Genetic autopsies reveal secrets of life to researchers

NEW HAVEN — Death is not final in the Yale New Haven Hospital Pathology Department.

By going beyond the standard autopsy to examine a deceased patient’s DNA, the team led by Dr. Jon Morrow can find out the cause of an unexplained sudden death, including newborns, and inform families of inherited diseases that could help them make decisions about their health care.

“As our knowledge of the genome has expanded … there has increasingly been identified a number of genetic changes … that have turned out to be causal in many of these cases of sudden death,” said Morrow, chief of pathology for the hospital.

Yale New Haven is one of the few hospitals to do the intensive postmortem examination, and Morrow said they are interested in performing molecular autopsies on anyone whose family is willing to have one done or who has requested it before death, That’s because every exam adds to the body of knowledge about how genes contribute to disease.

“It builds a database that helps us understand disorders at a deeper level than we’ve been able to do from normal autopsy,” Morrow said.

Morrow’s team collaborates with the Yale School of Medicine’s Center for Genomic Health, which launched the Generations Project, which began in September with a goal of sequencing the DNA of 100,000 patients.

In a molecular autopsy, the pathology team looks at the exome, the 3 percent or less of the human genome that includes all of the genes involved in producing proteins. “That 3 percent is responsible for everything you see in the body,” Morrow said, because our organs are all made up of proteins. “It’s a very efficient way to look at almost everything that’s important,” he said.

The rest of the genome is involved in cellular structure, regulatory processes, how and when genes are switched on and off

By examining the exome, pathologists can compare the individual to a reference database at the National Institutes of Health. The individual differences, called polymorphisms, are what can tell the doctors whether a patient who died from cancer did so simply because he smoked or because he had a genetic predisposition.

“You always run what you find against this reference database,” Morrow said.

“You can expect up to 70,000 variations in an individual. … Most of those variations are innocuous. They don’t have any real or deep pathologic significance.”

By sequencing the genome, variations in alleles — the pairs of genes that control characteristics — will be identified and, “if you find a variation in a patient that is extremely rare, lightbulbs go off,” Morrow said. “If that was a variation in a gene that’s rare and a gene is known to control cardiac function, you would be very suspicious that that had to do with a cardiac malfunction.”

In addition to finding the cause of death when a regular autopsy does not, Morrow said molecular autopsies have a larger goal of finding answers on the genetic level. He and his staff hope many people will consent to the procedure. Now, 12 to 14 percent of deceased patients undergo autopsies.

“By looking at this exome, we get a pretty good view of what should be right. … There’s wide variations in individuals,” Morrow said. “Some are pathologic, disease- causing. By moving beyond sudden death and extending these studies to all individuals now, we have a hope of explaining causes of all these conditions.”

When word got out about Yale New Haven’s program, “We had almost universal enthusiasm from a number of major medical centers [ asking], ‘ Can we partner with you?’” Morrow said. “I’m hopeful we’d be able to expand this to multi- institutional practices.”

Some diseases, such as many cancers, start with genetic mutations that are caused by external factors, such as smoking. Those are called somatic mutations. What the molecular autopsy finds are inherited mutations that may give a predisposition to the cancer.

“We’re not sequencing tumors, we’re sequencing normal tissue,” Morrow said. “When we find a damaging lesion, that gene was present from birth and that gene was inherited.”

Another example is alpha- 1 antitrypsin deficiency, an inherited disorder that is responsible for both lung and liver disease.

“It’s not that uncommon in the population and people get emphysema and liver disease later in life because of it,” Morrow said. Finding out that a deceased relative had the disorder can help family members lessen their risk, by not smoking, for example.