After years of searching for a diagnosis that would explain their 16-year-old son’s developmental delays and self-injury, a BC family finally has answers thanks to state-of-the-art genomic sequencing provided by the Treatable Intellectual Disability Endeavour in British Columbia (TIDE-BC), a 5-year program at CFRI and BC Children’s Hospital, funded by BC Children’s Hospital Foundation.

Tanja Bartel first suspected something was wrong with her son when he was eight months old. He crawled off the blanket where she’d set him and started rubbing his forehead on the carpet. He continued to rub the area even when it became raw and bloody.

As her son grew, he missed developmental milestones and didn’t respond to his name. When he was eighteen months old, he was diagnosed with autism and began therapy; however, his self-injury became increasingly severe. “He was banging his head thousands of times a day,” Tanja says. “I didn’t see the same behaviour in other autistic children.”

Over the course of his childhood, Tanja’s son had over 50 different appointments with a range of specialists including neurologists, psychiatrists and gastroenterologists. Every diagnostic test came back normal.

"There was clearly something wrong with him, but all the tests were negative,” Tanja says. “He was a true medical mystery.”

When Tanja’s son was sixteen years old, Dr. Mary Connolly, head of the paediatric neurology division at BC Children’s Hospital, referred him to the multi-disciplinary TIDE BC Complex Diagnostic Clinic at BC Children’s Hospital, led by CFRI investigator and UBC Assistant Professor of Pediatrics Dr. Clara van Karnebeek. TIDE BC is dedicated to improving outcomes for children with intellectual disability using both conventional and more extensive genome-wide sequencing to diagnose underlying genetic disorders, some of which are treatable.

Tanja admits that after so many years of fruitless testing, she wasn’t optimistic that genomic sequencing could provide answers.

“I remember Tanja told me, ‘I wish you luck, but after 16 years, I don’t believe you’ll find anything,’” Dr. van Karnebeek said. 

Researchers took blood samples from Tanja, her husband and their son and performed genome-wide sequencing with interpretation by Dr. Maja Tarailo-Graovac, a research associate in Dr. Wyeth Wasserman’s lab at CFRI.

About five weeks later, Tanja got a phone call from Dr. van Karnebeek. “She told me, ‘We found it. We have a diagnosis. We know what’s causing your son’s problems,’” Tanja says.

The researchers found both Tanja and her son carry a mutation on a gene called PAK3, which is located on the X chromosome. Dr. Margot Van Allen, a CFRI investigator and Professor in the Department of Medical Genetics at the University of British Columbia, provided genetic counselling to the family to help them understand the diagnosis. Because women have two X chromosomes, they have two copies of the PAK3 gene, which means they have a back-up if one copy is mutated. As a result, Tanja doesn’t experience any symptoms from her PAK3 mutation. Men only have one X chromosome and when Tanya’s son inherited her mutated PAK3 gene, he didn’t have a healthy back-up.

The mutation Tanya’s son inherited affects the structure and health of his brain, leading to his severe developmental delays, autism and self-injury. Only a few other people in the world have been reported with a PAK3 mutation. Most, like Tanja, are of Finnish descent.

After Tanja’s son was diagnosed, further testing by Dr. Gabriela Horvath, a CFRI investigator and Clinical Assistant Professor in the Department of Pediatrics at UBC, revealed that a medication called Levo-CarbiDopamine might relieve some of his symptoms by increasing the levels of neurotransmitters in his brain. Neurotransmitters are chemicals that relay signals between nerve cells, allowing the brain to communicate with the body. Tanja’s son has now been taking this medication for several months. He’s self-injuring less and his mood has improved. “The change is unbelievable,” Tanja says. “He’s been smiling and listening to music. The quality of our family time has really improved.”

Tanja and her husband also have a healthy daughter who is now in her late teens. As a young teenager, she decided she would never have children because of the risk of passing on her brother’s illness. The genetic testing offered by TIDE BC revealed she is not a carrier of the PAK3 mutation and there is no chance her children will inherit her brother’s disorder.

“My daughter's gone from thinking she can never have kids to thinking about the possibility of having a family for the first time in her life,” Tanja says. “This is really life-changing news for her.”

In June 2015, thanks to the support of Mining for Miracles and Genome BC, the CAUSES Research clinic opened at BC Children’s Hospital. CAUSES is dedicated to finding answers for children with complex, undiagnosed conditions like Tanja’s son. Over the next three years, CAUSES will provide genome-wide sequencing to at least 500 families whose children suffer unexplained medical problems. The clinic also provides genetic counselling, interpretation of complex test results and personalized treatment recommendations.

Tanja’s son now lives in a care facility and goes home to have dinner with his family every night. He will always have severe health problems and will likely have a shorter lifespan as the result of the brain injuries caused by his head banging. Nonetheless, Tanja and her family are grateful to have finally have answers. “We’ve already accepted that there is no cure for his condition,” Tanja says, “but it makes a huge difference to have the closure of a diagnosis and to have new treatment options that improve his quality of life.”

Dr. Clara van Karnebeek is a certified Paediatrician and Biochemical Geneticist, an investigator at CFRI and the Centre for Molecular Medicine and Therapeutics, and an Assistant Professor in the Department of Pediatrics at the University of British Colombia. Her research programs TIDE-BC and Omics2TreatID are made possible by support from BC Children’s Hospital Foundation.

Mining for Miracles, BC’s mining community’s longstanding fundraising campaign through BC Children’s Hospital Foundation, committed $3-million in 2015/16 towards the development of CAUSES. Genome British Columbia has pledged to match Mining for Miracles’ commitment up to an additional $1-million and CAUSES is seeking opportunities to leverage this partnership to secure additional funding. CAUSES is supported by the Provincial Health Services Authority and the University of British Columbia.