Discovery of genetic root of son's autism gives Calgary family hope for a cure

A Calgary family wanted to try whole genome sequencing (a study of the entire sequence of one's DNA) after they heard about it on Facebook from other parents of autistic children. (Sangharsh Lohakare/Unsplash - image credit)
A Calgary family wanted to try whole genome sequencing (a study of the entire sequence of one's DNA) after they heard about it on Facebook from other parents of autistic children. (Sangharsh Lohakare/Unsplash - image credit)

A Calgary family has learned a rare genetic mutation is the root of their son's severe autism, and now they hope the discovery will lead to a cure.

Mousumee Dutta and Ian Holloway have struggled over the years to make life better for their son.

Ishaan Holloway, 17, was diagnosed with severe autism when he was a young boy.

The family hopes pinpointing the cause could help eventually treat and maybe even cure it.

In many cases, treatments and therapies can lead to behavioural changes or reduce health deterioration. They tried various treatments, but Ishaan's condition did not improve. His parents were eager to find out if a genetic mutation was blocking the treatments of his neurological pathways.

"I knew there had to be more," Dutta said.

They wanted to try whole genome sequencing (a study of the entire sequence of one's DNA) that they had heard about on Facebook from other parents of autistic children.

From 2013 up until 2018, the family did not have access to the testing. Ishaan was not eligible for the testing because he was not diagnosed with a syndrome.

His parents were adamant about finding answers for Ishaan's severe medical condition.

After years of advocating, doctors finally found out that Ishaan has epilepsy and seizures every 10 seconds. This opened the door to an application for funding for whole genome testing. It was discovered Ishaan has a rare NLGN4 X mutation.

"Is it rare because it has not been studied well, it is not accessible, or is it actually rare? We don't know," Mousumee said.

To date, more than a hundred mutations have been found to have a direct link with autism and blocking synaptic function (transmitting messages between neurons and muscles).

Submitted by Mousumee Dutta
Submitted by Mousumee Dutta

Time and money needed for further research 

The family is asking for a second and final stage of the research to determine if drug repurposing can reduce the effects the mutation has on the brain.

"Such research is very expensive, and we don't have that kind of money left," Mousumee said.

The family has spent over $100,000 in tests and treatments. This personalized research alone will cost them $200,000.

This research will determine if existing drugs for syndromes can be repurposed to cure the effects of the genetic mutation that Ishaan has.

Steve Scherer, chief researcher at the Hospital for Sick Children in Toronto, said new technology is playing a role.

"Lots of the pharmaceutical companies and biotech now have jumped into the game because they're very good at screening their existing compounds that they have against cells," he said.

"The Holloway family are involved in such studies, and I know that their cells are being turned in the laboratory into what we call stem cells and then turned into brain cells to screen for."

Mousumee Dutta
Mousumee Dutta

Even though technological advances have sped up the research, "it's essentially a 10-year process, and we're [still]  learning more," he said.

Since autism cases are unique, the research is focusing on precision medicine. That means there won't be a single drug or medicine that will impact all of those who have an autism diagnosis.

"We have to kind of break this up and look at it based on the genetic form that that person has. Some of these trials that are ongoing are targeting some of the genes like the MECP 2 gene, for example, in the neuroligin genes. These are some of the genes that encode these proteins. That's why it's important to enrol the right patient or individual in the study for a medicine that may actually work with them," Scherer said.

Groundbreaking research in Canada giving answers 

The MSSNG project is a collaboration between the Hospital for Sick Children, University of Toronto, Autism Speaks, Verily and DNAstacks. It has collected data from over 12,000 families using whole genome sequencing to build a database on autism with deep phenotyping. One of those families is the Holloway family.

This database is available only to certified researchers to develop personalized treatments.

"We think that 90 per cent of why autism comes about has to do with genetic factors," Scherer said.

This project is the only one of its kind in the world. It has found that in 20 per cent of the participants, the mutation was the root cause of autism.

Once the study shows the family has hit one of the listed genetic conditions, they are provided the information through a genetic counsellor to predict the behavioural trajectory and appropriate interventions to treat it. Parents can also predict the chances of their next child having autism.

Dutta reached out to hundreds of doctors, including Nobel laureate Thomas Südhof. He responded to her email and encouraged the family to move forward with the research.

Dr. Soham Chanda, one of Südhof's former students, agreed to include Ishaan's genetic mutation in his study on the impact of how it blocks amino acids.

He is an assistant professor at Colorado State University who started a lab with a team of researchers to carry out the first stage of the intensive research on the effects of genetic mutations on our neurological pathways.

Robert Teteruck/The Canadian Press
Robert Teteruck/The Canadian Press

In his 2019 study, Chanda was able to identify some amino acids that were blocked by the mutation, which led to behavioural issues like hyperactivity and secretion of acids.

"We were super happy to know why Ishaan has this type of autism. If somehow we can unblock this with treatment … there is hope," Dutta said.

Stigma around genetic testing 

Dutta does not want to wait years for someone to volunteer for this research so her son can get answers about a cure.

"Time is of the essence," she said.

"We are doing this not just for our son. But if this is successful, many parents will be able to help children on the severe end of the spectrum."

As the family pushes for education and health rights, they have been called "abusive" by some.

"Not giving him a chance will be abuse," Dutta said.

Scherer said the study should remove any stigma.

"It explains why autism came about in that child, so it wasn't something that the mom did during pregnancy or something that the parents did in raising the child," he said. "It's really a genetic change, and these are sporadic genetic changes that happen in all of our DNA."