According to a study, researchers examined that molecular autopsies can reveal genetic risk factors in young people who unexpectedly die, but the proper interpretation of the results can be challenging. The study was published in Circulation.
Following guidelines set by the American College of Medical Genetics and Genomics (ACMG) can help assess the risk of certain genetic variants, enabling proper counseling of surviving family members.
While genetic testing may help in understanding the underlying pathology in sudden, unexpected death, the greatest benefit is to surviving family members with the hope of preventing future deaths, further highlighting that autopsies, whether conventional or molecular, are performed to benefit the living.
Coronary Artery Disease
Sudden cardiac death is a major health burden, killing as many as 450,000 people annually in the United States. According to the study, the majority of these deaths are caused by coronary artery disease or related conditions. However, up to 5,000 young people, every year die suddenly, and about 40% of these cases remain unexplained after the autopsy.
Lethal and inheritable cardiomyopathies or channelopathies, diseases that affect the heart muscles or heart rhythm, may be responsible for a substantial portion of these unexplained cases. A whole-exome or whole genome molecular autopsy can reveal genetic variants that can potentially cause sudden cardiac death.
However, erroneously judging variants as pathogenic has the potential to harm patients and their families. According to the authors, as much as 10 percent of the variants associated with the long-QT syndrome, a common arrhythmia disorder, may be classified incorrectly in literature, emphasizing the importance of corroborating evidence when determining pathogenicity.
In the new study, investigators examined 25 cases of sudden unexplained death in young adults from Cook County, IL, analyzing 99 gene variants thought to be associated with sudden cardiac death. They found 27 ultra-rare variants present among 16 of the victims, meriting further investigation. Following the ACMG framework, the investigators next used weighted factors to determine clinical relevance.
Whether the gene was major or minor, whether its phenotype matched the patient's presentation at autopsy, and any resemblance to previously established pathogenic gene variants are all factors that have point values, which are combined to establish classification. In the end, four of the 25 patients examined in this study were found to have clinically actionable genetic variants, warranting genetic testing of surviving family members.
In addition to the cost reductions in genetic testing, clinicians and pathologists see the benefits of postmortem genetic testing. These benefits include counseling and treating surviving family members and gaining a better understanding of the causes of sudden, unexpected death in cases where a conventional autopsy fails to reveal an anatomic cause of death.
White continues to investigate sudden, unexpected death in children and young adults. They conducted genetic testing on the deceased and surviving family members, coupling that data with clinical testing to counseling surviving family.