Lethal variants in humans: lessons learned from a large molecular autopsy cohort

Area of Science:

• Genetics
• Genomic Medicine
• Molecular Biology

Background:

• Molecular autopsy, a DNA-based approach, is typically used for sudden unexplained deaths in young adults.
• Recent efforts aim to expand its application beyond its traditional scope.
• This study explores the broader utility of molecular autopsy in identifying lethal genetic variants.

Purpose of the Study:

• To demonstrate the effectiveness of molecular autopsy in identifying lethal genetic variants in a large cohort.
• To assess the diagnostic yield of molecular autopsy compared to standard methods.
• To investigate the role of molecular autopsy in understanding genetic causes of premature death.

Main Methods:

• A cohort of 481 cases with premature death underwent molecular autopsy using DNA analysis.
• Exome sequencing was the primary tool, supplemented by targeted approaches like gene panels and chromosomal microarray.
• Analysis included cases from consanguineous families and simplex cases, with ages ranging from embryos to 18 years.

Main Results:

• A likely causal variant was identified in 63.8% of cases, significantly higher than the general diagnostic yield (43%).
• Molecular autopsy by proxy was successfully applied in 55 couples, yielding a high success rate (63.6%).
• The study identified novel disease genes and expanded understanding of phenotypic variability and lethal forms of genetic disorders.

Conclusions:

• Molecular autopsy, when broadly defined, is a valuable clinical tool for identifying lethal genetic variants.
• It provides crucial insights into the genetic basis of premature death and aids in human genome annotation.
• The findings highlight the importance of genetic analysis in unexplained deaths and rare diseases.