B.C. boy Max Jones earns a place in lore of Weaver syndrome research

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Max Jones is a big boy. At age four, he already weighs 75 pounds, and is as tall as an average nine-year-old.

"He's a linebacker – a very cute one," his mother, Allison Jones, says with a chuckle.

But a football career is not in the cards for Max. He has a rare disease that has caused developmental delays and mobility issues, among other challenges.

But how he came to have a diagnosis – Weaver syndrome – will likely earn Max a place in medical textbooks and the lore of genomics.

Max was born at Lions Gate Hospital in North Vancouver six weeks premature, and spent his first five weeks of life in the neo-natal intensive care unit because of problems feeding and breathing.

Then came repeated bouts of near-fatal pneumonia, seizures and the realization that the boy had polymicrogyria, a condition in which the folds on the surface of the brain are unusually small, causing developmental problems.

He had many other symptoms, but no diagnosis. Thus began the search for the cause. "It's an odyssey that parents of children with rare diseases know all too well," said Clay Jones, Max's dad.

Genetic disorders are individually rare but collectively common. All told, about 500,000 children in Canada have rare disorders that cause birth defects, intellectual disabilities, difficulties with growth, or organ failure, often in odd combinations.

In Canada, children are screened at birth for about two dozen rare but treatable disorders (the number and type varies by province) but most genes that cause rare diseases have not been identified. Diagnosis is done by a process of elimination, based on a constellation of symptoms.

It was clear that Max, given his size, had an overgrowth syndrome. His parents, in addition to being caregivers, became disease detectives, scouring medical literature for clues.

"I never thought words like polymicrogyria would roll so easily off my tongue but, by necessity, you become an expert," Ms. Jones said. "Max's condition is so rare that we often know more than his doctors." Max's parents became convinced he had Weaver syndrome, a condition first reported in 1974, and so rare that only 40 cases are found in medical literature.

But doctors were not sure. Max had some, but not all, of the signs – rapid growth, development delay, macrocephaly (an unusually large head), retrognathia (a very small chin) and advanced bone age.

One of few experts on Weaver syndrome was based in Vancouver, and he was a key player in an initiative called FORGE (Finding of Rare Disease Genes) Canada, a consortium that is using advances in genomic technology to identify rare childhood genetic disorders. More than 200 are under investigation.

In 2012, William Gibson, a senior clinician-scientist at B.C. Children's Hospital, and his team sequenced the entire genome of members of three families with a child suspected of having Weaver syndrome (including the Joneses) and, by comparing them, identified a mutation in a gene called EZH2 as the cause. The study was published in The American Journal of Human Genetics.

Max had that rare mutation.

The discovery means doctors now have a test for patients who show the symptoms of the disorder.

For Max's parents, it was a relief, even though naming his condition does not change anything.

"Having a firm diagnosis doesn't make a difference in Max's care. But it provides us with closure in a way," said Ms. Jones. "Just as importantly, it means other families won't have to go through what we did."

Dr. Gibson said that after years working with families whose children have rare conditions, he knows a definite, DNA-based diagnosis matters.

"Imagine having a fundamental question about a loved one in your mind for many years. It haunts you," he said. "Families often feel a tremendous sense of relief when we can finally answer the question." Having a diagnosis can also make children eligible for educational opportunities and subsidies. Families of children with disabilities often need to modify their homes and get wheelchair-friendly vehicles and specialized medical equipment.

This is not a big issue for the Jones family because, as a lawyer and a trademark agent, they are financially comfortable, and Max will soon make the transition from daycare to kindergarten.

The genetic discovery also opens the door to research and, on Sunday, the first-ever symposium on Weaver syndrome will be held in Vancouver. Given the controversy over patenting genes in Canada, Dr. Gibson stressed that the EZH2 gene will not be patented and testing will be available to anyone who needs it.

"Let me put it this way: We didn't discover this gene so people could not be tested."

The diagnosis raises further concern for the Jones family, because children with Weaver syndrome have a much higher risk of developing cancers of the white blood cells such as leukemia and lymphoma.

Still, his parents have their eyes fixed on the future. "We don't spend a lot of time dwelling on 'why?' or 'what if?'" Ms. Jones said.

Her husband nods in agreement and adds: "When we first brought Max home, we said: 'Thank God he's our kid because we're up to the challenge.'"