNA from the index or relatives (molecular autopsy by proxy). Molecular autopsy tool was typically exome sequencing although some were investigated using targeted approaches in the earlier stages of the study; these include positional mapping, targeted gene sequencing, chromosomal microarray, and gene panels.ResultsThe study includes 449 cases from consanguineous families and 141 lacked family history (simplex). The age range was embryos to 18 years. A likely causal variant (pathogenic/likely pathogenic) was identified in 63.8% (307/481), a much higher yield compared to the general diagnostic yield (43%) from the same population. The predominance of recessive lethal alleles allowed us to implement molecular autopsy by proxy in 55 couples, and the yield was similarly high (63.6%). We also note the occurrence of biallelic lethal forms of typically non-lethal dominant disorders, sometimes representing a novel bona fide biallelic recessive disease trait. Forty-six disease genes with no OMIM phenotype were identified in the course of this study. The presented data support the candidacy of two other previously reported novel disease genes (FAAH2 and MSN). The focus on lethal phenotypes revealed many examples of interesting phenotypic expansion as well as remarkable variability in clinical presentation. Furthermore, important insights into population genetics and variant interpretation are highlighted based on the results.ConclusionsMolecular autopsy, broadly defined, proved to be a helpful clinical approach that provides unique insights into lethal variants and the clinical annotation of the human genome.
Highlights
Molecular autopsy refers to DNA-based identification of the cause of death
There has been a sustained growth of the literature on molecular autopsy with evolution of the technology used from targeted variant analysis to Sanger sequencing of one or more genes of interest to nextgeneration sequencing gene panels to whole-exome sequencing
The term remained largely confined to the study of unexplained death among young adults, e.g., a very recent “genomic autopsy” study reported the use of whole-genome sequencing to determine the cause of death in young adults averaging 23 years of age [3]
Summary
Molecular autopsy refers to DNA-based identification of the cause of death. Despite recent attempts to broaden its scope, the term remains typically reserved to sudden unexplained death in young adults. Leveraging the power of DNA to reveal the cause of death, Ackerman and colleagues coined the term “molecular autopsy” in 1999 when describing their approach of sequencing KVLQT1 in a cohort of young adults who died of unexplained drowning [2]. In 2018, we suggested an expansion of molecular autopsy to include its application in maternal-fetal medicine (lethal malformation, stillbirths, intrauterine fetal deaths, etc.), which was subsequently endorsed by others [4, 5]
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