Are CNV Risk Scores Linked to Neurodevelopmental and Mental Health Characteristics Within CNV-Associated Intellectual Disability?

Higher CNV risk scores may predict fewer mental health difficulties in children with intellectual disability, but this relationship is complex and varies by score range.

Summary and findings

The study examined the relationship between copy number variant (CNV) risk scores and neurodevelopmental (ND) and mental health (MH) characteristics in children and young people (CYP) with intellectual disability (ID). The analysis included 1,640 CYP aged 4–19 years with clinically-reported CNVs. Higher summed pLI scores unexpectedly predicted fewer MH difficulties and a lower likelihood of ND diagnoses.

Abstract

<h4>Background</h4> Children and young people (CYP) with intellectual disability (ID) frequently have co-occurring neurodevelopmental (ND) and mental health (MH) difficulties. While copy number variants (CNVs) are identified as an important aetiology of ID, it is unclear whether and how CNV risk scores predict ND and MH characteristics within the CNV-associated ID population. <h4>Methods</h4> We analysed data from the UK-based IMAGINE-ID cohort of CYP (aged 4–19 years) with ID and clinically-reported CNVs (N = 1,640). CNVs were annotated with Gencode 19 in ENSEMBL to calculate CNV risk scores, including summed probability of loss-of-function intolerance (pLI) and dosage sensitivity. Multivariate regression models examined the prediction of CNV variables and inheritance on ND and MH characteristics, assessed via the Development and Well-Being Assessment (DAWBA). Post-hoc analyses explored CNV variable stratification (lower vs. higher range pLI). <h4>Results</h4> Higher summed pLI scores (indexing CNV genes’ intolerance to loss of function) unexpectedly predicted fewer MH difficulties and a lower likelihood of ND diagnoses, even after accounting for demographic factors and CNV inheritance. Post-hoc analyses identified a threshold effect. Within the lower pLI range, higher pLI scores were associated with greater MH difficulties, consistent with findings from population-based samples. In contrast, within the higher pLI range, higher pLI scores were associated with fewer MH difficulties (among individuals more likely to have severe ID). <h4>Conclusion</h4> These findings challenge the assumption that CNV genomic “risk scores” universally predict ND and MH difficulties. Instead, within CNV-associated ID, complex relationships exist between CNV risk scores, inheritance and phenotypes. These insights emphasise the necessity of integrating genomic results with familial and developmental context to understand individual vulnerabilities and support needs.

Elsewhere in the PNC-27 corpus