Molecular autopsy of dried blood spots can identify the underlying cause of sudden cardiac death in a youngster

The underlying cause of sudden cardiac death (SCD) in a young person is often difficult to identify. DNA testing could provide more information in many cases, but blood samples are not taken routinely at the time of death, and DNA extracted from tissues taken at autopsy is damaged due to the way they are passed. are fixed in formalin and embedded in paraffin. But finding the cause is vital if relatives who may be carriers of the same genetic variant as the victim are to be traced. Today, for the first time, Swedish researchers were able to perform molecular autopsies of sickle cell disease nationwide, using Dried Blood Drops (DBS) collected up to 40 years ago as part of the screening routine for newborns. Their results will be presented at the annual conference of the European Society of Human Genetics today (Saturday).

Dr Angelica Delgado-Vega, MD, clinical genetics specialist at Uppsala University Hospital, Uppsala, Sweden, and colleagues from Uppsala and Gothemburg, identified 22 Swedish sickle cell cases between 2000 and 2010 in people under 35 who have undergone an autopsy. diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited disease of the heart muscle that affects approximately 1 in 1,000 to 1 in 5,000 people. Using whole exome sequencing, they extracted DNA from DBS, formalin-fixed, paraffin-embedded post-mortem heart tissue (FFPE); and frozen blood samples from victims, where they exist.

Although the researchers found a lower yield of DNA from DBS compared to FFPE, all DBS samples passed quality control, compared to 62.5% of the FFPE samples. The quality of the DBS results was similar to that of frozen blood samples, and analysis showed clinically relevant genetic variants in 12 of 19 families. “Four were located in the ARVC genes and six in another gene known to cause arrhythmic syndrome,” explains Dr. Delgado-Vega. “In addition, we identified one case of hemochromatosis, an iron overload disorder, and one case of myotonic dystrophy, a disorder of muscle function. This not only showed us that the molecular autopsy of DBS gave a reliable result in ARVC, but also allowed us to identify parents who might be at risk for other disorders.We were delighted to find that the quality of the sequence data of such small amounts of DNA was better than expected. we expected. “

The researchers now intend to offer carrier tests to these relatives and to monitor them clinically. They will also apply the DBS molecular autopsy technique to a larger group of 903 SCD victims from SUDDY, the Swedish Sudden Cardiac Death Cohort of the Young Cohort. Even though their first results are impressive, it was not an easy task, they say.

It was difficult to obtain the samples from the biobanks even if we have the ethical authorizations and the consent of relatives, because of the logistical and internal rules specific to each of them. The Swedish Board of Forensic Medicine, for example, did not provide any samples due to legal regulations. Even though the results of the FFPE samples were of lower quality than those of DBS, it still works with them. The acquisition of FFPE samples is also important because DBS was not available until 1976, when newborn screening began in Sweden. “

Dr Angelica Delgado-Vega, MD, Specialist, Clinical Genetics, Uppsala University Hospital, Uppsala, Sweden

The sudden and often unexplained death of a young person is a devastating event for their family.

By identifying disease-causing variants, health systems can offer an explanation. “And the identification of loved ones who are carriers and therefore at risk of sudden cardiac death means that we can offer them treatment and other preventive measures, because this is an preventable outcome. Unfortunately, many of our families have already lost several members due to SCD, ”says Dr. Delgado-Vega.

“As this is a post-mortem study, we cannot be completely sure whether the identified arrhythmogenic syndromes were a cause of death or an alternative diagnosis or an overlapping phenotype. However, our results provide valuable new insight into the condition. biology of cardiomyopathies, where genes overlap and phenotypes are common. We assess each family individually. In several cases, there are relatives diagnosed with arrhythmogenic syndrome identified without evidence of ARVC. We hope that our results will lead to a better risk assessment and better management in these cases, ”she concluded.

ESHG conference chair Professor Alexandre Reymond, director of the Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland, said: “Arrhythmogenic syndromes are ‘sneak killers’ and it would seem logical to try to identify This is a typical example where an established practice, i.e. systematic screening of newborns via dried blood drops, could and should be modernized in the coming years to assess more genes for the most. great good.