Epigenetic Changes in ADNP Syndrome, a Cause of Autism, Do Not Indicate Profound Presentation of the Disorder
Study Finds Epigenetic Signatures Show Little Correlation to Severity of Symptoms
A study led by the Seaver Autism Center for Research and Treatment at Mount Sinai found that two different blood epigenetic signatures associated with ADNP syndrome (also known as Helsmoortel-Van Der Aa syndrome) have only a modest correlation with clinical manifestations of the syndrome. The study results were published online August 5 in the American Journal of Human Genetics.
ADNP syndrome, one of the most common single-gene causes of autism spectrum disorder, is a neurodevelopmental condition that is also associated with intellectual disability, developmental delay, and multiple medical comorbidities.
Researchers at the Seaver Center first replicated previously published findings demonstrating that individuals with ADNP syndrome have profound DNA methylation changes in their blood, and these changes are contingent on the type of activity dependent neuroprotective protein (ADNP) mutation that they carry. Individuals with the disorder segregate into two groups based on the location of their mutations.
"DNA methylation is a chemical modification of the DNA molecule, and is one of the epigenetic mechanisms that control the activity of our genes, defining where and when they are expressed. In the past few years, several neurodevelopmental disorders have been associated with specific changes in DNA methylation,” said Silvia De Rubeis, PhD, Assistant Professor of Psychiatry, at the Seaver Autism Center and co-senior author of the paper.
The team then used behavioral and neurobiological data from two cohorts of individuals with a genetic diagnosis of ADNP syndrome to examine the relationship between these epigenetic signatures and clinical presentation. Results showed limited differences between the two ADNP groups, and no evidence that individuals with more widespread methylation changes were more profoundly affected.
The lack of correspondence between blood molecular signatures and clinical manifestations cautions against making phenotypic inferences based on the blood-based methylation profiles. This is important to consider when evaluating the use of these episignatures as biomarkers for patient stratification and response to pharmacological agents in clinical trials.
The Seaver researchers concluded that while the two unique blood epigenetic signatures may be valuable for complementing clinical genetics and enhancing accuracy of diagnosis, they need to be carefully evaluated before being considered as a tool to predict behavioral outcomes or to stratify patients with ADNP syndrome into clinically meaningful subgroups.
“As clinical trials in ADNP syndrome begin, understanding the utility of biomarkers and their relationship to clinical symptoms becomes critical. Our results caution against using episignatures as a biomarker for clinical trials,” said Paige Siper, PhD, Chief Psychologist at the Seaver Autism Center and senior co-leading author on the study.
To date, ADNP syndrome has no FDA-approved treatment options, but the Seaver Center recently began recruitment for the first-ever clinical trial for ADNP syndrome. The trial will evaluate the safety, tolerability, and efficacy of a low dose of ketamine in children with the disorder.
“The Seaver Autism Center is making huge strides forward every day in ADNP research, unlike anywhere else in the world,” said Sandra Bedrosian Sermone, Founder and President of the ADNP Kids Research Foundation. “Our Foundation’s open collaboration with the Center has helped us rally patient participation and financial support for their research to help improve the lives of children around the world with this rare disorder.”
This work was supported by grants from the Beatrice and Samuel A. Seaver Foundation and the ADNP Kids Research Foundation.
About the Seaver Autism Center for Research and Treatment
The Seaver Autism Center is one of the most recognized institutions of its kind in the world because of its ability to translate breakthroughs in the lab to clinical trials that bring cutting-edge treatment to individuals affected by autism spectrum disorder (ASD) and associated neurodevelopmental disorders. We offer compassionate care, including assessment and behavioral health services, to children and families, as well as educational and community outreach programs. Founded in 1993 and located at the Icahn School of Medicine at Mount Sinai, families come from around the world to seek our services and the expert counsel of our team of scientists, researchers and clinicians.
For more information, visit: www.seaverautismcenter.org, or find the Seaver Autism Center on Facebook, Twitter and Instagram.
About the Mount Sinai Health System
Mount Sinai Health System is one of the nation’s leading integrated academic health systems and one of the largest in the New York metropolitan area. Its comprehensive system includes seven hospitals, more than 400 outpatient practices, over 600 research and clinical laboratories, the Icahn School of Medicine at Mount Sinai, the Graduate School of Biomedical Sciences, and the Mount Sinai Phillips School of Nursing. Together, the Health System comprises approximately 48,000 employees, more than 9,000 physicians, and 8,600 nurses.
As a leading learning health system, Mount Sinai combines clinical expertise with scientific discovery to improve patient care while training the next generation of health care and biomedical leaders. The Health System provides care across every stage of life, from prenatal care through geriatrics, while advancing personalized medicine through artificial intelligence, data science, and biomedical research.
Mount Sinai is consistently recognized among the nation’s leading academic health systems for patient care, research, and education. The Mount Sinai Hospital is ranked No. 1 in New York by Newsweek and No. 5 on the magazine’s World’s Best Hospitals list. The Icahn School of Medicine at Mount Sinai ranks No. 11 among U.S. medical schools and No. 1 among freestanding medical schools for National Institutes of Health funding, reflecting the strength of its scientific enterprise and leadership in biomedical research.