Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CNV analysis of 140 Filipinos with Cleft Lip and/or Palate

ABSTRACT: Orofacial clefts are one of the most common birth defects, affecting 1-2 per 1000 births, and have a complex etiology. High-resolution array-based comparative genomic hybridization has increased the ability to detect copy number variants that can be causative for complex diseases such as cleft lip and/or palate. Utilizing this technique on 97 non-syndromic cleft lip and palate cases and 43 cases with cleft palate only, we identified a heterozygous deletion of Isthmin 1 in one affected case, as well as a deletion in a second case which removes putative 3' regulatory information. Isthmin 1 is a strong candidate for clefting as it is expressed in orofacial structures derived from the first branchial arch and is also in the same synexpression group as fibroblast growth factor 8 and sprouty RTK signaling antagonist 1a and 2, all of which have been associated with clefting. Copy number variants affecting Isthmin 1 are exceedingly rare in control populations, and Isthmin 1 scores as a likely haploinsufficiency locus. Confirming its role in craniofacial development, knockdown or CRISPR/Cas9-generated mutation of isthmin 1 in Xenopus laevis resulted in mild to severe craniofacial dysmorphologies, with several individuals presenting with median clefts. Moreover, knockdown of isthmin 1 produced decreased expression of LIM homeobox 8, itself a gene associated with clefting, in regions of the face that pattern the maxilla. Our study demonstrates a successful pipeline from copy number variant identification of a candidate gene to functional validation in a vertebrate model system and reveals Isthmin 1 as both a new human clefting locus as well as a key craniofacial patterning gene.

ORGANISM(S): Homo sapiens

PROVIDER: GSE100845 | GEO | 2018/01/17

SECONDARY ACCESSION(S): PRJNA393297

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

CNV analysis of 233 individuals of European ancestry and 6 individuals of non-European ancestry with cleft lip and/or cleft palate

Project description:Cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex, heterogeneous etiology. It is well-established that both common and rare sequence variants contribute to the formation of CL/P, however, the contribution of copy number variants (CNVs) to cleft formation remains relatively understudied. To fill this knowledge gap, we conducted a large-scale comparative analysis of genome-wide CNV profiles of 869 individuals from the Philippines and 233 individuals of European ancestry with CL/P with three primary goals: first, to evaluate whether differences in CNV number, amount of genomic content, or amount of coding genomic content existed within clefting subtypes; second, to assess whether CNVs in our cohort overlapped with known Mendelian clefting loci; and third, to identify unestablished Mendelian clefting genes. Significant differences in CNVs across cleft types or in individuals with non-syndromic versus syndromic clefts were not observed, however, several CNVs in our cohort overlapped with known syndromic and non-syndromic Mendelian clefting loci. Moreover, employing a filtering strategy relying on population genetics data that rare variants are on the whole more deleterious than common variants, we identify several CNV-associated gene losses likely driving non-syndromic clefting phenotypes. By prioritizing genes deleted at a rare frequency across multiple individuals with clefts yet enriched in our case cohort compared to controls, we identify COBLL1, RIC1, and ARHGEF38 as clefting genes. CRISPR/Cas9 mutagenesis of these genes in Xenopus laevis and Danio rerio yielded craniofacial dysmorphologies, including clefts analogous to those seen in human clefting disorders.

2022-12-01 | GSE212165 | GEO

CNV analysis of 869 individuals from the Philippines with cleft lip and/or cleft palate

2022-12-01 | GSE212166 | GEO

Transcription profiling of skin from interferon regulatory factor 6 (Irf6) knockout mice and wild type mice to study the role for Irf6 in epidermal development.

Project description:Transcription factor paralogs may share a common role (e.g. Hox) in staged or overlapping expression in specific tissues. In other examples, members have distinct roles in a range of embryologic, differentiation or response pathways (e.g. Tbx, Pax). For the Interferon Regulatory Factor (IRF) family of transcription factors, mice deficient in Irf1, Irf2, Irf3, Irf4, Irf5, Irf7, Irf8 or Irf9, have defects in the immune response but display no embryologic abnormalities. Mice deficient for Irf6 have not been reported, but in humans, mutations in IRF6 cause two Mendelian orofacial clefting syndrome, and genetic variation in IRF6 confers risk for isolated cleft lip and palate. Mice deficient for Irf6 have abnormal skin, limb and craniofacial development. Histological and gene expression analyses indicate that the primary defect is in keratinocyte differentiation and proliferation. This study describes a novel role for an IRF family member in epidermal development. Experiment Overall Design: Skin from E17.5 mice was removed and flash frozen for RNA extraction and hybridization on Affymetrix microarrays.

2007-11-13 | E-GEOD-5800 | biostudies-arrayexpress

Expression data from mouse IRF6 null and wt skin

2006-10-01 | GSE5800 | GEO

Disruption of DNA methylation-mediated cranial neural crest proliferation and differentiation causes orofacial clefts in mice

Project description:Orofacial clefts of the lip and palate are widely recognized to result from complex gene–environment interactions, but inadequate understanding of environmental risk factors has stymied development of prevention strategies. We interrogated the role of DNA methylation, an environmentally malleable epigenetic mechanism, in orofacial development. Expression of the key DNA methyltransferase enzyme DNMT1 was detected throughout palate morphogenesis in the epithelium and underlying cranial neural crest cell (cNCC) mesenchyme, a highly proliferative multipotent stem cell population that forms orofacial connective tissue. Genetic and pharmacologic manipulations of DNMT activity were then applied to define the tissue- and timing-dependent requirement of DNA methylation in orofacial development. cNCC-specific Dnmt1 inactivation targeting initial palate outgrowth resulted in OFCs, while later targeting during palatal shelf elevation and elongation did not. Conditional Dnmt1 deletion reduced cNCC proliferation and subsequent differentiation trajectory, resulting in attenuated outgrowth of the palatal shelves and altered development of cNCC-derived skeletal elements. Finally, we found that the cellular mechanisms of cleft pathogenesis observed in vivo can be recapitulated by pharmacologically reducing DNA methylation in multipotent cNCCs cultured in vitro. These findings demonstrate that DNA methylation is a crucial epigenetic regulator of cNCC biology, define a critical period of development in which its disruption directly causes OFCs, and provide opportunities to identify environmental influences that contribute to OFC risk.

2023-12-20 | GSE250370 | GEO

Microarray analysis of palatal shelves from wild-type versus p63-null mouse embryos

Project description:Mutations in the transcription factor p63 underlie of a series of human malformation syndromes which are defined by a combination of epidermal, limb and craniofacial abnormalities including cleft lip and palate. Transcription profiling was performed to determine the role of p63 in vivo mouse palatal shelves. Microarray analysis was done of palatal shelves dissected from E14.0 wild-type versus p63-null mouse embryos.

2017-06-12 | E-MTAB-3145 | biostudies-arrayexpress

Genome wide identification of p63 binding sites in human neonatal foreskin keratinocytes

Project description:We report here genome wide identification of p63 binding sites in cycling neonatal foreskin keratinocytes using high throughput sequencing of ChIP enriched DNA. Analysis of gene ontology, database mining with integration with publicly available data, reveals a role for p63 in transcriptional regulation of multiple genes genetically linked to cleft palate. In addition, we identify AP-2Î±, a transcription factor which, when mutated, also results in craniofacial clefting syndrome, as a co-regulator of p63 responsive genes. Examination of p63 binding sites in neonatal foreskin keratinocytes

2012-06-07 | E-GEOD-32061 | biostudies-arrayexpress

Transcription profiling by RNA-Seq mouse embryos

Project description:Mutations in the transcription factor p63 underlie of a series of human malformation syndromes which are defined by a combination of epidermal, limb and craniofacial abnormalities including cleft lip and palate. Transcription profiling was performed to determine the role of p63 in vivo mouse palatal shelves. RNA-seq analysis was done of palatal shelves dissected from E10.5, E11.5, E12.5, E13.5 and E14.5 mouse embryos.

2017-06-12 | E-MTAB-3157 | biostudies-arrayexpress

Embryonic transcriptome analysis of wt vs irf6-/- zebrafish at 4hpf

Project description:We report transcriptional profiles of 4hpf zebrafish embryos from either wild-type or a CRISPR-targeted irf6 loss-of-function mutant. Irf6 is a transcription factor implicated in syndromic and nonsyndromic forms of cleft palate. To define critical genes involved in palate development, we harvested RNA from irf6-/- embryos before an embryonic lethal stage in zebrafish and carried out RNA-sequencing and subsequent analysis. We identify top differentially expressed genes that include genes involved in periderm development, genes expressed in developmental processes (such as Fgfs and Wnt-pathway genes), and genes involved in orofacial clefting. We identify a crucial gene esrp1 that we chose for further validation and downstream analysis.

2020-12-10 | GSE153828 | GEO

NSCLP-Twins

Project description:this study analyzes the WGBS of twins discordant for non syndromic cleft lip and palate

2021-04-24 | GSE173211 | GEO