̽��ֱ�� of Cambridge - Lucy Raymond

Children with rare genetic disorders more likely to be diagnosed with developmental, behavioural and mental health problems

cjb250 — Wed, 03 Aug 2022 22:30:47 +0000

With the advent of rapid whole genome sequencing, children presenting with an intellectual disability or developmental delay are recommended to have their DNA sequenced to identify the underlying genetic cause.

To capitalise on this recent NHS development, researchers at the ̽��ֱ�� of Cambridge, ̽��ֱ�� College London and Cardiff ̽��ֱ�� established IMAGINE ID, a national UK cohort study that aims to discover how genetic changes affect children and young people’s behaviour, in order to inform better care of families and children now and in the future.

Writing in ̽��ֱ��Lancet Psychiatry today, the researchers have published the results of an analysis of data from almost 2,800 young people with rare genomic variants – changes to their DNA – that are associated with intellectual disability.

Professor Lucy Raymond from the ̽��ֱ�� of Cambridge, the study’s senior author, said: “Thanks to all the families that have taken part in our research, we’ve been able to conduct the largest study to date of the impact of rare genetic variants associated with intellectual disability. What we’ve found from parents is that these children are extremely likely to develop other neurodevelopmental or mental health conditions, which can present additional challenges both to the children and their families.”

All the participants were aged between four and 19 years. Just under three-quarters (74%) had an intellectual disability caused by a duplication or deletion of sections of DNA – a so-called copy number variant (CNV). ̽��ֱ��remaining young people had a disability caused by a single ‘spelling error’ in their DNA – a change in the A, C, G or T nucleotides – referred to as a single nucleotide variant (SNV).

Compared to the English national population, children in the study were almost 30 times as likely to have been diagnosed as autistic. In the general population, 1.2% of people are diagnosed with the condition compared to 36% of the study participants. Similarly, 22% of the study population were diagnosed with ADHD, compared to 1.6% of the general population, meaning that they were more than 13 times more likely to have the condition.

Around one in eight children (12%) had been diagnosed with oppositional defiant disorder, in which children are uncooperative, defiant, and hostile toward others – a rate 4.4 times higher than in the general population.

One in ten (11%) had an anxiety disorder, a 1.5 times increased risk. Rates of childhood depression were significantly lower, at just 0.4% compared with 2.1% of the general population, but this may increase over the next few years as some mental health disorders do not start until later adolescence or early adult life. Almost all of the children (94%) were reported to have at least one significant physical health problem, including disturbed sleep (65%), motor or movement disorders (64%) or seizures (30%).

Dr Jeanne Wolstencroft from Great Ormond Street Institute of Child Health, ̽��ֱ�� College London, said: “Routine genomic testing now allows parents to understand the genetic cause of intellectual disabilities in an increasing number of children but, because so many of these conditions are rare, we still lack information on the impact this has on their children’s future mental health.

“We already know that intellectual disabilities tend to be associated with an increased likelihood of neurodevelopmental conditions, as well as emotional and behavioural difficulties, but we found that where there is an identifiable genetic cause, the likelihood is amplified considerably. This suggests that these children should be provided with early assessment and help where appropriate.”

̽��ֱ��team has also shown for the first time that children with intellectual disability caused by a genetic variant inherited from a family member, are more likely to come from a more deprived socioeconomic background. This suggests that some parents or family members with the same variant may also have unrecognised difficulties that placed them at a social and educational disadvantage. These children were more likely to be diagnosed with a neuropsychiatric condition and were also more likely to exhibit behavioural difficulties.

Professor David Skuse from Great Ormond Street Institute of Child Health, ̽��ֱ�� College London, said: “We hope this work helps improve the targeting of assessments and interventions to support families at the earliest opportunity. We’d like to see better training for health care providers about the wider use and utility of genetic testing. We have identified its potential value in terms of prioritising children with mental health needs for child mental health services, who are currently hugely limited in the UK.”

̽��ֱ��research was funded by the Medical Research Council (part of UK Research & Innovation) and the Medical Research Foundation. Additional support was provided by the NIHR Cambridge Biomedical Resource Centre and the NIHR GOSH BRC.

Reference
Wolstencroft, J et al. Neuropsychiatric risk in children with intellectual disability of genetic origin: IMAGINE - ̽��ֱ��UK National Cohort Study. Lancet Psychiatry; 4 Aug 2022; DOI: 10.1016/PIIS2215-0366(22)00207-3

A major study of children with intellectual disabilities has highlighted the additional challenges that they often face, including a much-increased likelihood of being diagnosed as autistic, as well as Attention Deficit Hyperactivity Disorder (ADHD) and other mental health difficulties.

Thanks to all the families that have taken part in our research, we’ve been able to conduct the largest study to date of the impact of rare genetic variants associated with intellectual disability

Lucy Raymond

PhotoAlto/Laurence Mouton (Getty Images)

Toddler's hands touching tree bark

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

̽��ֱ��Big Dating Game

cjb250 — Tue, 09 Jun 2015 11:25:51 +0000

At some point in their career, every doctor will encounter a patient whose condition perplexes them, requiring detailed investigation and discussion with colleagues before diagnosis is possible. After all, not every disease is as common as cancer, which affects around one in three of us, or depression, which affects one in 10.

Dr Lucy Raymond from the Department of Medical Genetics specialises in rare diseases. Technically, this means diseases that affect fewer than one in 2,000 people, but in fact, Raymond sees children with learning disabilities so rare that they may be the only person in the UK to be affected.

These conditions are usually caused by one of two scenarios: a spontaneous change to their DNA, not inherited, or a ‘recessive disorder’ where two copies of the same, rare variant are necessary for the disease and each parent unwittingly passes on a copy. Comparing the child’s and their parents’ genomes enables the researchers to pinpoint the gene responsible. In extremely rare cases – where the patient appears to be truly unique – the researchers need to study whether the same variant in mice or zebrafish creates a similar condition.

“Or,” Raymond explains, “we might essentially generate a ‘dating agency’ to try to match our patient with a similar case somewhere else in the world.” With these diseases as rare as they are, the only way for this to be viable would be to have access to tens, possibly hundreds, of thousands of potential matches: something the era of ‘big data’ makes possible.

But this presents a potential problem: how to share information about the patient without breaking their confidentiality. Unlike in the USA, where projects such as the Broad Institute’s Exome Aggregation Consortium (ExAC) place genome data in the public domain, data in the UK is deposited in a ‘managed-access’ database: bona fide researchers with a clear research proposal are allowed access, and only then after signing a commitment saying they will not attempt to identify individual patients.

“We have to remember that big data is great, but it isn’t our data: it’s people’s data and we need to be respectful of this. People in the UK are often altruistic; we have free blood donation, we have a tremendous tradition of patients giving to help others. We must not jeopardise this relationship.

“Parents know that even if finding the gene abnormality that is responsible will not immediately help their child, it may help ensure that others don’t have to wait 20 years before their child receives a diagnosis. They’re happy to share the data on that basis, but are less keen on the idea that they’ll lose control of the information.”

For several years, Raymond, Professor Willem Ouwehand and Dr John Bradley have been leading the National Institute for Health Research BioResource for Rare Diseases in Cambridge, which has recruited some 5,800 patients. They are now part of a major initiative launched by Prime Minister David Cameron: the 100,000 Genomes Project. Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust will lead the East of England Genomic Medicine Centre, one of 11 centres across the UK aimed at realising this project and sequencing the genomes of patients affected by cancer or rare diseases.

“ ̽��ֱ��100,000 Genomes Project is about going forward to having a truly national health service, not a provincial, regional health service,” explains Raymond. “ ̽��ֱ��data will be central, will be national, will be available to researchers and healthcare professionals across the country.”

̽��ֱ��sheer number of people recruited will create a powerful dataset and ensure that clinicians and researchers don’t have to start from scratch each time they encounter a new case. In fact, the value of a patient’s genome extends beyond just helping identify the cause of their disease: it’s also important as a ‘control’ to compare against and help find the cause of another patient’s disease. “It’s a form of ‘enforced altruism’. Having all the data stored in a central place means that everybody’s data acts as a control for everybody else’s. It has a multiplying effect.”

Big data also reveals an otherwise glaringly obvious fact that the name ‘rare diseases’ obscures: one in 2,000, even in a population of 64 million, is not an insignificant number of people. “Ten years ago people used to ask ‘Why study rare diseases when they’re so rare?’ It’s only recently that people are coming round to see that, with big data, rare is common.

“Rare diseases are becoming increasingly tractable, too, so now there’s a huge interest in them, which is good: it’s not your fault if your disease is rare. Solving these problems is the next big challenge,” says Raymond with a glint in her eye. “If it was all easy, we wouldn’t be doing it – in typical Cambridge style.”

When is a rare disease not a rare disease? ̽��ֱ��answer: when big data gets involved. An ambitious new research project aims to show patients that they are not alone.

We might essentially generate a ‘dating agency’ to try to match our patient with a similar case somewhere else in the world

Lucy Raymond

Duncan Hull

DNA/protein function finder from the Wellcome Trust, Sanger Institute, emblebi and YourGenome

Trust me, I’m an e-doctor

Big data ‘dating agencies’ are not just for people with rare conditions. A similar concept could help patients with far more common conditions receive the best possible hospital treatment.

Addenbrooke’s Hospital in Cambridge is one of the first ‘eHospitals’ in England, explains Dr Lydia Drumright from the Department of Medicine. Everything that happens to you within the hospital – every test result, every diagnosis, every drug prescribed – is captured in an electronic record. Drumright and her colleague Dr Afzal Chaudhry believe that the wealth of information in these records can be used to better inform the treatments of individuals.

“Around 10–20% of our patients may have diabetes or acute kidney injury, but that’s not necessarily why they’re here,” explains Drumright. “They might have had a heart attack, so they’re being cared for by the cardiology team, but the drugs they’re prescribed might have an impact on their other conditions. Added to that, they’re now more susceptible to infection.

“It’s the junior doctors that have to look after the patients and do the basic prescribing. They’re still learning, but need to know which drugs work best and the hospital’s policy for prescribing antibiotics.”

Could a patient ‘dating agency’ not dissimilar to that suggested by Raymond, based on everyone’s medical records, help these junior doctors? “ ̽��ֱ��doctor can search for other patients that look like their own. They can go back historically and see what drugs were prescribed and what their outcomes looked like.”

Drumright is mindful of setting up a system that tells doctors what to prescribe; the literature about how we interface with technology suggests that people can too easily surrender their responsibility. Instead, it’s about building on collective knowledge, “What we’re trying to do is enhance the doctor’s experience so that it’s not ‘my experience as me’, it’s the experience of every prescriber in the hospital.”

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

Licence type:

Attribution