Cardiff University researchers uncover link between irritability and rare genetic disorders in young people

Researchers working on the Rare Genetic Research Variant Programme based at Cardiff University have recently published new research investigating irritability in young people with a rare genetic condition.

The paper, ‘Irritability in young people with copy number variants associated with neurodevelopmental disorders (ND-CNVs)’ utilised one of the largest research cohorts of individuals with neurodevelopmental genetic conditions in the world, developed by senior author Professor Marianne van den Bree.

This study involved interviews with the parents of 485 children with CNVs, and 164 siblings with no known genetic condition. Parents were asked in detail about their child’s feelings and behaviours in an interview called the Child and Adolescent Psychiatric Assessment (CAPA). Children were also asked to complete tasks including a test of intelligence, or IQ, called the Weschler Abbreviated Scale of Intelligence (WASI).

The research team compared the results from children with a known ND-CNV with a group of siblings who did not have a genetic condition, and identified that children with ND-CNVs were almost four times more likely to be irritable when compared to their siblings.

Dr Jessica Hall, a Research Associate on the project, conducted research interviews with parents of children with a rare genetic condition.

Dr Hall said: “We worked closely with families during the study and interviewed parents of children with a rare genetic conditions. The sentiment from parents was that they worried their child would get labelled as naughty, difficult, or even unlikeable, in relation to the often irritable behaviour their children displayed.”

This led the researchers to consider whether irritability might be widespread challenge for families of children with rare genetic conditions, and to the development of new research which aimed to investigate this, with a particular focus on copy number variants that are associated with neurodevelopmental disorders.

Explaining copy number variants

DNA is an instruction manual containing all the information needed for creating and maintaining life. It is stored in chromosomes, which humans have 23 pairs of.

A copy number variant, or a ‘CNV’ is a genetic change. CNVs can occur when a large section of a chromosome is either deleted or duplicated, meaning a person can have either too little or too much DNA.

Dr Hall explained “Most people will have a CNV of some sort, but the majority are harmless. However, if the CNV occurs in a particular position on the chromosome, then it can impact our development or physical health. In fact, we know from research that there are a range of CNVs that impact child development, and we call these neurodevelopmental CNVs, or ‘ND-CNVs’.”

The interplay of irritability and ND-CNVs

Irritability is a common emotional state where a person feels easily annoyed or upset. Most people are familiar with the idea of toddler tantrums, and whilst this isn’t everyday emotion that is considered problematic, irritable behaviour that is unusual for a child's age can be challenging for families.

Clinically, a child may be considered irritable if they are quicker to anger than their peers. Irritability is also a common reason why children are referred to child and adolescent mental health services, and it is a key feature of many neurodevelopmental and psychiatric conditions.

However, whilst there has been lots of work to understand irritability, there is very little information available that is specific to children with ND-CNVs.

The research team aimed to delve deeper into the reasons behind irritability and ND-CNVs. It is already known that children with ND-CNVs are more likely to have a neurodevelopmental or psychiatric condition, such as attention deficit hyperactivity disorder, anxiety, or autism, and that irritability is a common feature of these conditions.

Therefore, it was important for researchers to consider whether higher levels of irritability identified in children with ND-CNVs was directly related to one of these conditions, regardless of whether they had a ND-CNV or not.

This further analysis revealed that higher levels of irritability in children with ND-CNVs were not simply because of a higher likelihood of other conditions associated with irritability. Children with ND-CNVs can also experience difficulties with learning, and young people who find it harder to learn may find it more difficult to complete tasks or communicate effectively. This can be frustrating, and lead to irritable behaviour.

However, these analyses of learning ability and irritability found no strong evidence of association between learning ability and high levels of irritability. Additionally, children with a ND-CNV were more likely to be irritable than siblings who did have a similar learning ability.

Dr Hall added, “We learned that children with ND-CNVs are more likely to be irritable, regardless of other preexisting mental health and neurodevelopmental conditions or difficulty with learning.

“However, it is important that we use this information in the most effective ways possible. Irritable behaviour is something that clinicians may not notice, and so we are advising doctors to be aware of this high risk of irritability in young people with rare genetic conditions, to provide the most suitable treatment or intervention.

“Although learning ability doesn’t make children irritable, young people with genetic conditions who are irritable may still have difficulty with learning. Therefore, if we want to intervene and help families manage or improve their child’s irritability, we may need to take learning ability into account.”

The team recommended modifications to interventions like cognitive behavioural therapy to make sure that treatments are more accessible for this group of young people. Additionally, parents and teachers would also benefit from support with managing irritable behaviour at home and in school.

This research has highlighted the need for further research into irritability and ND-CNVs and whether this could be an early indication of later mental health problems.

Dr Hall concluded “Carrying out further research with people multiple times and at multiple ages will help us to figure out whether this might be the case. This would give us more information about whether early irritability interventions could help prevent later mental health problems, and this is something we plan to investigate next.”

The Rare Genetic Research Variant Programme would like to thank the children and families who took part in the study and the charities Max Appeal and Unique.

‘Irritability in young people with copy number variants associated with neurodevelopmental disorders (ND-CNVs)’ is available to read online in Translational Psychiatry.

This blog has been adapted from a piece written by Dr Hall originally published in Springer Nature.