De novo variants in the Helicase-C domain of CHD8 are associated with severe phenotypes including autism, language disability and overgrowth

An, Yu; Zhang, Linna; Liu, Wenwen; Jiang, Yunyun; Xue, Chen; Lan, Xiaoping; Gan, Li; Hang, Qiang; Wang, Jian; Gusella, James F.; Du, Yasong; Shen, Yiping

doi:10.1007/s00439-020-02115-9

Cited by 37 publications

(36 citation statements)

References 39 publications

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“…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%

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: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…An auxiliary peak was observed within the CHD7-binding region, especially due to pathogenic variations within exon 30. ASD population recorded a significantly higher frequency of truncating SNPs (P < 0.0001) (Wilkinson et al, 2015) (An et al, 2020). Although ASD variants were not localised to any specific regions of CHD8, >30% of ASD SNPs, remarkably occurred frequently within the highly conserved signature regions in contrast to the observations made in the general population.…”

Section: Discussionmentioning

confidence: 97%

“…Although ASD variants were not localised to any specific regions of CHD8, >30% of ASD SNPs, remarkably occurred frequently within the highly conserved signature regions in contrast to the observations made in the general population. Notably, the Helicase-Cterminal region had the highest accumulation of truncating SNPs and severely damaging nsSNPs than the general population (An et al, 2020). Gene CHD8 recorded 12 different independently occurring recurrent ASD SNPs, 8 of these SNPs (66.7%) were located within signature regions, 3 and 2 out of 7 such truncating SNPs occurred within CHD7-binding motif and SANT and SLIDE DNA binding domain which could lead to loss of PTM sites and alter CHD8's chromatin remodelling functions, respectively, known to disrupt protein function.…”

Section: Discussionmentioning

confidence: 99%

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Autism Spectrum Disorder is burdened by severely pathogenic variations within core domains of CHD8 and its CHD7-binding motif

Snm

Balakrishnan

Ramachandra

2020

Preprint

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Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder presented with social and communication deficits, restricted, repetitive behaviours and interest. Several recurrently mutated genetic risk-factors have been implicated in ASD manifestation. Chromodomain helicase remodeller (CHD8) is one such gene that is a master regulator mediating the expression of genes controlling neuron functions. We collected 8,124 exonic SNPs in CHD8 from 4 databases representing the general and ASD populations; subjected them to multi-layered analyses on >20 computational tools. We observed that nsSNPs were common in the general population. Distinct hotspots for truncating and nsSNPs were identified within exons encoding the N and C terminals, respectively. Evolutionarily conserved regions involving CHD8 core domains: Helicase-C-terminal, Helicase-ATPbinding and SNF2 N domains, recorded the lowest density but severely pathogenic SNPs. Conversely, evolutionarily variable regions-CHD7-binding and BRK domains-hosted the highest SNPs, but were benign. Post-Translational-Modifications (PTMS) occurred on residues outside domains (P<0.01) i.e., non-conserved regions of CHD8 including the N and C terminals that were determined to be Intrinsically-Disordered-Protein-Regions (IDPRs) with 9 Molecular-Recognition-Features sites. Contrastingly, ASD population recorded significantly higher incidences of truncating SNPs than general population (P<0.0001). ASD-SNPs frequently occurring within core domains were severely damaging and accounted for >30% of all ASD variations. The CHD7-DNA-binding motif, with most PTMs, recorded the highest recurring truncating ASD-SNPs. The CHD8 PPIs effortlessly recapitulated the phenotypes presented by children with CHD8 mutations. 11/13 (84.6%) interacting molecules were IDPs. We identified 9 CHD8 nsSNPs that produced the strongest long-range disturbances, altering the modelled protein's global conformational dynamics.

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“…Most often WES is a powerful approach to study Mendelian inherited diseases because highly functional impact variants rarely appear in the healthy populations 6 7 . In humans, exome sequencing has been used to study a wide-range of diseases, cancers, and analysis of autism spectrum disorder 8,9,10 . The discovery of exome variants has led to therapeutic targets for drug development, and genetic markers for innovative clinical applications in companion animals and humans 11,3 .…”

Section: Introductionmentioning

confidence: 99%

A domestic cat whole exome sequencing resource for trait discovery

Rodney

Buckley

Fulton

et al. 2020

Preprint

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Over 94 million domestic cats are considered pets, who, as our companions, are also susceptible to cancers, common and rare diseases. Whole exome sequencing (WES) is a cost-effective strategy to study their putative disease-causing variants. Presented is ~35.8 Mb exome capture design based on the annotated Felis_catus_9.0 genome assembly, covering 201,683 regions of the cat genome. WES was conducted on 41 cats from various breeds with known and unknown diseases and traits, including 10 cats with prior whole genome sequence (WGS) data available, to test WES capture probe performance. A WES and WGS comparison was completed to understand variant discovery capability of each platform. At ~80x exome coverage, the percent of on-target base coverage >20x was 96.4% with an average of 10.4% off-target. For variant discovery, greater than 98% of WGS SNPs were also discovered by WES. Platform specific variants were mainly restricted to a small number of sex chromosome and olfactory receptor genes. Within the 41 cats with ~31 diseases and normal traits, 45 previously known disease or trait causal variants were observed, such as Persian progressive retinal degeneration and hydrocephalus. Novel candidate variants for polycystic kidney disease and atrichia in the Peterbald breed were also identified as well as a new cat patient with a known variant for cystinuria. These results show the discovery potential of deep exome sequencing to validate existing disease gene models and identify novel gene candidate alleles for many common and rare diseases in cats.

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De novo variants in the Helicase-C domain of CHD8 are associated with severe phenotypes including autism, language disability and overgrowth

Cited by 37 publications

References 39 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

Autism Spectrum Disorder is burdened by severely pathogenic variations within core domains of CHD8 and its CHD7-binding motif

A domestic cat whole exome sequencing resource for trait discovery

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