Genotype–phenotype associations in children with copy number variants associated with high neuropsychiatric risk in the UK (IMAGINE-ID): a case-control cohort study

Chawner, Samuel J. R. A.; Owen, Michael John; Holmans, Peter; Raymond, F. Lucy; Skuse, David; Hall, Jérémy; Bree, Marianne B. M. van den

doi:10.1016/s2215-0366(19)30123-3

Cited by 99 publications

(142 citation statements)

References 45 publications

(49 reference statements)

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“…Recent work suggests that CNV-specific phenotypic outcomes are limited, pointing instead to a large degree of similarity across phenotypes associated with different ND-CNVs 2,3 . Focusing on convergent neural alterations across different genotypes can thus help elucidate the mechanisms linking ND-CNVs at different loci to a shared psychopathology and increase in neurodevelopmental risk.…”

Section: Introductionmentioning

confidence: 99%

Electrophysiological network alterations in adults with copy number variants associated with high neurodevelopmental risk

et al. 2020

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Rare copy number variants associated with increased risk for neurodevelopmental and psychiatric disorders (referred to as ND-CNVs) are characterized by heterogeneous phenotypes thought to share a considerable degree of overlap. Altered neural integration has often been linked to psychopathology and is a candidate marker for potential convergent mechanisms through which ND-CNVs modify risk; however, the rarity of ND-CNVs means that few studies have assessed their neural correlates. Here, we used magnetoencephalography (MEG) to investigate resting-state oscillatory connectivity in a cohort of 42 adults with ND-CNVs, including deletions or duplications at 22q11.2, 15q11.2, 15q13.3, 16p11.2, 17q12, 1q21.1, 3q29, and 2p16.3, and 42 controls. We observed decreased connectivity between occipital, temporal, and parietal areas in participants with ND-CNVs. This pattern was common across genotypes and not exclusively characteristic of 22q11.2 deletions, which were present in a third of our cohort. Furthermore, a data-driven graph theory framework enabled us to successfully distinguish participants with ND-CNVs from unaffected controls using differences in node centrality and network segregation. Together, our results point to alterations in electrophysiological connectivity as a putative common mechanism through which genetic factors confer increased risk for neurodevelopmental and psychiatric disorders.

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Section: Introductionmentioning

confidence: 99%

Electrophysiological network alterations in adults with copy number variants associated with high neurodevelopmental risk

et al. 2020

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“…In a clinical setting, the same variants would not be classified as pathogenic since no single established PNES gene exists. Nevertheless, the detection of pathogenic variants that are likely to cause Mendelian forms of neurological or psychiatric disorders in individuals with PNES is in line with emerging evidence that neurological or psychiatric disorders share a broad range of pleiotropic acting genetic variation 8,11,31 . Our results are also in line with the observation that up to 48% of all individuals with PNES report a family history of epilepsy and 22% a family history of psychiatric disorders 6 .…”

Section: Discussionmentioning

confidence: 64%

Neurological disorder-associated genetic variants in individuals with psychogenic nonepileptic seizures

Leu

Bautista

Sudarsanam

et al. 2020

Sci Rep

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Psychogenic nonepileptic seizures (PNES) are diagnosed in approximately 30% of patients referred to tertiary care epilepsy centers. Little is known about the molecular pathology of PNES, much less about possible underlying genetic factors. We generated whole-exome sequencing and whole-genome genotyping data to identify rare, pathogenic (P) or likely pathogenic (LP) variants in 102 individuals with PNES and 448 individuals with focal (FE) or generalized (GE) epilepsy. Variants were classified for all individuals based on the ACMG-AMP 2015 guidelines. For research purposes only, we considered genes associated with neurological or psychiatric disorders as candidate genes for PNES. We observe in this first genetic investigation of PNES that six (5.88%) individuals with PNES without coexistent epilepsy carry P/LP variants (deletions at 10q11.22-q11.23, 10q23.1-q23.2, distal 16p11.2, and 17p13.3, and nonsynonymous variants in NSD1 and GABRA5). Notably, the burden of P/LP variants among the individuals with PNES was similar and not significantly different to the burden observed in the individuals with FE (3.05%) or GE (1.82%) (PNES vs. FE vs. GE (3 × 2 χ2), P = 0.30; PNES vs. epilepsy (2 × 2 χ2), P = 0.14). The presence of variants in genes associated with monogenic forms of neurological and psychiatric disorders in individuals with PNES shows that genetic factors are likely to play a role in PNES or its comorbidities in a subset of individuals. Future large-scale genetic research studies are needed to further corroborate these interesting findings in PNES.

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“…We were therefore not able to evaluate the impact of inheritance status independently. Previous studies have described high rates and complex presentations of psychiatric and neurodevelopmental difficulties in individuals with ND-CNVs (Chawner et al, 2019;Niarchou et al, 2014;Schneider et al, 2014;Steinman et al, 2016) using standard psychiatric assessments. Our findings, using a measure designed for use in ID that focuses on emotion and behaviour disturbance, offers further evidence for elevated rates of psychopathology in individuals with ND-CNVs.…”

Section: Discussionmentioning

confidence: 99%

Assessment of emotions and behaviour by the Developmental Behaviour Checklist in young people with neurodevelopmental CNVs

et al. 2020

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Abstract Background A number of genomic conditions caused by copy number variants (CNVs) are associated with a high risk of neurodevelopmental and psychiatric disorders (ND-CNVs). Although these patients also tend to have cognitive impairments, few studies have investigated the range of emotion and behaviour problems in young people with ND-CNVs using measures that are suitable for those with learning difficulties. Methods A total of 322 young people with 13 ND-CNVs across eight loci (mean age: 9.79 years, range: 6.02–17.91, 66.5% male) took part in the study. Primary carers completed the Developmental Behaviour Checklist (DBC). Results Of the total, 69% of individuals with an ND-CNV screened positive for clinically significant difficulties. Young people from families with higher incomes (OR = 0.71, CI = 0.55–0.91, p = .008) were less likely to screen positive. The rate of difficulties differed depending on ND-CNV genotype (χ2 = 39.99, p < 0.001), with the lowest rate in young people with 22q11.2 deletion (45.7%) and the highest in those with 1q21.1 deletion (93.8%). Specific patterns of strengths and weaknesses were found for different ND-CNV genotypes. However, ND-CNV genotype explained no more than 9–16% of the variance, depending on DBC subdomain. Conclusions Emotion and behaviour problems are common in young people with ND-CNVs. The ND-CNV specific patterns we find can provide a basis for more tailored support. More research is needed to better understand the variation in emotion and behaviour problems not accounted for by genotype.

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Genotype–phenotype associations in children with copy number variants associated with high neuropsychiatric risk in the UK (IMAGINE-ID): a case-control cohort study

Cited by 99 publications

References 45 publications

Electrophysiological network alterations in adults with copy number variants associated with high neurodevelopmental risk

Electrophysiological network alterations in adults with copy number variants associated with high neurodevelopmental risk

Neurological disorder-associated genetic variants in individuals with psychogenic nonepileptic seizures

Assessment of emotions and behaviour by the Developmental Behaviour Checklist in young people with neurodevelopmental CNVs

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