Tatiana Legkiy was only two months old when she was rushed to a hospital in San Francisco after an echocardiogram showed that her heart was malfunctioning. A recent article in STAT recounts efforts to save her life. Tatiana was put on emergency life support. Remarkably the medication she was receiving began to work and her heart started pumping normally again.
An Incomplete Diagnosis
For the past twelve years, researchers have been searching for answers to the abnormal development of Tatiana’s heart. They found a few clues. One such clue involved her mother’s miscarriage. A fetus had died from the condition. The second discovery pertained to an undiagnosed heart problem in her older sister. Both discoveries created theories about how disease-causing-mutations may be inherited.
Heritable Diseases and Oligognic Diseases
Researchers agree that heritable diseases such as Huntington’s disease, cystic fibrosis, or sickle cell anemia, are the result of a mutation in one gene. But sometimes genetic mutations of a few genes collectively cause “oligogenic” diseases meaning that they are influenced by more than one gene.
In a paper published in the journal Science, scientists from the Gladstone Institutes and the University of California, San Francisco (UCSF) used technological advances to prove that three subtle genetic mutations inherited within a family worked together to cause heart disease in multiple siblings at a very young age.
Tatiana’s case remained unsolved until the advent of CRISPR genome editing and advances in stem cell technology. The researchers decided that they finally had the tools and the right case to test their theory.
And Now to Test the Theory
Scientists from Gladstone Institutes and UCSF wrote a paper that was published in the Science journal. They reported that three genetic mutations were inherited within one family. That the children’s heart disease was a result of the combination of genes from both their mother and father. The team explained that the combination of these mutations caused heart disorders in the young siblings.
The researchers used genome sequencing to test their theory. They were able to identify two mutations in the father’s genes that increased his risk of heart disease.
The siblings inherited the two mutations from their father plus one mutation from their mother who had no apparent symptoms.
Her older sister Anna, who was four years old when Tatiana was hospitalized, does not seem to have any symptoms. It appears that her heart is able to compensate for the abnormalities.
Tissue samples from the fetus that had survived in the womb for six months were analyzed. The team found that his heart had not developed.
In addition, skin cells from the Legkiy family were converted into stem cells. The specific stem cells used by the researchers have the ability to morph into other cells. In this case, they became cardiac cells.
Using Mouse Models
The researchers, using CRISPR genome editing, duplicated the mutations in mice that had been found in Tatiana and her family. The mice that had either one copy of the two mutations from Tatiana’s father or one mutation from her mother had no signs of heart disease.
However, the mice with all three mutations had evidence of heart defects which were identical to those that appeared in the children. Not only damage to the heart’s function and structure but changes to genes that are vital to the heart’s development.
One of the researchers summarized the results by explaining that the body may be able to tolerate a bad copy but when the variants are combined they can cause serious heart problems.
The study also demonstrates how multiple genes function and how they cause disease in humans. This discovery allows scientists to target genetic modifiers that cause disease. Then they can develop appropriate therapies.
Anna and Tatiana who live in Texas, are now fifteen and eleven. The girls visit their cardiologists regularly but are not taking any medication. Their mother was pleased to report that their hearts are functioning normally.
If you know of similar cases we would love to hear from you.
