Identifying genetic risk variants for nonsyndromic cleft palate only
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB44884 | ENA |
REPOSITORIES: ENA
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Project description:Tamoxifen (TAM), a widely-used drug in treating breast cancer, has been reported to be associated with craniofacial defects including micrognathia and cleft palate in humans. However, the exact effects of TAM on the developing palate remain unclear. In the present study, we conclude that excess TAM exposure causes cleft palate defect in mice by regulating MAPK pathways, which implicates the importance of tightly regulated MAPK signaling in palate development and provides a basis for further exploration of the molecular etiology of cleft palate defects caused by environmental factors.
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Project description:The identification of the genetic risk factors in patients with isolated cleft palate by whole genome sequencing analysis. Pathogenic or likely pathogenic variants were discovered in genes associated with CP (TBX22, COL2A1, FBN1, PCGF2, and KMT2D) in five patients; hence, rare disease variants were identified in 17% of patients with non-syndromic isolated CP. Our results are relevant to routine genetic counselling practice and genetic testing recommendations.
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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.
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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.
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Project description:The Chinese sturgeon (Acipenser sinensis) is anadromous fish distributed in Yangtze River and East China Sea. In this study, we reported cleft-palate Chinese sturgeons in artificial population for the first time. In order to explore the genetic basis of palate malformation in A. sinensis, Illumina RNA-seq technology was used to analyze the transcriptome data of normal and cleft-palate individuals in farmed Chinese sturgeons. Raw reads were obtained and assembled into 808,612 unigenes, with an average length of 509.33 bp and an N50 of 574 bp. Sequence similarity analyses against four public databases (Nr, Uniprot, KEGG and COGs) found 158,642 unigenes that can be annotated. GABAergic synapse and TGF-β signal pathway were the most two enriched pathways with high Richfactor in the analyses of different expressed genes. In these two signal pathways, six genes (GABRA4, GS, GNS, S6K, PITX2, and BMP8) were found as cleft-palate genes in Chinese sturgeon. These findings contribute to our understanding of the genetic basis of cleft palate in sturgeon, while simultaneously adding to our knowledge about craniofacial development.
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Project description: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.
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Project description:The overall goal of this project is to investigate the role of TGF-beta signaling in palate development in order to discover candidate therapeutics for preventing and treating congenital birth defects. Here, we conducted gene expression profiling of embryonic palatal tissue from wild type mice as well as those with a neural crest specific conditional inactivation of the Tgfbr2 gene. The latter mice provide a model of cleft palate formation. To investigate the mechanism of cleft palate resulting from mutations in TGFBR2, we analyzed neural crest specific conditional inactivation of Tgfbr2 in mice (Tgfbr2fl/fl;Wnt1-Cre). We performed microarray analyses using the palatal tissue of Tgfbr2fl/fl;Wnt1-Cre mice at embryonic day E13.5 (prior to palatal fusion, n=6 per genotype) and E14.5 (during palatal fusion, n=5 per genotype) to examine the genes regulated by Tgf-beta during palate formation.
2011-11-29 | E-GEOD-22989 | biostudies-arrayexpress
Project description:Discovering the Genetic Basis of Cleft Palate: CIDR
| PRJNA671433 | ENA