Mount Sinai Researchers Identify Gene Mutations in Congenital Heart Disease
Using high-throughput sequencing, an international research team including Mount Sinai discovers causes of severe congenital heart disease
Mutations in eight genes have been linked to severe forms of congenital heart disease (CHD), according to a study involving investigators at the Icahn School of Medicine at Mount Sinai.The study used an advanced technique known as high-throughput sequencing that enables scientists to obtain the sequence of all 22,000 human genes and the entire human genome at one time. Results from the study are published online today in the journal Nature.
The research was conducted through the National Heart, Lung, and Blood Institute (NHLBI)-supported Pediatric Cardiac Genomics Consortium, an international, multi-center collaborative effort. The NHLBI is part of the National Institutes of Health (NIH).
“The eight genes that we identified are important in chromatin remodeling,” said a study coinvestigator, Bruce D. Gelb, MD, Director of The Mindich Child Health and Development Institute (MCHDI) at the Icahn School of Medicine at Mount Sinai.
Chromatin remodeling controls which genes work in which cells. For example, chromatin remodeling makes sure that only genes that control the heart are used in the heart, and genes that are used in the brain are turned on and off in the brain. When chromatin remodeling genes are altered, the on/off status of many genes is altered.
“Together, all of the gene mutations we found account for about 10 percent of the severe congenital heart disease,” said Dr. Gelb. “We may eventually be able to offer better early interventions that slow the natural history of congenital heart disease.”
Congenital heart disease affects approximately 8 in 1,000 newborns. It encompasses a wide variety of defects. Some forms of CHD can be lethal, complex to treat, and can lead to serious intellectual and developmental disabilities. Other forms of CHD require no treatment or can easily be fixed. Congenital heart disease is rarely inherited.
Mutations in genes that control chromatin remodeling have already been implicated in cancers. Some drugs that target chromatin remodeling have already been approved and many more are in the pipeline, according to Dr. Gelb.
With only 30 genes identified out of more than 400 genes believed to be important in congenital heart disease, Dr. Gelb says that researchers will next examine many more parents and their affected children.
As the genetic architecture underlying congenital heart disease becomes better understood, genetic testing will become more widely used. What is clear, thus far, is “that parents participating in these studies take comfort in learning that a congenital heart defect or another problem results from a cause that no one had any control over,” said Dr. Gelb. “That is, it wasn’t their fault or the fault of the medical care that they received.”
For the study, researchers used exome sequencing of 362 parent-child trios: parents with no identifiable heart disease and a child with severe congenital heart disease. The major types of severe congenital heart disease among the children included conotruncal defects (abnormal heart outflow formation), left ventricular obstruction (impaired blood flow from the heart’s main pumping chamber), and heterotaxy (abnormal formation of the left-right sides of the body). The children also had other impairments related to the heart problems, especially neurodevelopmental delays and poor growth.
About The Mount Sinai Medical Center
The Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and Icahn School of Medicine at Mount Sinai. Established in 1968, the Icahn School of Medicine at Mount Sinai is one of the leading medical schools in the United States. The Icahn School of Medicine is noted for innovation in education, biomedical research, clinical care delivery, and local and global community service. It has more than 3,400 faculty members in 32 departments and 14 research institutes, and ranks among the top 20 medical schools both in National Institutes of Health (NIH) funding and by U.S. News & World Report.
The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation’s oldest, largest and most-respected voluntary hospitals. In 2012, U.S. News & World Report ranked The Mount Sinai Hospital 14th on its elite Honor Roll of the nation’s top hospitals based on reputation, safety, and other patient-care factors. Mount Sinai is one of just 12 integrated academic medical centers whose medical school ranks among the top 20 in NIH funding and by U.S. News & World Report and whose hospital is on the U.S. News & World Report Honor Roll. Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and approximately 560,000 outpatient visits took place.