Researchers have discovered the genetic mutation behind a Brisbane boy’s rare condition known to affect only seven people in the world.
The Queensland team hopes their work will be used as a model for diagnosing and treating other rare diseases.
Eleven-year-old Seth De Rooy is one of only seven people in the world diagnosed with Temple-Baraitser syndrome (TBS), which causes severe epilepsy, intellectual disability, low muscle tone and missing nails on the thumbs and big toes.
Dr Cas Simons from the University of Queensland’s Institute for Molecular Bioscience and Dr Michael Gabbett and Dr Julie McGaughran from Genetic Health Queensland teamed up with colleagues from around the world to create a genetic profile for six of the patients and their parents.
“From a small blood sample from each individual we were able to sequence and analyse their exomes, which are the protein-coding sections of our genes that are home to many of the disease-causing mutations in our DNA,” Dr Simons said.
They then compared the genetic differences between patients and their parents and found a number of damaging mutations in each patient’s KCNH1 gene.
KCNH1 is known to be important for the function of the central nervous system, but hasn’t been associated with disease before.
Dr Simons said the critical part of the discovery was confirming findings in the lab.
“Once we knew what these mutations were, we recreated versions of the human KCNH1 protein with and without the mutations, and designed a series of experiments to understand how the function of the protein was changed by the mutations,”Dr Simons said.
“From these tests, we found that all of the mutated versions of KCNH1 were hyperactive, which is consistent with our understanding of how defects in potassium channels can result in epilepsy,” he said.
Dr Michael Gabbett said he hoped the team’s work would be used as a model for diagnosing and treating rare diseases.
“Through this study we found that some of the parents of TBS patients have a very small amount of these mutations in their own cells – nowhere near as many as their children, but still enough that could be immediately useful in prenatal genetic screening to help future parents make informed choices,” Dr Gabbett said.
“These findings could also help us identify existing drugs that could be effective on this gene and
help minimise some of the symptoms of TBS.”
Chris de Rooy, Seth’s mother, said the findings brought hope to her family and helped remove some of the mystery around Seth’s condition.
“Seth was only the second person in the world to be diagnosed with TBS and is now the eldest known patient, so we have no idea about what the future holds for him, which can be scary at times,” she said.
“It’s hard to think about it now, but for many years I blamed myself for Seth’s condition – ‘what did I do wrong?’ I’d ask myself; ‘why is he developing differently to his brother and sister?’ and ‘when will he learn to walk and talk?’
“We hope this discovery can inspire more awareness and research into treatments to improve quality of life for Seth and other families like ours living with rare genetic conditions.”
The results of the study are published in the journal Nature Genetics.
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