Inheritance Matters: Behavioural and emotional difficulties in intellectual disability associated with copy number variants
by Jeanne Wolstencroft, Ramya Srinivasan, Ellie Kerry, Prof David Skuse & the IMAGINE ID Consortium
Poster presented at: Faculties of Child & Adolescent Psychiatry and General Adult Psychiatry Annual Conference 2016, 6-7 October 2016, Birmingham
Background: Gains or losses of genetic material, known as copy number variants (CNVs) have been strongly associated with intellectual disability (ID). The relative contribution of de novo vs inherited CNVs to clinically relevant phenotypes requires elucidation. Previous research suggests that morphological phenotypes are more severe with de novo CNVs but few studies have focused on behavioural phenotypes.
This study aimed to identify whether there are any significant differences in the severity of emotional or behavioural difficulties experienced by children diagnosed with a single pathogenic or likely pathogenic CNV according to inheritance pattern.
Methods: The Strengths and Difficulties Questionnaire (SDQ) and the Everyday Feelings Questionnaire (EFQ) were administered to caregivers of children with CNVs. The SDQ is a validated measure which assesses common areas of emotional and behavioural difficulties. The EFQ is a self-report measure which assesses the emotional wellbeing of children’s caregivers. Participants were recruited by the IMAGINE ID Study, which comprises children with ID of genetic aetiology.
Results: The sample consisted of 121 children with de novo CNVs and 72 children with inherited CNVs; all children were aged 4-18 years. The total SDQ score was significantly higher for children with inherited CNVs in comparison to de novo CNVs (mean SDQ score=22.4 vs 18.4; p=0.00). Caregivers of children with inherited CNVs were significantly more likely to require help with completing the assessments (11% vs 42%; p=0.00). There were no significant differences in caregiver EFQs between the two groups.
Conclusion: The interpretation of CNVs in children with ID is complex. It is generally assumed that de novo CNVs are more likely to be clinically significant, however this is debatable. Our results suggest that it is the children with inherited CNVs that have more emotional and behavioural difficulties. The caregivers of children with inherited CNVs were also more likely to request help in completing the assessments. This could be related to a higher level of need in this group. It is interesting to note that there were no significant differences in the self-report measures of caregiver emotional wellbeing.
Why are we interested in Copy Number Variants (CNVs)?
Our poster gives a very simplified definition of CNVs, but there is a lot more to be said and learnt about them. The most referenced definition of CNVs was posited by Redon et al. (2006) as deletions, insertions, duplications and complex multi-site variants of DNA segments of one kilobase (kb) or larger that are present at a variable copy number in comparison with a reference genome.
As this Nature article explains, CNVs are now believed to be as important to genetic diversity as single nucleotide polymorphisms (SNPs). We all have CNVs (see Figure 1 below), in fact, researchers are still compiling a catalogue of all the known CNVs. We know from genome-wide maps that no region of the genome is exempt from CNVs, and that the percentage of an individual’s chromosomes that have CNVs can vary anywhere from 6% to 19% (Figure 1; Redon et al., 2006). CNVs are found in all human populations and in some other mammalian species too (Freeman et al., 2006). But it’s important to remember that not all CNVs are associated with adverse effects.
In this research we’ve only looked at patients who have a single CNV that is known to have an adverse effects on physical or mental health. It may be that individuals with multiple CNVs have worse phenotypes or that individuals with a single CNV of unknown significance need additional genetic or environmental factors for the CNV to have a detectable effect, but this is beyond the scope of the current poster we’ve presented.
Figure 1: Genomic distribution of copy number variable regions (CNVRs)
The chromosomal locations of 1,447 CNVRs are indicated by lines to either side of the ideograms. Green lines denote CNVRs associated with segmental duplications; blue lines denote CNVRs not associated with segmental duplications. The length of right-hand side lines represents the size of each CNVR. The length of left-hand side lines indicates the frequency with which a CNVR is detected (minor call frequency among 270 HapMap samples). When both platforms identify a CNVR, the maximum call frequency of the two is shown. For clarity, the dynamic range of length and frequency are log transformed (see scale bars). Reproduced from Redon et al., 2006
More about our measures:
The Strengths and Difficulties Questionnaire (SDQ) and the Everyday Feelings Questinnaire (EFQ) were administered to parents of participating children. Both the SDQ and EFQ are widely used and validated instruments which can be administered online.
- The Strengths and Difficulties Questionnaire (SDQ)
The Strengths and Difficulties Questionnaire (SDQ) is a brief behavioural screening questionnaire. The SDQ asks about 25 psychological attributes, some positive and others negative. These 25 items are divided between 5 scales:
1) emotional symptoms (5 items)
2) conduct problems (5 items)
3) hyperactivity/inattention (5 items)
4) peer relationship problems (5 items)
5) prosocial behaviour (5 items)
- Everyday Feelings Questionnaire (EFQ)
IMAGINE ID Study
Our research group is part of the IMAGINE ID Consortium, which aims to collect detailed phenotypic information on 5000+ children with intellectual disability due to a rare genetic cause. Find out more about the IMAGINE ID Study here: http://www.imagine-id.org/