| 1 | Cell 2012 Apr 149: 525-37 |
|---|---|
| PMID | 22521361 |
| Title | Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. |
| Abstract | Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g.,CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and�a significant enrichment of polygenic risk alleles from genome-wide association studies of autism andschizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages. |
| SCZ Keywords | schizophrenia |
| 2 | Mol. Psychiatry 2014 Jun 19: 652-8 |
| PMID | 24776741 |
| Title | De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability. |
| Abstract | schizophreniais a serious psychiatric disorder with a broadly undiscovered genetic etiology. Recent studies of de novo mutations (DNMs) inschizophreniaand autism have reinforced the hypothesis that rare genetic variation contributes to risk. We carried out exome sequencing on 57 trios with sporadic or familialschizophrenia. In sporadic trios, we observed a ~3.5-fold increase in the proportion of nonsense DNMs (0.101 vs 0.031, empirical P=0.01, Benjamini-Hochberg-corrected P=0.044). These mutations were significantly more likely to occur in genes with highly ranked probabilities of haploinsufficiency (P=0.0029, corrected P=0.006). DNMs of potential functional consequence were also found to occur in genes predicted to be less tolerant to rare variation (P=2.01 � 10(-)(5), corrected P=2.1 � 10(-)(3)). Genes with DNMs overlapped with genes implicated in autism (for example, AUTS2,CHD8and MECP2) and intellectual disability (for example, HUWE1 and TRAPPC9), supporting a shared genetic etiology between these disorders. FunctionallyCHD8, MECP2 and HUWE1 converge on epigenetic regulation of transcription suggesting that this may be an important risk mechanism. Our results were consistent in an analysis of additional exome-based sequencing studies of other neurodevelopmental disorders. These findings suggest that perturbations in genes, which function in the epigenetic regulation of brain development and cognition, could have a central role in the susceptibility to, pathogenesis and treatment of mental disorders. |
| SCZ Keywords | schizophrenia |
| 3 | Mol Autism 2015 -1 6: 55 |
| PMID | 26491539 |
| Title | CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in neurodevelopment. |
| Abstract | Disruptive mutation in theCHD8gene is one of the top genetic risk factors in autism spectrum disorders (ASDs). Previous analyses of genome-wideCHD8occupancy and reduced expression ofCHD8by shRNA knockdown in committed neural cells showed thatCHD8regulates multiple cell processes critical for neural functions, and its targets are enriched with ASD-associated genes. To further understand the molecular links betweenCHD8functions and ASD, we have applied the CRISPR/Cas9 technology to knockout one copy ofCHD8in induced pluripotent stem cells (iPSCs) to better mimic the loss-of-function status that would exist in the developing human embryo prior to neuronal differentiation. We then carried out transcriptomic and bioinformatic analyses of neural progenitors and neurons derived from theCHD8mutant iPSCs. Transcriptome profiling revealed thatCHD8hemizygosity (CHD8(+/-)) affected the expression of several thousands of genes in neural progenitors and early differentiating neurons. The differentially expressed genes were enriched for functions of neural development, ?-catenin/Wnt signaling, extracellular matrix, and skeletal system development. They also exhibited significant overlap with genes previously associated with autism andschizophrenia, as well as the downstream transcriptional targets of multiple genes implicated in autism. Providing important insight into howCHD8突变可能引起宏cephaly, we found that seven of the twelve genes associated with human brain volume or head size by genome-wide association studies (e.g., HGMA2) were dysregulated inCHD8(+/-) neural progenitors or neurons. We have established a renewable source ofCHD8(+/-) iPSC lines that would be valuable for investigating the molecular and cellular functions ofCHD8. Transcriptomic profiling showed thatCHD8regulates multiple genes implicated in ASD pathogenesis and genes associated with brain volume. |
| SCZ Keywords | schizophrenia |
| 4 | Am. J. Med. Genet. A 2016 May 170: 1225-35 |
| PMID | 26789910 |
| Title | A de novo frameshift mutation in chromodomain helicase DNA-binding domain 8 (CHD8): A case report and literature review. |
| Abstract | Mutations in chromodomain helicase DNA-binding domain 8 (CHD8) have been identified in independent genotyping studies of autism spectrum disorder. To better understand the phenotype associated withCHD8mutations, we genotyped allCHD8exons in carefully assessed cohorts of autism (n?=?142),schizophrenia(SCZ;n = ? 143),和智力残疾(ID;n?=?94). We identified one frameshift mutation, seven non-synonymous variants, and six synonymous variants. The frameshift mutation, p.Asn2092Lysfs*2, which creates a premature stop codon leading to the loss of 212 amino acids of the protein, was from an autism case on whom we present multiple clinical assessments and pharmacological treatments spanning more than 10 years. RNA and protein analysis support a model where the transcript generated from the mutant allele results in haploinsufficiency ofCHD8. This case report supports the association ofCHD8mutations with classical autism, macrocephaly, infantile hypotonia, speech delay, lack of major ID, and psychopathology in late adolescence caused by insufficient dosage ofCHD8. Review of 16 otherCHD8mutation cases suggests that clinical features and their severity vary considerably across individuals; however, these data support aCHD8mutation syndrome, further highlighting the importance of genomic medicine to guide clinical assessment and treatment. � 2016 Wiley Periodicals, Inc. |
| SCZ Keywords | schizophrenia |