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The need to know: deciphering developmental disorders

28 Feb, 2013
The Oakes family

The Oakes family

Life can be challenging for the families of children with developmental disorders. About 1 in 1000 babies are born with an error in their genetic make-up that causes delays in their development. Although many people are affected by developmental disorders, the specific conditions are very rare; often, only one or two children in the world have the same genetic error.

There is no cure for these disorders, and often there isn’t even a diagnosis. Deciphering Developmental Disorders, a Wellcome Trust and Department of Health-funded study, aims to give families the diagnosis they want and need.

When Joel Oakes arrives home from pre-school with his dad, he is in a good mood. He bounds into his house with a great big smile on his face, running straight into the dining room to play with his electric train set. Through a set of glass doors, he can see me chatting to his parents. As the afternoon goes on, Joel tires of his trains and ventures into the living room to find his mum and dad. They put on ‘Total Wipeout’, Joel’s favourite television show, and he sits down to watch the contestants leap over an obstacle course.

Every time a contestant meets their fate and plunges into the water, Joel squeals with delight. He balls up his fists, bends his arms and pumps them back and forth, reminding me of a cartoon character about to sprint off. And, of course, there’s his charming smile again.

Joel has autism, which means he finds interacting with new people difficult and has poorly developed speech and communication skills. But some of Joel’s features aren’t explained by autism. He is smaller than other boys his age, and some of his facial characteristics are unlike either of his parents’ and notably different to those of his twin brother, Toby.

Toby arrives home later than Joel, as the boys go to different pre-schools two days a week. Even for non-identical twins, they don’t share many physical features. Toby’s hair is blond and curly, whereas Joel’s is brown and straight. Toby’s eyes are wide and round; Joel’s are smaller and oval. Toby acts as I expect a little boy to act: he is shy at first, but curious enough about me to peek out from behind his dad’s legs to see what is going on. Joel doesn’t want to interact at all.

When Joel and Toby were born, they were both healthy and happy. Joel had slightly low blood sugar, but nothing the doctors were too concerned about. After a few months, though, Joel was clearly falling behind. He couldn’t hold his head up and hadn’t been able to breastfeed. Joel’s parents, Sarah and Nigel, were told it was probably nothing but were referred to see a physiotherapist anyway. At 12 months the physiotherapist started to have concerns about Joel’s general development, so they arranged an appointment with a paediatrician, who suspected a genetic abnormality causing his slow development, and consulted a geneticist.

The geneticist agreed that Joel seemed to have a genetic disorder that caused him to develop differently to his brother. But after several tests and countless hospital appointments, the family still didn’t have a name for Joel’s developmental delay. All that could be said about Joel’s condition was that one or more unknown mutations in his genes had caused delays in his physical and psychological development. His condition is otherwise undiagnosed.

The family can’t put a name to Joel’s disorder or understand what’s causing it. They don’t know whether he may begin to catch up with Toby or whether their differences will become more obvious. Developmental disorders manifest themselves through a combination of learning difficulties, physical disabilities and behavioural problems, caused by additional or missing pieces of DNA, or a change in how the DNA is ordered.

It is almost impossible to tell how a particular child’s symptoms will progress, so Sarah and Nigel don’t know what Joel’s disorder means for his future. “I’ve spent hours Googling all his symptoms, trying to come up with an answer,” says Sarah. “So many of his features fit so many different things, so it comes up with loads of possibilities. It’s my worst enemy sometimes.” But it’s hard to resist anything that might give a lead to a diagnosis.


Dr Helen Firth, a clinical geneticist at Addenbrooke’s Hospital in Cambridge, recognises the parent’s need to know: she has seen it in many of her patients’ families. “A diagnosis enables improved management of the child’s condition and accurate advice for parents wishing to have further children,” she says. “It also takes away a sense of isolation that many parents feel.”

The DDD team

The DDD team

Dr Firth wants more families to have the benefit of a diagnosis, which is why she and Dr Nigel Carter, a researcher at the Wellcome Trust Sanger Institute a short drive away from Addenbrooke’s, just outside Cambridge, set up Deciphering Developmental Disorders (DDD) in 2011. It is a nationwide study that uses some of the latest genetic tests to examine and compare thousands of participants’ genes. A key aspect of the study is that patients from across the UK are recruited to take part through the existing network of regional genetic services in NHS hospitals. The DDD team hopes that it will improve our understanding of the rare disorders being studied, as well as giving the families involved the answers they need.

Joel’s geneticist told his family about the DDD study after routine tests hadn’t picked up anything. The standard, and fastest, test involves a specialist doctor looking at a sample of a patient’s blood through a microscope to examine their DNA. The DNA is dyed to show subtle differences to its expected appearance. Recently, a more detailed test has become available in NHS genetics services; known as a microarray, it allows a specialist to examine many fragments of DNA in detail. The DDD study has the resources to carry out more detailed microarrays than are available on the NHS.

Joel, Sarah and Nigel each filled a test-tube-sized container to about an inch deep with saliva and sent the samples off to the study for their tests to be carried out. For the microarray, fragments of reference DNA are labelled with a coloured dye and put on a glass slide. DNA extracted from the saliva samples is then washed over the slide. A high-resolution photograph is taken, and a researcher compares millions of sites within a patient’s genome against another, unaffected genome to identify any variations. By carrying out tests using Joel’s parents’ DNA and his own, they can see whether any mutations are inherited or have occurred for the first time in Joel.

If the microarray doesn’t yield a diagnosis, the next step is to sequence their genomes. This examines the DNA in the most detailed way possible, by studying the order of the individual building blocks that make up our genomes. Interpreting this data is extremely time-consuming and difficult, so getting results can take a long time.

Everybody has mutations in their genome: some are inherited from their parents, and some are random. To pinpoint which genetic mutation causes a rare genetic disease like Joel’s, the child’s DNA needs to be compared with many other people’s genomes.

The benefit of DDD being such a large study is that lots of patients’ DNA can be compared and the specific mutations can be identified. Dr Firth believes the study offers the best of both worlds: it is large enough to get reliable and powerful data, but patients get their individual results back through their regional geneticist. Thousands of families have sent off samples to DDD, and testing and analysing all their data takes time. The Oakes family knew when they sent off their samples that they were likely to have to wait at least a year. After 15 months, they’re still waiting.

Sampling tubesThe DDD researchers send an annual newsletter to families to help keep them informed of the progress being made. But with so many patients, personal updates on research are impossible, so families like the Oakeses are still in the dark. “We want the big picture, not just segments of information here and there,” says Nigel. “We need a professional to explain what’s going on in the study and break it down for us.” Not knowing what has happened to their samples, waiting to find out whether scientists they have never met can give them the diagnosis they so desperately want, is frustrating and difficult for the whole family.


At the moment Joel goes to his special needs pre-school on two afternoons a week and to a mainstream pre-school, with Toby, two mornings a week. Joel doesn’t cope well with unfamiliar situations, so having a routine during the week is important – weekends are more challenging. “Joel tends to find Saturdays very difficult,” explains Sarah. “He can get violent, to himself and to us.” A trip to the shops or to the cinema becomes complicated.

This particularly affects Toby, who has a lot more to cope with than other three-year-old boys. He misses out on some of the normal family days out that most children enjoy, and the boys have never had the chance to feel like twins. “I think that’s really sad,” Sarah says, “because they’ve never really had that identity.

“Joel tends to cruise alongside Toby,” she continues, meaning Joel stays close to Toby without interacting with other children, “but Toby worries a lot about Joel. They’re going to different schools soon, and it’s sad they can’t stay together, but Toby needs that space.”

Sarah and Nigel were worried about how to describe Joel’s condition when they were applying for school places for him. Without a diagnosis, every time a form or document had to be filled in, there was a question of how to describe his disorder. “Some sort of answer would be excellent,” Sarah says, “even if it’s just a long string of letters.”

Many of Joel’s characteristics are not obvious to those who don’t know him, so people sometimes question whether there’s anything wrong with him at all. “When you don’t know what his condition is, a lot of people tend to think you’re making it up,” says Sarah. “Some members of the family have said he’ll grow out of it, and that the doctors are only basing his disorder on what we’ve told them, like we’re making it up! I can’t imagine why anyone would do that.”

Nigel finds it more difficult to ignore the comments, especially when they are made by people who don’t know them. “It makes me angry,” he admits, “but you have to try and get on with it. I was using a disabled toilet with Joel once, and somebody stopped me because they thought we didn’t need to. He hasn’t got an obvious disability and he’s not in a wheelchair, but he is still disabled.”

Although some people don’t understand what is wrong with Joel, the Oakes family have found support from others. “The special needs world is all new to us, and in a lot of ways much nicer,” says Sarah. “It’s more tolerant. You meet people who’ve been through all kinds of experiences.” The family have joined an online community called SWAN (Syndromes Without A Name), part of Genetic Alliance UK, which brings together families of undiagnosed children to swap experiences and advice. Their new community has even inspired their oldest child, 16-year-old Ben, to volunteer at the special needs school that Joel will go to in

One common concern with many SWAN families is whether subsequent generations could inherit the same defect in their genes. Sarah and Nigel also have a daughter, Immy, aged 15. As she gets older, she becomes more aware of the possible implications of Joel’s condition. Immy has severe dyslexia and, although it is very unlikely to be connected, the family can’t help but wonder whether there could be a link. In any case, she knows that if Joel inherited the mutation from his parents, then she and her siblings might be carrying it too; that they might have children with the same genetic defect. Of course, without a diagnosis, her parents can’t give her an answer.

DDD is the only study of its kind in the UK, so the family knows they won’t have any other avenues to explore if it doesn’t produce answers for them. They’re also aware that if they do get news, it might not be good news.

Peace of mind

Jez Fowler hung up the phone. Many things were flying around his mind. He composed himself for a moment, and then called his wife, Vicky: “You’d better sit down.”

Jez and Vicky joined the DDD study to see if they could find out what was wrong with their seven-year-old daughter, Freya. The process of joining was straightforward: they sent off samples of their saliva and carried on with their lives, not expecting to hear back for at least a year.

Then the call came, after just seven months. Jez was taken aback. He was told to make an appointment with Freya’s geneticist. And it dawned on him: the results could indicate what Freya’s future held and whether the disorder was inherited, and the answers might not be the ones they wanted to hear.

Suddenly, waiting became difficult. One long month later, the appointment arrived. A mutation had been found. Three other girls had the same mutation and research was being done on it in Canada. The specific mutation didn’t tell them much, but it didn’t give them cause to worry any more than before.

Freya Fowler; photo taken by her Dad, Jez

Freya Fowler; photo taken by her Dad, Jez

They were also told that the mutation was random: Freya didn’t inherit it from Jez or Vicky. They were hugely relieved that the genetic change would not be passed on if they were to have more children. “It looks as if they’ve just discovered it, so it’s all new,” Jez tells me. “The Canadian study basically lists the symptoms at the moment, which match with Freya’s.”

The diagnosis gives the Fowlers peace of mind, but it also contributes to the DDD study as a whole. “Finding a small cluster of children who have the same genetic mutation and the same clinical features can help to define the role of a gene,” says Dr Firth. And although no treatment is available yet, the more that is found out about Freya’s condition, the more likely future advances become.

From a researcher’s point of view, increasing our knowledge of genetic disorders is a major incentive for working on the study. “But,” Dr Firth says, “Many of the children I see in clinic have severe problems and undergo frequent hospital admissions and appointments. One of the main motivations behind the DDD study is to provide families with an explanation of their child’s condition and a launch pad for accessing information to guide their care for the future.”

Meanwhile, Nigel and Sarah continue to wait for an explanation for Joel. “We’re pinning all our hopes on the DDD study,” Sarah admits. “What do we do if they find nothing?” She knows that this is the best chance they’ll get to find a diagnosis for Joel’s condition, which would change so much for Joel and for his family. “It feels like this is all or nothing. If we don’t get an answer now, I think we’ll just have to live with it.”

When Nigel brought Joel home on the day I visited, the first thing he told Sarah was that Joel had gone in a lift. At his special needs pre-school, the lifts are essential for helping children with physical disabilities travel between floors. Until today, Joel had always insisted on taking the stairs, because he had a fear of lifts. Nigel and Sarah were delighted that he’d conquered his phobia, and Joel was obviously pleased with himself, too.

All three-year-old children overcome obstacles every day, but going in a lift isn’t usually considered one of them. “When you have a child who finds life more difficult,” says Sarah, “you learn to celebrate the small things.”

Note: Deciphering Developmental Disorders is funded through the Health Innovation Challenge Fund, a partnership between the Wellcome Trust and the Department of Health.

Image credits: Sampling tubes, Wellcome Images. SWAN UK, SWAN UK logo.


Deciphering Developmental Disorders


Genetic Alliance UK


One Comment leave one →
  1. Stephanie Monk permalink
    28 Feb, 2013 3:43 pm

    My son Charlie is 22 now and Nigel and Sarah’s story is a familiar one. Charlie is happy and well he has a small piece of genetic information missing from his chromosome no. 2, the short terminal arm to be precise. A diagnosis when he was 3 was very useful, at last we had a reason for his difficulties. It wasn’t easy but I’ve had so much joy around Charlie and his younger brothers have grown up as empathetic and caring young men, I’m sure partly due to having Charlie in the family. He is a vulnerable person and will always need to be looked after and at present is in sheltered accommodation and attends an agricultural college 4 days a week. He loves life and we love him. Good luck on your journey with Joel.

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