Cause of a rare genetic metabolic disorder – ScienceDaily

Hereditary metabolic disorders – where the body can not break down certain nutrients in foods, leading to a series of serious health problems – are often caused by a defective gene.

In this important study, researchers discovered an unusual mutation behind three undiagnosed degenerative conditions in three children: a repeated expansion of DNA. In this specific mutation, the gene appears intact but does not work because the DNA that is adjacent to it has spread several hundred times its normal length.

"To detect this type of DNA multiplication, you can only use whole genome sequencing and search for billions of pieces of DNA; it is actually a search for the needle in the haystack, "said lead author Clara van Karnebeek. "Thanks to our new approach, we have finally solved our mystery cases and we now expect to find the genetic cause of other genetic metabolic diseases, yet unexplained."

To date, repeated developments in DNA have been linked to approximately 30 different diseases.

"For children with rare diseases and their families, it is extremely important to find the root causes of their disorders," said Dr. Wyeth Wbaderman, co-author of the study. "A diagnosis gives us the potential to intervene, relieves undeserved parental guilt and provides insight into more common diseases."

For a child whose health status is unexplained, a diagnosis lays the foundation for new research that may lead to new interventions such as gene therapy to "activate" the altered gene, to a modification of the gene. diet or supplements that provide the nutrients that the body lacks. Effective treatment can slow down or stop the damaging symptoms, improving the quality of life of children with rare diseases and their families.

In this study, the initial work of van Karnebeek and his research team restricted the search for genetic causes of this rare disorder to key areas of the genome. However, after further investigations using exome sequencing and whole genome sequencing, the international search team was unable to identify the error in the DNA.

It is here that BC Children's researchers have taken an innovative approach. Through extensive manual badysis and the use of tools and emerging techniques in bioinformatics, study co-authors, Dr. Britt Drögemöller and Phillip Richmond, have discovered and confirmed that the The gene responsible for the disease was intact, but a repeated expansion error prevented it from working.

"In our research, we focused on the variations that would have been difficult to discover through exome sequencing," said Drögemöller. "After months of experimenting with various badyzes, we finally discovered this new genetic variant using new, targeted approaches to identify DNA repetition extensions."

"These results have been made possible through a multidisciplinary approach and advances in technology, techniques and software," said Richmond. "It would not have been possible two years ago and, most importantly, it tells us what to look for in other undiagnosed cases."

The gene identified as being at the origin of this particular disorder is an enzyme that allows the body to transform an amino acid called glutamine into glutamate. More work is needed to determine exactly how this genetic error leads to the disease, but it is likely that either glutamine accumulation, or glutamate deficiency, has led to developmental delays and severe disabilities, including language difficulties. , speech, balance and coordination.

Through collaborations with sequencing consortia from around the world, the researchers were able to confirm that this repeated expansion was only found in 1 in 8,000 people, which allowed the mutation to occur. be very rare.

More than one million Canadians suffer from a rare disease and in more than 50% of cases, the underlying genetic cause of the disease remains unknown.

"We can do better for children with rare diseases – for the 50% of people who do not find answers, this discovery and this new approach will help us better identify and potentially find the causes of their disease," said M Richmond.