Regulatory mutations missed in standard genetic screening lead to congenital diseases

May 25, 2018, The Mount Sinai Hospital
Credit: CC0 Public Domain

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 called epivariations are involved in these diseases could lead to more advanced diagnostic tools for many congenital and , 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, Ph.D., 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 mutations could help us uncover causative defects in congenital and neurodevelopmental diseases that have eluded us for years."

Explore further: First 'non-gene' mutations behind neurodevelopmental disorders discovered

Related Stories

First 'non-gene' mutations behind neurodevelopmental disorders discovered

March 21, 2018
In the largest study of its kind, genetic changes causing neurodevelopmental disorders have been discovered by scientists at the Wellcome Sanger Institute and their collaborators in the NHS Regional Genetics services. The ...

New brain development disorder identified by scientists

May 22, 2018
Researchers have identified a new inherited neurodevelopmental disease that causes slow growth, seizures and learning difficulties in humans.

Researchers uncover new congenital heart disease genes

October 9, 2017
Approximately one in every 100 babies is born with congenital heart disease (CHD), and CHD remains the leading cause of mortality from birth defects. Although advancements in surgery and care have improved rates of survival ...

Familial breast cancer not only inherited genetically, finds new study

February 28, 2018
Mutations in known breast cancer genes such as BRCA1 and BRCA2 are identified in only approximately 20 per cent of women who are offered genetic testing for familial breast cancer.

Genetic underpinning found for shared risk of congenital heart and neurodevelopmental disease

December 4, 2015
Children with significant congenital heart disease have a far better chance of surviving today than in decades past, thanks to major advances in surgery. But some infants who recover from repairs to their hearts later show ...

New neurodevelopmental syndrome identified

April 21, 2016
A multicenter research team led by Columbia University Medical Center (CUMC) has discovered a new neurodevelopmental syndrome and the genetic mutations that cause it. The discovery is an important step toward creating targeted ...

Recommended for you

RNA thought to spread cancer shows ability to suppress breast cancer metastasis

October 22, 2018
Researchers at The University of Texas MD Anderson Cancer Center have discovered that a form of RNA called metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) appears to suppress breast cancer metastasis in mice, ...

New tool gives deeper understanding of glioblastoma

October 22, 2018
Researchers in the lab of Charles Danko at the Baker Institute for Animal Health have developed a new tool to study genetic "switches" active in glioblastoma tumors that drive growth of the cancer. In a new paper in Nature ...

Researchers find common genetic link in lung ailments

October 22, 2018
An international research team led by members of the University of Colorado School of Medicine faculty has identified a genetic connection between rheumatoid arthritis-associated interstitial lung disease and idiopathic pulmonary ...

A single missing gene leads to miscarriage

October 19, 2018
A single gene from the mother plays such a crucial role in the development of the placenta that its dysfunction leads to miscarriages. Researchers from the Medical Faculty of Ruhr-Universität Bochum (RUB) have observed this ...

Making gene therapy delivery safer and more efficient

October 18, 2018
Viral vectors used to deliver gene therapies undergo spontaneous changes during manufacturing which affects their structure and function, found researchers from the Perelman School of Medicine at the University of Pennsylvania ...

Student develops microfluidics device to help scientists identify early genetic markers of cancer

October 16, 2018
As anyone who has played "Where's Waldo" knows, searching for a single item in a landscape filled with a mélange of characters and objects can be a challenge. Chrissy O'Keefe, a Ph.D. student in the Department of Biomedical ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.