Risk of Pediatric Neuropsychiatric Conditions Linked to Rare Genomic Variants, Intellectual Disability

Early genomic testing could identify the children who are most at risk and provide opportunities to intervene as early as possible.

Next-generation sequencing has made it possible to identify an increasing number of genomic variants associated with intellectual disabilities, and a national cohort study in the United Kingdom highlighted the likelihood of children with such disabilities developing other neurodevelopmental or mental health conditions. Genomic testing early on could identify the children who are most at risk and provide opportunities to intervene as early as possible.

Exome or genome sequence analysis is recommended for children presenting with developmental delays or intellectual disabilities in the United Kingdom, but there has been limited research on rare genomic variants and long-term outcomes for such children. Most existing research is limited by modest sample sizes or small proportions of children with moderate to severe disabilities. The current study, published in The Lancet Psychiatry, aimed to evaluate the influence of environmental and genetic factors on their prognosis.

“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,” senior study author Lucy Raymond, MD, professor at the University of Cambridge School of Clinical Medicine, said in a statement.

The study comprised a subset of 2770 patients aged 4 to 19 years who were part of the Intellectual Disability and Mental Health: Assessing the Genomic Impact on Neurodevelopment (IMAGINE) study. Patients eligible for IMAGINE had developmental delays or intellectual disabilities diagnosed by a multidisciplinary care team, as well as a molecular genetic diagnosis. Patients were referred by regional UK genetic centers or patient support groups, or were self-referred.

Of the children in the study, 2397 had a basic mental health assessment completed by their families and 1277 completed medical history questionnaires. Seventy-four percent showed a pathogenic copy number variant, and 26.1% had a pathogenic single nucleotide variant.

The relative risk of parallel neuropsychiatric diagnoses was significantly higher in the study cohort compared with the general population. Children in the study were 29.2 times more likely to be diagnosed with autism spectrum disorder and 13.5 times more likely to be diagnosed with ADHD. Children in the study were also more likely to be diagnosed with oppositional defiant disorder or anxiety disorders than the general population.

“We already know that intellectual disabilities tend to be associated with an increased likelihood of neurodevelopmental conditions, as well as emotional and behavioral difficulties, but we found that where there is an identifiable genetic cause, the likelihood is amplified considerably,” study author Jeanne Wolstencroft, PhD, from Great Ormond Street Institute of Child Health at University College in London, said. “This suggests that these children should be provided with early assessment and help where appropriate.”

Physical health problems were also prevalent in the study cohort, with 64.6% reporting disturbed sleep; 63.7%, motor or movement disorders; 46%, fine motor problems; and 1.9%, cerebral palsy.

The study is also the first to find that children with inherited genomic variants were more likely to have intellectual disabilities then those with de novo variants. These children were also more likely to come from a more deprived socioeconomic background, suggesting family members could possibly have some degree of undiagnosed cognitive impairment putting them at a social and educational disadvantage.

Study limitations included its mostly referral-based recruitment and that variant inheritance information was only available for 64% of study participants. Mental health assessments were also mostly done online based on parental or caregiver reporting, and parents who may have rare genetic disorders themselves or those living in socioeconomically deprived circumstances may provide different behavior ratings than those with no underlying disorders or living in less deprived situations.

This study is the largest to date of rare genomic variants associated with intellectual disabilities, and future research should assess the occurrence of new mental health outcomes over time. The authors of this study are following up with families after 5 years to gain insight into the educational needs of these children.

“We hope this work helps improve the targeting of assessments and interventions to support families at the earliest opportunity,” study author David Skuse, MD, professorial research associate at the Great Ormond Street Institute of Child Health, said. “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 prioritizing children with mental health needs for child mental health services, who are currently hugely limited in the UK.”


Wolstencroft J, Wicks F, Srinivasan R, et al. Neuropsychiatric risk in children with intellectual disability of genetic origin: IMAGINE, a UK national cohort study. Lancet Psychiatry. Published online August 3, 2022. doi:10.1016/S2215-0366(22)00207-3

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