In the Genetics of Congenital Heart Disease, Noncoding DNA Fills in Some Blanks

Nancy Fliesler, from the Boston’s Children Hospital, talks about how for a couple decades now, researchers have been trying to find out what are the genetic causes for congenital heart disease (CHD). Some causes include chromosomal abnormalities, genetic variants affecting protein-coding genes, and environmental factors, but this only accounts for about 45 percent of cases of CHD. There has been evidence that noncoding DNA does contribute to CHD. It’s difficult to find out which noncoding variants are involved in heart disease, and which are not. Statistical filters were applied to separate the noncoding variants that were not contributing to CHD. 7,000 variants in noncoding DNA regions were left after the separation. 403 affected the activity of transcription enhancers out of the 7,000 variants they tested. 

They then had to introduce 10 of the noncoding variants into normal human stem cells at a certain location on the genome. Four out of the ten variants altered the expression of neighboring genes when the stem cells formed into cardiomyocytes. The research conducted suggest that hundreds more noncoding variants contribute to CHD which could explain cases that are negative by exome sequencing. Future findings could eventually be used to classify patients’ risks, predict outcomes of surgery, or change the course of structural heart disease during pregnancy or after birth. This is important research as we didn’t know for sure what was causing CHD. To know now that there is a noncoding DNA that is the culprit for this disease is revolutionary. 

Main Article: https://answers.childrenshospital.org/congenital-heart-disease-noncoding-dna/

2nd link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892081/ 

Gene Mutations Linked to Ebstein's Anamoly

An article in Science Daily states that researchers at the Academic Medical Center Amsterdam in the Netherlands have found mutations of a gene in patients with a heart defect called Ebstein’s anomaly. Ebstein’s anomaly is a defect in which the right heart valve cannot close properly. Patients with Ebstien’s anamoly also may suffer from a disease called left ventricle noncompaction (LVNC), which has been found to be linked to an increased risk of cardiac death or improper heart function. In a study of LVNC, Professor Ludwig Thierfelder and Dr. Sabine Klaassen discovered mutations in three different genes for muscle structural proteins. Mutations in one gene, MYH7, were found to cause patients with LVNC to have muscle tissue in the heart to protrude into the left ventricle, affecting the ability of the heart to contract properly.  Dr. Alex Postma wanted to see if there was a correlation between Ebstien’s anamoly, LVNC, and the mutations in MYH7. Six out of eight patients studied were found to have mutations in the gene as well as suffer from LVNC and Ebsien’s anamoly.

Based on their findings, the researchers say that one mutation can lead to other heart diseases. This is seen in the patients with Ebstein’s anomaly and LVNC. Dr. Klaassen suggests that family members of patients with these diseases receive cardiac examinations and genetic testing. The risk is increased in those who possess the mutation gene even if they don’t have a heart defect. The researchers hope that with this knowledge, patients can be treated earlier and more effectively.

Understanding Congenital Heart Disease

 

According to an article in Science Daily, Scientists at the Gladstone institute have been studying a certain aspect of fetal heart development that may give a new insight to the understanding of Congenital Heart Disease.  The gene Ezh2 has been found to act as a regulator of another important gene in fetal heart development, Six1.  Without Ezh2 present, as tested in mice, the Six1 gene remains on increasing the activity of other genes that should not be active.  In the study this caused the hearts of the mice to become enlarged and weakened after birth inhibiting the heart from working properly.  An article on the Ezh2 gene in Nature Genetics also confirms the role of the Ezh2 gene in fetal heart development and Six1 regulation.  After reading the two articles I agree that knowledge of the Ezh2 gene in the role of fetal heart development can contribute to a better understanding of congenital heart disease.