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Oligodendrocyte precursor cells (OPCs) constitute the main proliferative cells in the adult brain, and deregulation of OPC proliferation-differentiation balance results in either glioma formation or defective adaptive (re)myelination. OPC differentiation requires significant genetic reprogramming, implicating chromatin remodeling. Mounting evidence indicates that chromatin remodelers play important roles during normal development and their mutations are associated with neurodevelopmental defects, with CHD7 haploinsuficiency being the cause of CHARGE syndrome and CHD8 being one of the strongest autism spectrum disorder (ASD) high-risk–associated genes. Herein, we report on uncharacterized functions of the chromatin remodelers Chd7 and Chd8 in OPCs. Their OPC-chromatin binding profile, combined with transcriptome and chromatin accessibility analyses of Chd7-deleted OPCs, demonstrates that Chd7 protects nonproliferative OPCs from apoptosis by chromatin closing and transcriptional repression of p53. Furthermore, Chd7 controls OPC differentiation through chromatin opening and transcriptional activation of key regulators, including Sox10, Nkx2.2, and Gpr17. However, Chd7 is dispensable for oligodendrocyte stage progression, consistent with Chd8 compensatory function, as suggested by their common chromatin-binding profiles and genetic interaction. Finally, CHD7 and CHD8 bind in OPCs to a majority of ASD risk-associated genes, suggesting an implication of oligodendrocyte lineage cells in ASD neurological defects. Our results thus offer new avenues to understand and modulate the CHD7 and CHD8 functions in normal development and disease.

Regulation of chromatin plays fundamental roles in the development of the brain. Haploinsufficiency of the chromatin remodeling enzyme CHD7 causes CHARGE syndrome, a genetic disorder that affects the development of the cerebellum. However, how CHD7 controls chromatin states in the cerebellum remains incompletely understood. Using conditional knockout of CHD7 in granule cell precursors in the mouse cerebellum, we find that CHD7 robustly promotes chromatin accessibility, active histone modifications, and RNA polymerase recruitment at enhancers. In vivo profiling of genome architecture reveals that CHD7 concordantly regulates epigenomic modifications associated with enhancer activation and gene expression of topologically-interacting genes. Genome and gene ontology studies show that CHD7-regulated enhancers are associated with genes that control brain tissue morphogenesis. Accordingly, conditional knockout of CHD7 triggers a striking phenotype of cerebellar polymicrogyria, which we have also found in a case of CHARGE syndrome. Finally, we uncover a CHD7-dependent switch in the preferred orientation of granule cell precursor division in the developing cerebellum, providing a potential cellular basis for the cerebellar polymicrogyria phenotype upon loss of CHD7. Collectively, our findings define epigenomic regulation by CHD7 in granule cell precursors and identify abnormal cerebellar patterning upon CHD7 depletion, with potential implications for our understanding of CHARGE syndrome. CHARGE syndrome that affects cerebellar development can be caused by haploinsufficiency of the chromatin remodeling enzyme CHD7; however the precise role of CHD7 remains unknown. Here the authors show CHD7 promotes chromatin accessibility and enhancer activity in granule cell precursors and regulates morphogenesis of the cerebellar cortex, where loss of CHD7 triggers cerebellar polymicrogyria.

Inappropriate activation of the tumour-suppressor protein p53 during development can promote phenotypes similar to those of CHARGE syndrome, suggesting that p53 activation not only has a beneficial function in suppressing cancer but also a deleterious function in promoting developmental syndromes. CHARGE syndrome promoted by activated p53 The complex congenital disorder known as CHARGE syndrome results in many phenotypes, including heart defects, retarded growth and development, genital hypoplasia and ear abnormalities. Most CHARGE syndrome patients have mutations in the gene for the chromatin remodeller protein CHD7, but in mouse the Chd7 mutation is embryonically lethal, and not all CHARGE syndrome phenotypes are evident. Laura Attardi and colleagues now demonstrate that inappropriate activation of the p53 tumour suppressor gene during development can promote CHARGE phenotypes in mice, including ocular coloboma and defects of both the outer and inner ear, which are typical of CHARGE syndrome and rare in other conditions. The findings that p53 mutations can drive both cancer and developmental diseases throws a new light on the function of p53 in vivo . CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and ear abnormalities 1 . Despite 70–90% of CHARGE syndrome cases resulting from mutations in the gene CHD7 , which encodes an ATP-dependent chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood 2 . Surprisingly, our studies of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor protein p53 (p53 25,26,53,54 ) 3 , along with a wild-type allele of p53 (also known as Trp53 ), revealed late-gestational embryonic lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer ear malformations, heart outflow tract defects and craniofacial defects. We found that the p53 25,26,53,54 mutant protein stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, as p53 25,26,53,54 /− embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7 -null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome.

Purpose Congenital hypogonadotropic hypogonadism (CHH), a rare genetic disease caused by gonadotropin-releasing hormone deficiency, can also be part of complex syndromes (e.g., CHARGE syndrome). CHD7 mutations were reported in 60% of patients with CHARGE syndrome, and in 6% of CHH patients. However, the definition of CHD7 mutations was variable, and the associated CHARGE signs in CHH were not systematically examined. Methods Rare sequencing variants (RSVs) in CHD7 were identified through exome sequencing in 116 CHH probands, and were interpreted according to American College of Medical Genetics and Genomics guidelines. Detailed phenotyping was performed in CHH probands who were positive for CHD7 RSVs, and genotype–phenotype correlations were evaluated. Results Of the CHH probands, 16% (18/116) were found to harbor heterozygous CHD7 RSVs, and detailed phenotyping was performed in 17 of them. Of CHH patients with pathogenic or likely pathogenic CHD7 variants, 80% (4/5) were found to exhibit multiple CHARGE features, and 3 of these patients were reclassified as having CHARGE syndrome. In contrast, only 8% (1/12) of CHH patients with nonpathogenic CHD7 variants exhibited multiple CHARGE features ( P  = 0.01). Conclusion Pathogenic or likely pathogenic CHD7 variants rarely cause isolated CHH. Therefore a detailed clinical investigation is indicated to clarify the diagnosis (CHH versus CHARGE) and to optimize clinical management.

Epigenetic mechanisms play an important role in gene regulation during development. DNA methylation, which is probably the most important and best-studied epigenetic mechanism, can be abnormally regulated in common pathologies, but the origin of altered DNA methylation remains unknown. Recent research suggests that these epigenetic alterations could depend, at least in part, on genetic mutations or polymorphisms in DNA methyltransferases and certain genes encoding enzymes of the one-carbon metabolism pathway. Indeed, the de novo methyltransferase 3B (DNMT3B) has been recently found to be mutated in several types of cancer and in the immunodeficiency, centromeric region instability and facial anomalies syndrome (ICF), in which these mutations could be related to the loss of global DNA methylation. In addition, mutations in glycine- N -methyltransferase (GNMT) could be associated with a higher risk of hepatocellular carcinoma and liver disease due to an unbalanced S -adenosylmethionine (SAM)/ S -adenosylhomocysteine (SAH) ratio, which leads to aberrant methylation reactions. Also, genetic variants of chromatin remodeling proteins and histone tail modifiers are involved in genetic disorders like α thalassemia X-linked mental retardation syndrome, CHARGE syndrome, Cockayne syndrome, Rett syndrome, systemic lupus erythematous, Rubinstein–Taybi syndrome, Coffin–Lowry syndrome, Sotos syndrome, and facioescapulohumeral syndrome, among others. Here, we review the potential genetic alterations with a possible role on epigenetic factors and discuss their contribution to human disease.

Inactivating mutations in chromodomain helicase DNA binding protein 7 ( CHD7 ) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2% of the IGD cohort (73% missense and 27% splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75% of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings ( i ) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, ( ii ) reiterate the emerging genetic complexity of this family of IGD disorders, and ( iii ) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems. Significance Inactivating mutations in the chromodomain helicase DNA binding protein 7 ( CHD7 ) gene causes a severe developmental disorder known as CHARGE syndrome. Recently, several missense mutations in CHD7 have been reported in isolated gonadotropin-releasing hormone (GnRH) -deficiency (IGD) patients who lack full CHARGE features. However, the precise functional consequence of these IGD-associated missense mutations on the activity of CHD7 protein is not known. This study confirms the predominance of missense CHD7 alleles in 5% of IGD patients and provides, to our knowledge, first experimental evidence that functionally compromised CHD7 missense alleles contribute to the pathogenesis of both the anosmic and normosmic forms of IGD. These results imply a preferential sensitivity for CHD7 dysfunction in the developmental ontogeny as well as neuroendocrine regulation of GnRH neurons in humans.

Purpose CHARGE syndrome is an autosomal-dominant, multiple congenital anomaly condition characterized by vision and hearing loss, congenital heart disease, and malformations of craniofacial and other structures. Pathogenic variants in CHD7 , encoding adenosine triphosphate–dependent chromodomain helicase D NA binding protein 7, are present in the majority of affected individuals. However, no causal variant can be found in 5–30% (depending on the cohort) of individuals with a clinical diagnosis of CHARGE syndrome. Methods We performed whole-exome sequencing (WES) on 28 families from which at least one individual presented with features highly suggestive of CHARGE syndrome. Results Pathogenic variants in CHD7 were present in 15 of 28 individuals (53.6%), whereas 4 (14.3%) individuals had pathogenic variants in other genes ( RERE , KMT2D , EP300 , or PUF60) . A variant of uncertain clinical significance in KDM6A was identified in one (3.5%) individual. The remaining eight (28.6%) individuals were not found to have pathogenic variants by WES. Conclusion These results demonstrate that the phenotypic features of CHARGE syndrome overlap with multiple other rare single-gene syndromes. Additionally, they implicate a shared molecular pathology that disrupts epigenetic regulation of multiple-organ development.

CHD7 encodes an ATP-dependent chromatin remodeling factor. Mutation of this gene causes multiple developmental disorders, including CHARGE (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth/development, Genital abnormalities, and Ear anomalies) syndrome, in which conotruncal anomalies are the most prevalent form of heart defects. How CHD7 regulates conotruncal development remains unclear. In this study,we establish that deletion of Chd7 in neural crest cells (NCCs) causes severe conotruncal defects and perinatal lethality, thus providing mouse genetic evidence demonstrating that CHD7 cell-autonomously regulates cardiac NCC development, thereby clarifying a long-standing controversy in the literature. Using transcriptomic analyses, we show that CHD7 finetunes the expression of a gene network that is critical for cardiac NCC development. To gain further molecular insights into gene regulation by CHD7, we performed a protein–protein interaction screen by incubating recombinant CHD7 on a protein array. We find that CHD7 directly interacts with several developmental disorder-mutated proteins including WDR5, a core component of H3K4 methyltransferase complexes. This direct interaction suggested that CHD7 may recruit histone-modifying enzymes to target loci independently of its remodeling functions. We therefore generated a mouse model that harbors an ATPase-deficient allele and demonstrates that mutant CHD7 retains the ability to recruit H3K4 methyltransferase activity to its targets. Thus, our data uncover that CHD7 regulates cardiovascular development through ATP-dependent and -independent activities, shedding light on the etiology of CHD7-related congenital disorders. Importantly, our data also imply that patients carrying a premature stop codon versus missense mutations will likely display different molecular alterations; these patients might therefore require personalized therapeutic interventions.

Translocation of chromosomes can result in disruption of genes. In this case report, a sequencing approach was used to identify the cause and effect of a translocation within 13 days, a period consistent with use of the approach in prenatal diagnosis. Deep sequencing of the whole genome holds diagnostic promise but is currently thought to be impractical for routine prenatal care. In contrast, large-insert mate-pair, or jumping-library, sequencing provides a tractable approach for immediate clinical application and could complement conventional prenatal diagnostics. The risk of major structural birth defects among live births in the United States is approximately 3% 1 and is associated with inherited or de novo genetic rearrangements and mutations as well as with maternal factors, such as advanced age, certain clinical conditions, and exposure to teratogenic factors. Approximately 1 in 2000 prenatal cases analyzed with conventional karyotyping has a . . .

The clinical features of neurocristopathy-related hearing loss, and the correlation between these features and patient improvements after cochlear implantation (CI) are unknown. This study enrolled 16 children with sensorineural hearing loss due to four types of neurocristopathies, Waardenburg syndrome (WS), Noonan syndrome (NS), Kabuki syndrome (KS), and CHARGE syndrome (CS), who underwent CI. Neurodevelopmental assessment was conducted using the Gesell Developmental Schedules, ear development was evaluated using temporal bone computed tomography, and the post-CI auditory nerve response was assessed via neural response telemetry. Auditory performance was evaluated using the categories of the auditory performance scale. Genetic features were examined using whole-exome sequencing. WS/NS Groups achieved excellent auditory-speech outcomes (CAP_3 year/SIR_3 year: WS 7.3/4.0 n  = 3, NS 8.0/4.0 n  = 1), using Categories of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR), with minimal impact from SOX10 (WS) or PTPN11 (NS) mutations on neurodevelopment. CS Group showed poor recovery (CAP_3 year/SIR_3 year: 3.3/1.8 n  = 3) due to CHD7-related cochlear nerve dysplasia and central auditory deficits, Gesell_mean showed a significant positive correlation with CAP_1 year (ρ = 0.83 n  = 6 p  = 0.042), CAP_3 year was significantly correlated with both implantation CI_age_mon and Gesell_mean independently (ρ = 1.0, n  = 3, p  < 0.001). Non-CS Groups(WS/NS/KS)showed older CI_age_mon predicted higher 1-year SIR (ρ = 0.77 n  = 10 p  = 0.009), while structural abnormalities (abnormal_sum) trended toward worse 3-year SIR (ρ=-0.79 n  = 5). The integration of genetic, ear structure, and neurodevelopmental assessments can assist in clinical decision making for CI.