The <i>CHD8</i> overgrowth syndrome: A detailed evaluation of an emerging overgrowth phenotype in 27 patients

Ostrowski, Philip J.; Zachariou, Anna; Loveday, Chey; Beleza-Meireles, Ana; Bértoli, Marta; Dean, John; Douglas, Andrew G.L.; Ellis, Ian O.; Foster, Alison; Graham, John M.; Hague, Jennifer; Hilhorst‐Hofstee, Yvonne; Hoffer, Mariëtte J.V.; Johnson, Diana; Josifova, Dragana; Kant, Sarina G.; Kini, Usha; Lachlan, Katherine; Lam, Wayne; Lees, Melissa; Lynch, Sally Ann; Maitz, Silvia; McKee, Shane; Metcalfe, Kay; Nathanson, Katherine L.; Ockeloen, Charlotte W.; Parker, Michael; Pierson, Tyler Mark; Rahikkala, Elisa; Sanchez‐Lara, Pedro A.; Spano, Alice; Maldergem, Lionel Van; Cole, Trevor; Douzgou, Sofia; Tatton‐Brown, Katrina

doi:10.1002/ajmg.c.31749

Cited by 39 publications

(45 citation statements)

References 21 publications

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“…Behavioral abnormalities in the open-field test worsen with age in Chd8 V986*/+ mice ASD disproportionally affects males over females (~4:1), ASD-linked mutations in CHD8 are more common in males (3.5:1) [13] and only Chd8 mutant male mice (with a different heterozygous loss-of-function allele, Asn2371LysfsX2; shown in Fig. 1) had behavioral abnormalities [20].…”

Section: Resultsmentioning

confidence: 99%

“…Subsequent studies found that de novo heterozygous loss-of-function mutations in CHD8 are relatively common in ASD probands [4,[8][9][10][11][12]. Individuals with disruptive CHD8 mutations are disproportionately male (3.5:1) and present with shared symptoms, including macrocephaly, neonatal hypotonia, distinct facial features, and gastrointestinal problems [9,13,14].…”

Section: Introductionmentioning

confidence: 99%

“…However, phenotypes in these various Chd8 haploinsufficiency mouse lines are only partially concordant and are of small effect size. A recent study found that phenotypes were only detected in male Chd8 mutant mice [ 20 ], suggesting penetrance may be influenced by sex, as is the case in humans [ 13 ]. CHD8 disruption affects genes associated with neurodevelopment and synaptic function [ 21 – 24 ] .…”

Section: Introductionmentioning

confidence: 99%

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Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life

et al. 2020

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Background Chromodomain helicase DNA-binding protein 8 (Chd8) is a high-confidence risk gene for autism spectrum disorder (ASD). However, how Chd8 haploinsufficiency impairs gene expression in the brain and impacts behavior at different stages of life is unknown. Methods We generated a mutant mouse line with an ASD-linked loss-of-function mutation in Chd8 (V986*; stop codon mutation). We examined the behavior of Chd8 mutant mice along with transcriptional changes in the cerebral cortex as a function of age, with a focus on one embryonic (E14.5) and three postnatal ages (1, 6, and 12 months). Results Chd8V986*/+ mutant mice displayed macrocephaly, reduced rearing responses and reduced center time in the open field, and enhanced social novelty preference. Behavioral phenotypes were more evident in Chd8V986*/+ mutant mice at 1 year of age. Pup survival was reduced in wild-type x Chd8V986*/+ crosses when the mutant parent was female. Transcriptomic analyses indicated that pathways associated with synaptic and neuronal projections and sodium channel activity were reduced in the cortex of embryonic Chd8V986*/+ mice and then equalized relative to wild-type mice in the postnatal period. At 12 months of age, expression of genes associated with endoplasmic reticulum (ER) stress, chaperone-mediated protein folding, and the unfolded protein response (UPR) were reduced in Chd8V986*/+ mice, whereas genes associated with the c-MET signaling pathway were increased in expression. Limitations It is unclear whether the transcriptional changes observed with age in Chd8V986*/+ mice reflect a direct effect of CHD8-regulated gene expression, or if CHD8 indirectly affects the expression of UPR/ER stress genes in adult mice as a consequence of neurodevelopmental abnormalities. Conclusions Collectively, these data suggest that UPR/ER stress pathways are reduced in the cerebral cortex of aged Chd8V986*/+ mice. Our study uncovers neurodevelopmental and age-related phenotypes in Chd8V986*/+ mice and highlights the importance of controlling for age when studying Chd8 haploinsufficient mice.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life

et al. 2020

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“…CHD8, connecting BAF and COMPASS complexes, negatively regulates β-catenin-targeted gene expression important in cellular proliferation and differentiation ( 55 , 56 ). In Chd8 depleted mice, PRC2 regulation of WNT signaling appears to be the major altered pathway ( 57 ), and accordingly, an overgrowth phenotype with macrocephaly has been reported in CHD8-related NDD patients and animal models ( 28 , 58–60 ).…”

Section: Transcriptional Convergence In Neurogenesis: Wnt Signalingmentioning

confidence: 99%

The phenomenal epigenome in neurodevelopmental disorders

Ciptasari

Bokhoven

2020

Human Molecular Genetics

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Disruption of chromatin structure due to epimutations is a leading genetic etiology of neurodevelopmental disorders, collectively known as chromatinopathies. We show that there is an increasing level of convergence from the high diversity of genes that are affected by mutations to the molecular networks and pathways involving the respective proteins, the disrupted cellular and subcellular processes, and their consequence for higher order cellular network function. This convergence is ultimately reflected by specific phenotypic features shared across the various chromatinopathies. Based on these observations, we propose that the commonly disrupted molecular and cellular anomalies might provide a rational target for the development of symptomatic interventions for defined groups of genetically distinct neurodevelopmental disorders.

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“…In addition to ASD, CHD8 has been associated with other clinical features, such as macrocephaly, gastrointestinal problems, regression of acquired skills, intellectual disability, some recurring facial features, and seizures. The gene encodes for the chromatin remodeling factor CHD8, which is a member of the chromodomain‐helicase‐DNA binding proteins, involved in chromatin dynamics, transcriptional regulation, and cell survival 46–50 …”

Section: The Epileptic Phenotype Of Candidate Genesmentioning

confidence: 99%

Chromosome 14 deletions, rings, and epilepsy genes: A riddle wrapped in a mystery inside an enigma

Vaisfeld

Spartano

Gobbi³

et al. 2020

Epilepsia

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The ring 14 syndrome is a rare condition caused by the rearrangement of one chromosome 14 into a ring‐like structure. The formation of the ring requires two breakpoints and loss of material from the short and long arms of the chromosome. Like many other chromosome syndromes, it is characterized by multiple congenital anomalies and developmental delays. Typical of the condition are retinal anomalies and drug‐resistant epilepsy. These latter manifestations are not found in individuals who are carriers of comparable 14q deletions without formation of a ring (linear deletions). To find an explanation for this apparent discrepancy and gain insight into the mechanisms leading to seizures, we reviewed and compared literature cases of both ring and linear deletion syndrome with respect to both their clinical manifestations and the role and function of potentially epileptogenic genes. Knowledge of the epilepsy‐related genes in chromosome 14 is an important premise for the search of new and effective drugs to combat seizures. Current clinical and molecular evidence is not sufficient to explain the known discrepancies between ring and linear deletions.

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The CHD8 overgrowth syndrome: A detailed evaluation of an emerging overgrowth phenotype in 27 patients

Cited by 39 publications

References 21 publications

Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life

Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life

The phenomenal epigenome in neurodevelopmental disorders

Chromosome 14 deletions, rings, and epilepsy genes: A riddle wrapped in a mystery inside an enigma

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