Neuroimaging Findings in Neurodevelopmental Copy Number Variants: Identifying Molecular Pathways to Convergent Phenotypes

Silva, Ana Isabel; Ehrhart, Friederike; Ulfarsson, Magnus O.; Stefánsson, Kári; Wilkinson, Lawrence S.; Hall, Jérémy; Linden, David Edmund Johannes

doi:10.1016/j.biopsych.2022.03.018

Cited by 13 publications

(10 citation statements)

References 107 publications

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“…In addition to point mutations of nuclear genes, CNVs and mtDNA variants are also responsible for part of neurodevelopmental disorders ( Lam et al, 2019 ; Ullah et al, 2021 ; Silva et al, 2022 ; Sun et al, 2022 ). D’Gama has reported a case (AN00090) harboring a germline missense mutations in SETD2 predicted to be deleterious (responsible for ASD) and a 15q deletion consistent with her diagnosis of Angelman syndrome ( D'Gama et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

A novel SETD2 variant causing global development delay without overgrowth in a Chinese 3-year-old boy

Liu

Wan

et al. 2023

Front. Genet.

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Background: Luscan-Lumish syndrome is characterized by macrocephaly, postnatal overgrowth, intellectual disability (ID), developmental delay (DD), which is caused by heterozygous SETD2 (SET domain containing 2) mutations. The incidence of Luscan-Lumish syndrome is unclear. The study was conducted to provide a novel pathogenic SETD2 variant causing atypical Luscan-Lumish syndrome and review all the published SETD2 mutations and corresponding symptoms, comprehensively understanding the phenotypes and genotypes of SETD2 mutations.Methods: Peripheral blood samples of the proband and his parents were collected for next-generation sequencing including whole-exome sequencing (WES), copy number variation (CNV) detection and mitochondrial DNA sequencing. Identified variant was verified by Sanger sequencing. Conservative analysis and structural analysis were performed to investigate the effect of mutation. Public databases such as PubMed, Clinvar and Human Gene Mutation Database (HGMD) were used to collect all cases with SETD2 mutations.Results: A novel pathogenic SETD2 variant (c.5835_c.5836insAGAA, p. A1946Rfs*2) was identified in a Chinese 3-year-old boy, who had speech and motor delay without overgrowth. Conservative analysis and structural analysis showed that the novel pathogenic variant would loss the conserved domains in the C-terminal region and result in loss of function of SETD2 protein. Frameshift mutations and non-sense mutations account for 68.5% of the total 51 SETD2 point mutations, suggesting that Luscan-Lumish syndrome is likely due to loss of function of SETD2. But we failed to find an association between genotype and phenotype of SETD2 mutations.Conclusion: Our findings expand the genotype-phenotype knowledge of SETD2-associated neurological disorder and provide new evidence for further genetic counselling.

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Section: Discussionmentioning

confidence: 99%

A novel SETD2 variant causing global development delay without overgrowth in a Chinese 3-year-old boy

Liu

Wan

et al. 2023

Front. Genet.

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“…Here, we report a low similarity of intermediate phenotypes representing morphological CNV-specific brain signatures, in line with a documented broad diversity of regional morphometry patterns across genomic loci (Modenato et al, 2021b; Moreau et al, 2021a; Seidlitz et al, 2020). Conversely, the ramifications of carrying distinct CNV variants for cognition and behavior have previously been hypothesized to be more similar than those on brain anatomy (Raznahan et al, 2022; Silva et al, 2022). We here find strong evidence for substantial convergence of phenotypic measures across CNVs quantified by increased phenotypical similarity.…”

Section: Discussionmentioning

confidence: 99%

“…Concretely, CNVs overall have been shown to detrimentally affect cognition and raise the risk for psychiatric conditions (Huguet et al, 2021; Jacquemont et al, 2021). Nevertheless, the nature and specificity of CNV effects on phenotypic traits have become an arena of ongoing investigation (Jacquemont et al, 2021; Moberg et al, 2018; Silva et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…These parallel approaches to catalog CNVs highlighted a wide spectrum of robust effects on brain structure (Modenato et al, 2021b; Sønderby et al, 2021). Nevertheless, even though distinct rare CNVs are associated with a range of brain alterations, they have been argued to lead to a degree of similarity in associated behavioral phenotypes (Raznahan et al, 2022; Silva et al, 2022). However, it is unknown at which level of observation, from genes to large-scale brain networks to the phenome, the mechanisms of this disparate group of risk variants converge.…”

Section: Introductionmentioning

confidence: 99%

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Rare CNVs and phenome-wide profiling: a tale of brain-structural divergence and phenotypical convergence

Kopál

Kumar

Saltoun

et al. 2022

Preprint

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Copy number variations (CNVs) are rare genomic deletions and duplications that can exert profound effects on brain and behavior. Previous reports of pleiotropy in CNVs imply that they converge on shared mechanisms at some level of pathway cascades, from genes to large-scale neural circuits to the phenome. However, studies to date have primarily examined single CNV loci in small clinical cohorts. It remains unknown how distinct CNVs escalate the risk for the same developmental and psychiatric disorders. Here, we quantitatively dissect the impact on brain organization and behavioral differentiation across eight key CNVs. In 534 clinical CNV carriers from multiple sites, we explored CNV-specific brain morphology patterns. We extensively annotated these CNV-associated patterns with deep phenotyping assays through the UK Biobank resource. Although the eight CNVs cause disparate brain changes, they are tied to similar phenotypic profiles across ∼1000 lifestyle indicators. Our population-level investigation established brain structural divergences and phenotypical convergences of CNVs, with direct relevance to major brain disorders.

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“…Happé and Frith ( 56 ) optimistically predicted, “As sample sizes in autism genetic consortia rise, polygenic scores for autism may begin to explain a meaningful proportion of variance in autistic traits” (p. 224). There are polygenic risk scores for autism, however, as gene study sample size has increased, explaining autism variance has gotten more difficult and not less difficult, because larger samples have revealed more associations with ID, ADHD, anxiety disorders, schizophrenia, and other non-autism disorders and symptoms ( 57 ). Moreover, increasingly larger samples have led to the discovery of more CNVs and SNPs that converge on one autism behavior, and to the discovery of subsets of gene variants linked to subsets of autism behaviors ( 58 ).…”

Section: Efforts To Reduce Autism Heterogeneitymentioning

confidence: 99%

Heterogeneity thwarts autism explanatory power: A proposal for endophenotypes

Waterhouse

2022

Front. Psychiatry

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Many researchers now believe that autism heterogeneity is likely to include many disorders, but most research is based on samples defined by the DSM-5 Autism Spectrum Disorder (ASD) criteria. However, individuals diagnosed with autism have complex and varied biological causes for their symptoms. Therefore, autism is not a unitary biological entity. And although autism is significantly different from typical development, autism is not a unitary clinical disorder because diagnosed individuals vary in symptom patterns, comorbidities, biomarkers, and gene variants. The DSM-5 ASD criteria were designed to reduce heterogeneity, and there have been many other efforts to reduce autism heterogeneity including using more stringent clinical criteria, dividing autism into low and high functioning groups, creating subgroups, and by studying larger samples. However, to date these efforts have not been successful. Heterogeneity is extensive and remains unexplained, and no autism pathophysiology has been discovered. Most importantly, heterogeneity has hindered the explanatory power of the autism diagnosis to discover drug regimens and effective behavioral treatments. The paper proposes that possible transdiagnostic endophenotypes may reduce autism heterogeneity. Searching for transdiagnostic endophenotypes requires exploring autism symptoms outside of the framework of the DSM-5 autism diagnosis. This paper proposes that researchers relax diagnostic criteria to increase the range of phenotypes to support the search for transdiagnostic endophenotypes. The paper proposes possible candidates for transdiagnostic endophenotypes. These candidates are taken from DSM-5 ASD criteria, from concepts that have resulted from researched theories, and from symptoms that are the result of subtyping. The paper then sketches a possible basis for a future transdiagnostic endophenotypes screening tool that includes symptoms of autism and other neurodevelopmental disorders.

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Neuroimaging Findings in Neurodevelopmental Copy Number Variants: Identifying Molecular Pathways to Convergent Phenotypes

Cited by 13 publications

References 107 publications

A novel SETD2 variant causing global development delay without overgrowth in a Chinese 3-year-old boy

A novel SETD2 variant causing global development delay without overgrowth in a Chinese 3-year-old boy

Rare CNVs and phenome-wide profiling: a tale of brain-structural divergence and phenotypical convergence

Heterogeneity thwarts autism explanatory power: A proposal for endophenotypes

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