• Press Release

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

  • New York, NY
  • (August 05, 2020)

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

The Mount Sinai Health System is New York City's largest academic medical system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai is a national and international source of unrivaled education, translational research and discovery, and collaborative clinical leadership ensuring that we deliver the highest quality care—from prevention to treatment of the most serious and complex human diseases. The Health System includes more than 7,200 physicians and features a robust and continually expanding network of multispecialty services, including more than 400 ambulatory practice locations throughout the five boroughs of New York City, Westchester, and Long Island. The Mount Sinai Hospital is ranked No. 14 on U.S. News & World Report's "Honor Roll" of the Top 20 Best Hospitals in the country and the Icahn School of Medicine as one of the Top 20 Best Medical Schools in country. Mount Sinai Health System hospitals are consistently ranked regionally by specialty and our physicians in the top 1% of all physicians nationally by U.S. News & World Report.

For more information, visit https://www.mountsinai.org or find Mount Sinai on FacebookTwitter and YouTube.