Public Release: 

Regulatory mutations missed in standard genetic screening lead to congenital diseases

Novel epigenetic mutations identified as significant contributors to neurodevelopmental disorders and congenital anomalies

The Mount Sinai Hospital / Mount Sinai School of Medicine

Researchers have identified a type of genetic aberration to be the cause of certain neurodevelopmental disorders and congenital diseases, such as autism and congenital heart disease, which are undetectable by conventional genetic testing.

The discovery that genetic mutations called epivariations are involved in these diseases could lead to more advanced diagnostic tools for many congenital and neurodevelopmental disorders, say researchers from the Department of Genetics and Genomics Sciences at the Icahn School of Medicine at Mount Sinai and collaborators from Radboud University Medical Center (The Netherlands), University of Minho (Portugal), and Porto Hospital Center (Portugal). The research team's results were published in May 2018 in Nature Communications.

Epivariations are variations in the DNA molecule that do not affect the basic composition of the DNA molecule, called the DNA sequence, but result in a change in gene function. Because conventional genetic testing analyzes the DNA sequence, diseases that are caused by these epivariations need to be tested for using different mechanisms. The specific epivariation found in this study was caused by excess DNA methylation--when a methyl group, composed of hydrogen and carbon atoms, is attached to a DNA molecule.

"Our study suggests that these epigenetic mutations are a significant contributor to human disease," said Andrew Sharp, PhD, Associate Professor in the Department of Genetic and Genomic Sciences at the Icahn School of Medicine and lead investigator of the study.

The research team studied the genetic profiles of 489 patients with known neurodevelopmental or congenital disorders, who had all previously undergone genetic testing that identified no DNA mutations. These disorders had long been thought to have genetic origins, so the scientists suspected that even though conventional testing hadn't discovered a genetic cause for them, epivariations in their DNA could be present, resulting in gene dysfunction leading to disease. To assess for epivariations, Sharp's team conducted methylation profiling--determining the DNA methylation within each patient's genome--finding epigenetic mutations that could be the cause of disease in approximately 20 percent of the studied cohort. Furthermore, in analyzing more than 5,000 genome profiles of individuals with no known diagnosis of congenital disease or neurodevelopmental disorder, the team discovered epigenetic mutations to be relatively common, and that they could typically be identified via a blood test.

Standard genetic screening methods, such as whole-genome sequencing, are applied to thousands of human genomes around the world. What's missing, says Dr. Sharp, is epigenomic profiling. "These findings can open up a whole new world in what we know about disease and genetic profiling," Dr. Sharp continued. "Investigating DNA methylation when profiling genomes for disease mutations could help us uncover causative defects in congenital and neurodevelopmental diseases that have eluded us for years."

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About the Icahn School of Medicine at Mount Sinai

The Icahn School of Medicine at Mount Sinai is an international leader in medical and scientific training, biomedical research, and patient care. It is the medical school for the Mount Sinai Health System, which includes seven hospital campuses, and has more than 5,000 faculty and nearly 2,000 students, residents and fellows. The School is made up of 36 multidisciplinary research, educational, and clinical institutes and 33 academic departments. It ranks 13th among U.S. medical schools for NIH funding and 2nd in research dollars per principal investigator among U.S. medical schools by the Association of American Medical Colleges (AAMC). The School was named 4th among "World's Most Innovative Companies in Data Science" by Fast Company magazine in 2016. For more information, visit http://icahn.mssm.edu

About the Mount Sinai Health System

The Mount Sinai Health System is New York City's largest integrated delivery system encompassing seven hospital campuses, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai's vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The System includes approximately 7,100 primary and specialty care physicians; 10 joint-venture ambulatory surgery centers; more than 140 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. The Icahn School of Medicine is one of 3 medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools", aligned with a U.S. News & World Report's "Honor Roll" Hospital, No. 13 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 18 on U.S. News & World Report's "Honor Roll" of top U.S. hospitals; it is one of the nation's top 20 hospitals in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Geriatrics, Nephrology, and Neurology/Neurosurgery, and in the top 50 in four other specialties in the 2017-2018 "Best Hospitals" issue. Mount Sinai's Kravis Children's Hospital also is ranked in six out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 12th nationally for Ophthalmology and 50th for Ear, Nose, and Throat, while Mount Sinai Beth Israel, Mount Sinai St. Luke's and Mount Sinai West are ranked regionally. For more information, visit http://www.mountsinai.org/, or find Mount Sinai on Facebook, Twitter and YouTube.

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