YWHAG INTRODUCTION & OVERVIEW
GENETICS OVERVIEW
Our bodies are composed of millions of cells. In each cell, there are 23 pairs of chromosomes. One from each pair comes from each parent. Each chromosome is made up of DNA. DNA is the recipe book for how to make proteins that do jobs in your body. Genes like YWHAG are the individual recipes in that book that have the recipe for each protein. RNA then makes proteins from DNA’s instructions
VARIANT OVERVIEW
Variants are changes in a person’s DNA. You may hear the term “mutation” used in a similar way. Some people call variants that lead to genetic conditions like Developmental and Epileptic Encephalopathy 56 (DEE56) mutations, but the word variant will be used in this resource.
When a gene has a variant, it means there is a difference in the gene. A variant can be benign, pathogenic, or a variant of uncertain significance (VUS). Benign means that it is a difference that is a part of normal human variation, and does not cause a disease. Pathogenic means that the variant is associated with disease. A VUS is a variant that we do not have enough information about at this time to decisively say if it causes disease.
A variant can be inherited from a parent or de novo. An inherited variant comes from a parent if they have that variant and pass it down by chance. A de novo variant is one that occurs randomly when a fetus is growing. In either case, there is nothing a parent could have done to cause a genetic condition. Every person has between 44 and 82 de novo variants and are a standard part of human diversity. Only some will cause a genetic condition. It is usually because the change in the DNA causes the protein it codes for to either work differently or not work at all.
There are three different kinds of variants involved in genetic conditions: autosomal dominant, autosomal negative, and X-linked. Autosomal dominant means that only one copy of a gene needs to have a disease-causing variant in order to cause a condition. Autosomal recessive means that each gene in a pair has to have a disease-causing variant in order to cause a condition. X-linked conditions are caused by variants on the X chromosome, which typically makes up one or two of the 23rd pair of chromosomes. Variants in YWHAG are inherited in an autosomal dominant manner.
YWHAG PROTEIN EXPLANATION
YWHAG creates a protein called 14-3-3γ (14-3-3 gamma), and it is involved in cell survival, growth, and communication. This is a protein that is present in many parts of the body, and in the highest quantity in the brain, spinal cord, and skeleton. Variants in YWHAG cause there to not be enough functional protein. The main function of 14-3-3γ is to bind to other molecules in the body, and this binding process helps maintain the brain’s communication signals to itself, the brain’s communication to the rest of the body, the body’s communication to the brain, and developing parts of the brain. There is a thorough summary of each part of the brain impacted on the YWHAG Research Foundation’s website in the “Living With YWHAG Mutation” section.
CONDITION EXPLANATION
YWHAG mutation is a rare genetic condition that can affect brain development that may lead to seizures, developmental delays, and other neurological challenges. This condition is known as Developmental and Epileptic Encephalopathy 56 (DEE56). It was named this because YWHAG was the 56th gene discovered associated with DEE. The symptoms associated with this condition are different from person to person, but can include seizures, developmental delay, intellectual disability, uncoordinated walking, poor muscle control, speech delays/disability, behavioral difficulties, scoliosis, and autism. This is not a complete list of symptoms, but these are some of the most common findings in patients with DEE56. Not every child will have every symptom, and these symptoms can look different from person to person.
GETTING INVOLVED IN THE COMMUNITY
After receiving a diagnosis, many people wonder what they can do to get involved in the community. This is a way to help increase knowledge about the condition and further research efforts. Research is a critical way to help support patients and families, since more understanding can lead to new treatments and support for people with disease-causing YWHAG variants. These are all resources that can be found on the YWHAG Research Foundation’s website.
REGISTRY
You can register with Rare-X to join the patient registry for people with DEE56. This would involve answering caregiver surveys about the health of your child with the YWHAG variant in order to collect more data on the condition. All information is de-identified, meaning that anyone looking at the health information will not have patient details like names that could tell them who it is. A patient database can help draw interest from researchers, clinicians, and medication developers. It can also help researchers and clinicians understand better how this condition presents differently in different people.
NATURAL HISTORY STUDY
The natural history of a condition is the expected progression and changes that many patients experience during their lifetimes. This is a study being conducted through the summer of 2027 by researchers at the University of Rochester that would involve a virtual visit with the research team and filling out some surveys. All information will be de-identified.There is no cost to participate, and the virtual visits would happen approximately once every six months. This research can help improve understanding of DEE56, improve current treatment plans, and help create new treatments. New treatments would be able to be more targeted toward what families need based on the things they tell the researchers.
VOLUNTEER WORK
There are several different volunteer opportunities that families can participate in. Three main opportunities are becoming an ambassador, social media support, and translating information. Ambassadors reach out to the families of newly diagnosed patients to help make sure that no family goes through their journey alone. Photographs for social media are used largely for awareness and funding campaigns. Translators help the foundation reach out to families who speak languages other than English, and can help make informational materials more accessible. Even just following social media pages can be a great way to share information and stay up-to-date!
FUNDRAISING
Fundraising and donating to the YWHAG Research Foundation and related projects helps work toward increased understanding of DEE56, its progression, and possible treatments. Current projects include a natural history study and investigating some medications, like statins, as possible therapies. There are also private projects going on about DEE56 that need extra funding, and hopefully will lead to breakthrough discoveries and bring us closer to treatment.