SickKids researchers identify epigenetic signatures that may help with diagnosing and distinguishing two rare diseases

Researchers at The Hospital for Sick Children (SickKids) have identified specific epigenetic signatures that may help with diagnosis of two clinically overlapping genetic conditions. These signatures could also be used to identify new therapies which could improve the neurodevelopmental trajectories for individuals with these conditions. The findings are published in the May 4 online edition of the American Journal of Human Genetics.

First, what is epigenetics?

Epigenes are master programmers that determine how an individual’s genetic information will be expressed. From the very beginning of development every cell has an epigenetic program that provides instructions regarding its developmental path, for example whether it turns into a heart cell, a brain cell or a muscle cell. Epigenetics can modify the DNA by controlling which genes will be switched on or off, so the right type of cell is developed. Specific epigenetic programming is required for normal health and development. Epigenetic changes can lead to a variety of diseases.

Mutations in master programmer genes (epigenes) can result in the wrong genes being turned on and off in specific tissues at critical times in development, thereby causing disease, particularly involving neurodevelopment and growth.

The researchers studied mutations in two epigenes that are known to cause CHARGE and Kabuki syndromes. These two neurodevelopmental disorders share many clinical features including growth and developmental delays, congenital heart defects and hearing loss. The similarities between these syndromes can make it challenging to diagnose and distinguish between the two early in life.

Genes that function in epigenetic regulation are increasingly being identified as the cause of a variety of neurodevelopmental disorders. We sat down with Dr. Rosanna Weksberg, Staff Physician in Clinical and Metabolic Genetics and Senior Associate Scientist in Genetics & Genome Biology at SickKids, to learn more about this work and take a closer look into the potential impact of epigenetics on precision medicine.

How can understanding epigenetics improve care for kids with neurodevelopmental conditions?

Our study provides important clues about how embryonic development is disrupted by mutations in epigenes. These clues could lead to improved care on multiple levels; from a clinical perspective it will help with diagnosis by either confirming or ruling out the condition at an earlier stage in the child’s life.

The existing tools used in clinical labs to classify genetic changes as pathogenic (causal) or benign are less than perfect. The epigenetic signatures we have identified provide a new approach to classify genetic mutations in epigenes with a high degree of accuracy. For example; sometimes genetic sequencing will indicate a change in the DNA which suggests CHARGE syndrome, but the sequence result is insufficient to determine whether the genetic change is benign or whether it causes the syndrome. Our epigenetic signatures could be used as a novel diagnostic molecular test to help interpret the pathogenicity of the genetic variants involved in CHARGE and Kabuki syndromes.

From a research perspective, identifying the specific genes that are controlled by a particular epigene will enable future work focused on therapeutic interventions which may help to correct the way the genes are being expressed.

One wouldn’t think that these kind of genes would be modifiable by treatment after birth, but there is evidence from animal models of rare diseases, like Rett syndrome, that show this can be done. In fact, medications that target epigenetic changes are already being used to treat some human cancers. This is very exciting for the field of rare genetic diseases, as the potential impact is huge.

What are the next steps?

There are several hundred epigenes identified. Of these less than one hundred are currently known to be associated with diseases, with new ones being identified monthly. Scientists, including our team at SickKids, have identified epigentic signatures for about 10 to 15 of these conditions. We have a way to go, but we, and others, are committed to uncovering them all!

The research was funded by the Canadian Institutes of Health Research, the Ontario Brain Institute, the Rare Diseases Foundation and SickKids Foundation.

This project is an example of how SickKids is contributing to making Ontario Healthier, Wealthier and Smarter. www.healthierwealthiersmarter.ca.