The contribution of copy number variants to psychiatric symptoms and cognitive ability

Mollon, Josephine; Almasy, Laura; Jacquemont, Sébastien; Glahn, David C.

doi:10.1038/s41380-023-01978-4

Cited by 32 publications

(24 citation statements)

References 194 publications

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“…Finally, we analyzed the genes having a higher probability (>0.9) of loss-of-function (LoF) intolerance (pLI) score. High pLI genes have been shown to have a higher impact on intellectual quotient in copy number variants in individuals with developmental differences ( 51 , 52 ). Interestingly, we found that for those with high pLI genes, females had a significantly higher number of pathogenic variants per individual (0.59 vs. 0.52 for male, p = 1.7E-4) ( Figure 3B ).…”

Section: Resultsmentioning

confidence: 99%

Sex difference contributes to phenotypic diversity in individuals with neurodevelopmental disorders

Cuppens,

Shatto,

Mangnier

et al. 2023

Front. Pediatr.

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ObjectiveGain a better understanding of sex-specific differences in individuals with global developmental delay (GDD), with a focus on phenotypes and genotypes.MethodsUsing the Deciphering Developmental Disorders (DDD) dataset, we extracted phenotypic information from 6,588 individuals with GDD and then identified statistically significant variations in phenotypes and genotypes based on sex. We compared genes with pathogenic variants between sex and then performed gene network and molecular function enrichment analysis and gene expression profiling between sex. Finally, we contrasted individuals with autism as an associated condition.ResultsWe identified significantly differentially expressed phenotypes in males vs. females individuals with GDD. Autism and macrocephaly were significantly more common in males whereas microcephaly and stereotypies were more common in females. Importantly, 66% of GDD genes with pathogenic variants overlapped between both sexes. In the cohort, males presented with only slightly increased X-linked genes (9% vs. 8%, respectively). Individuals from both sexes harbored a similar number of pathogenic variants overall (3) but females presented with a significantly higher load for GDD genes with high intolerance to loss of function. Sex difference in gene expression correlated with genes identified in a sex specific manner. While we identified sex-specific GDD gene mutations, their pathways overlapped. Interestingly, individuals with GDD but also co-morbid autism phenotypes, we observed distinct mutation load, pathways and phenotypic presentation.ConclusionOur study shows for the first time that males and females with GDD present with significantly different phenotypes. Moreover, while most GDD genes overlapped, some genes were found uniquely in each sex. Surprisingly they shared similar molecular functions. Sorting genes by predicted tolerance to loss of function (pLI) led to identifying an increased mutation load in females with GDD, suggesting potentially a tolerance to GDD genes of higher pLI compared to overall GDD genes. Finally, we show that considering associated conditions (for instance autism) may influence the genomic underpinning found in individuals with GDD and highlight the importance of comprehensive phenotyping.

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Section: Resultsmentioning

confidence: 99%

Sex difference contributes to phenotypic diversity in individuals with neurodevelopmental disorders

Cuppens,

Shatto,

Mangnier

et al. 2023

Front. Pediatr.

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“…There are, genetically speaking (as observed for all complex traits [Boyle et al 2017] and in forward genetic screens in model organisms [Mitchell 2018a]), simply many more ways to impair the processes of neural circuit formation indirectly and nonspecifically than the converse. Some important principles of the genetic architecture of neurodevelopmental disorders are revealed by the study of a particular class of mutations: copy number variants (CNVs) (Mollon et al 2023). These are deletions or duplications of segments of chromosomes, or, as in Down syndrome, even whole chromosomes.…”

Section: The Genetics Of Neurodevelopment In Humansmentioning

confidence: 99%

Variability in Neural Circuit Formation

Mitchell

2024

Cold Spring Harb Perspect Biol

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“…Carriers of certain rare recurrent copy number variants (CNVs) - i.e., deletions or duplications of a segment of the genome - have a higher risk of developing psychiatric and neurodevelopmental disorders, including schizophrenia and autism spectrum disorder 1 – 5 Several rare recurrent CNVs have moderate to large effects on structural brain measures derived from magnetic resonance imaging (MRI) 6 , 7 . The effects of CNVs on brain structure have been suggested to occur primarily during early neurodevelopment 8 , and some rare recurrent CNVs have been associated with altered cellular function, composition and size derived from cortical organoids that models fetal and early neurodevelopment 9 – 12 .…”

Section: Introductionmentioning

confidence: 99%

Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers

Boen

Kaufmann

Meer

et al. 2024

Biological Psychiatry

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The contribution of copy number variants to psychiatric symptoms and cognitive ability

Cited by 32 publications

References 194 publications

Sex difference contributes to phenotypic diversity in individuals with neurodevelopmental disorders

Sex difference contributes to phenotypic diversity in individuals with neurodevelopmental disorders

Variability in Neural Circuit Formation

Beyond the Global Brain Differences: Intraindividual Variability Differences in 1q21.1 Distal and 15q11.2 BP1-BP2 Deletion Carriers

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