ACGH assay in a Chinese family with syndactyly type 1-c
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE55181 | GEO | 2014/06/01
SECONDARY ACCESSION(S): PRJNA238834
REPOSITORIES: GEO
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Project description:Syndactyly type 1 (SD1) is an autosomal dominant limb malformation characterized in its classical form by complete or partial webbing between the third and fourth fingers and/or the second and third toes. Four subtypes (a, b, c and d) are defined based on variable phenotypes, but the disease genes remain unidentified. SD1-a have been mapped to chromosome 3p21.31 and SD1-b to 2q34-q36. SD1-c and SD1-d are very rare and no gene loci are known for them. We performed linkage and haplotype analyses in two Han Chinese families with SD1-c, and refined the disease locus to 2q31- 2q32. In the large family A, mutation of c.917G>A (p.R306Q) in the homodomain of HOXD13 was indentified. Family B was confirmed with genetic homogeneity and the mutation was c.916C>G (p.R306G). CNV analysis by array CGH excluded possible microdeletion or microduplication. SD1c patient sample in the SD1c family vs common control outside the family, healthy control sample in the SD1c family vs common control outside the family
2014-06-01 | E-GEOD-55181 | biostudies-arrayexpress
Project description:Some human families display severe shortening and bending of the radius and ulna, a condition referred to as mesomelic dysplasia. Many of these families contain chromosomal rearrangements at 2q31, where the human HOXD locus maps. In mice, the dominant X-ray-induced Ulnaless inversion of the HoxD gene cluster produces a similar phenotype suggesting that the same pathological mechanism is at work in humans and mice. A tentative hypothesis was proposed where the various alterations to the genomic structure of HOXD could translocate Hoxd13 near to proximal limb enhancers, leading to its deleterious gain-of-expression in the embryonic forelimb. We evaluated this hypothesis by engineering a ca. 1Mb large inversion including the HoxD gene cluster, in order to position Hoxd13 within a chromatin domain rich in proximal limb enhancers. We show that these enhancers contact and activate Hoxd13 in proximal cells, concomitant to the formation of a mesomelic dysplasia phenotype. A secondary mutation in the coding frame of the HOXD13 protein in-cis with the inversion completely rescued the limb alterations, demonstrating that ectopic HOXD13 is indeed the unique cause of this bone anomaly. Single cell expression analysis and evaluation of HOXD13 binding sites in cells from this ectopic expression domain suggests that the phenotype arises primarily by acting through genes normally controlled by HOXD13 in distal limb cells. Altogether, these results provide a conceptual and mechanistic framework to understand and unify the molecular origins of human mesomelic dysplasia associated with 2q31.
2021-07-20 | GSE165490 | GEO
Project description:Some human families display severe shortening and bending of the radius and ulna, a condition referred to as mesomelic dysplasia. Many of these families contain chromosomal rearrangements at 2q31, where the human HOXD locus maps. In mice, the dominant X-ray-induced Ulnaless inversion of the HoxD gene cluster produces a similar phenotype suggesting that the same pathological mechanism is at work in humans and mice. A tentative hypothesis was proposed where the various alterations to the genomic structure of HOXD could translocate Hoxd13 near to proximal limb enhancers, leading to its deleterious gain-of-expression in the embryonic forelimb. We evaluated this hypothesis by engineering a ca. 1Mb large inversion including the HoxD gene cluster, in order to position Hoxd13 within a chromatin domain rich in proximal limb enhancers. We show that these enhancers contact and activate Hoxd13 in proximal cells, concomitant to the formation of a mesomelic dysplasia phenotype. A secondary mutation in the coding frame of the HOXD13 protein in-cis with the inversion completely rescued the limb alterations, demonstrating that ectopic HOXD13 is indeed the unique cause of this bone anomaly. Single cell expression analysis and evaluation of HOXD13 binding sites in cells from this ectopic expression domain suggests that the phenotype arises primarily by acting through genes normally controlled by HOXD13 in distal limb cells. Altogether, these results provide a conceptual and mechanistic framework to understand and unify the molecular origins of human mesomelic dysplasia associated with 2q31.
2021-07-20 | GSE165761 | GEO
Project description:Some human families display severe shortening and bending of the radius and ulna, a condition referred to as mesomelic dysplasia. Many of these families contain chromosomal rearrangements at 2q31, where the human HOXD locus maps. In mice, the dominant X-ray-induced Ulnaless inversion of the HoxD gene cluster produces a similar phenotype suggesting that the same pathological mechanism is at work in humans and mice. A tentative hypothesis was proposed where the various alterations to the genomic structure of HOXD could translocate Hoxd13 near to proximal limb enhancers, leading to its deleterious gain-of-expression in the embryonic forelimb. We evaluated this hypothesis by engineering a ca. 1Mb large inversion including the HoxD gene cluster, in order to position Hoxd13 within a chromatin domain rich in proximal limb enhancers. We show that these enhancers contact and activate Hoxd13 in proximal cells, concomitant to the formation of a mesomelic dysplasia phenotype. A secondary mutation in the coding frame of the HOXD13 protein in-cis with the inversion completely rescued the limb alterations, demonstrating that ectopic HOXD13 is indeed the unique cause of this bone anomaly. Single cell expression analysis and evaluation of HOXD13 binding sites in cells from this ectopic expression domain suggests that the phenotype arises primarily by acting through genes normally controlled by HOXD13 in distal limb cells. Altogether, these results provide a conceptual and mechanistic framework to understand and unify the molecular origins of human mesomelic dysplasia associated with 2q31.
2021-07-20 | GSE165494 | GEO
Project description:Some human families display severe shortening and bending of the radius and ulna, a condition referred to as mesomelic dysplasia. Many of these families contain chromosomal rearrangements at 2q31, where the human HOXD locus maps. In mice, the dominant X-ray-induced Ulnaless inversion of the HoxD gene cluster produces a similar phenotype suggesting that the same pathological mechanism is at work in humans and mice. A tentative hypothesis was proposed where the various alterations to the genomic structure of HOXD could translocate Hoxd13 near to proximal limb enhancers, leading to its deleterious gain-of-expression in the embryonic forelimb. We evaluated this hypothesis by engineering a ca. 1Mb large inversion including the HoxD gene cluster, in order to position Hoxd13 within a chromatin domain rich in proximal limb enhancers. We show that these enhancers contact and activate Hoxd13 in proximal cells, concomitant to the formation of a mesomelic dysplasia phenotype. A secondary mutation in the coding frame of the HOXD13 protein in-cis with the inversion completely rescued the limb alterations, demonstrating that ectopic HOXD13 is indeed the unique cause of this bone anomaly. Single cell expression analysis and evaluation of HOXD13 binding sites in cells from this ectopic expression domain suggests that the phenotype arises primarily by acting through genes normally controlled by HOXD13 in distal limb cells. Altogether, these results provide a conceptual and mechanistic framework to understand and unify the molecular origins of human mesomelic dysplasia associated with 2q31.
2021-07-20 | GSE165491 | GEO
Project description:Some human families display severe shortening and bending of the radius and ulna, a condition referred to as mesomelic dysplasia. Many of these families contain chromosomal rearrangements at 2q31, where the human HOXD locus maps. In mice, the dominant X-ray-induced Ulnaless inversion of the HoxD gene cluster produces a similar phenotype suggesting that the same pathological mechanism is at work in humans and mice. A tentative hypothesis was proposed where the various alterations to the genomic structure of HOXD could translocate Hoxd13 near to proximal limb enhancers, leading to its deleterious gain-of-expression in the embryonic forelimb. We evaluated this hypothesis by engineering a ca. 1Mb large inversion including the HoxD gene cluster, in order to position Hoxd13 within a chromatin domain rich in proximal limb enhancers. We show that these enhancers contact and activate Hoxd13 in proximal cells, concomitant to the formation of a mesomelic dysplasia phenotype. A secondary mutation in the coding frame of the HOXD13 protein in-cis with the inversion completely rescued the limb alterations, demonstrating that ectopic HOXD13 is indeed the unique cause of this bone anomaly. Single cell expression analysis and evaluation of HOXD13 binding sites in cells from this ectopic expression domain suggests that the phenotype arises primarily by acting through genes normally controlled by HOXD13 in distal limb cells. Altogether, these results provide a conceptual and mechanistic framework to understand and unify the molecular origins of human mesomelic dysplasia associated with 2q31.
2021-07-20 | GSE165492 | GEO
Project description:Df16(A)+/- mice line is a model of human 22q11 microdeletion syndrome. We conducted an unbiased evaluation of the transcriptional difference in the prefrontal cortex and hippocampus areas between mutant and wild type animals at two early developmental stages (embryonic day 17 and postnatal day 6). These mice were generated by chromosomal engineering and carry a microdeltion of ~1.3Mb in the mouse locus syntenic to the human 22q11.1 The reasoning behind this expression profiling is that consistent alterations in transcriptional programs reflect either downstream (immediate or remote) effects of the deficiency or reactive (compensatory) changes, and can thus point to affected biological processes and molecular functions. Df(16)A+/- mice line is a model of human 22q11 microdeletion syndrome and Dp(16)B mice line is a model of human 22q11 microduplication. We conducted an unbiased evaluation of the transcriptional difference in the prefrontal cortex and hippocampus areas between the mice with microdeletion, microduplication and heterogygous balanced normal copy number of the mouse syntenic locus. Mutant mice and their wild type littermate from two development stages (embryonic day 17 and postnatal day 6) were selected. Hipocampal and prefrontal cortex tissues were dissected, total RNA were extracted, processed and hybridized on Affymetrix microarrays. We sought to obtain temporal gene expression difference of expression profiles between mutant and wild mice. Adult male mice of microdeletion, microduplication were used and mice with heterozygous balanced copy number as reference. Hipocampal and prefrontal cortex tissues were dissected, total RNA were extracted, processed and hybridized on Affymetrix microarrays. we attempted to distinguish primary versus secondary gene targets of the 22q11.2 microdeletion by looking for genes whose expression changes in negative correlation as a result of genomic losses or gains in this locus.
2013-01-17 | E-GEOD-29767 | biostudies-arrayexpress
Project description:Df16(A)+/- mice line is a model of human 22q11 microdeletion syndrome. We conducted an unbiased evaluation of the transcriptional difference in the prefrontal cortex and hippocampus areas between mutant and wild type animals at two early developmental stages (embryonic day 17 and postnatal day 6). These mice were generated by chromosomal engineering and carry a microdeltion of ~1.3Mb in the mouse locus syntenic to the human 22q11.1 The reasoning behind this expression profiling is that consistent alterations in transcriptional programs reflect either downstream (immediate or remote) effects of the deficiency or reactive (compensatory) changes, and can thus point to affected biological processes and molecular functions. Df(16)A+/- mice line is a model of human 22q11 microdeletion syndrome and Dp(16)B mice line is a model of human 22q11 microduplication. We conducted an unbiased evaluation of the transcriptional difference in the prefrontal cortex and hippocampus areas between the mice with microdeletion, microduplication and heterogygous balanced normal copy number of the mouse syntenic locus.
2013-01-17 | GSE29767 | GEO
Project description:We designed a microarray to test at exonic resolution for genomic imbalance for genes representative of all known chromosomal microdeletion/microduplication syndromes, all known causative genes for ID, all known genes encoding glutamate receptors and their known encoding proteins and all known genes encoding proteins with epigenetic regulatory function. We found 36 de novo copy number variants affecting 35 children in this study.
2012-07-24 | GSE39533 | GEO
Project description:With the advancement of molecular technology, fetal talipes equinovarus (TE) is believed to be not only associated with chromosome aneuploidy, but also related to chromosomal microdeletion and microduplication. The study aimed to explore the molecular etiology of fetal TE and provide more information for the clinical screening and genetic counseling of TE by CMA.This retrospectively study included 131 fetuses with TE identified by ultrasonography. Conventional karyotyping and SNP array analysis were performed for all the subjects. They were divided into isolated TE group (n=55) and complex group (n=76) according to structural anomalies.Among the total of 131 fetuses, karyotype analysis found 12(9.2%) abnormal results, while SNP array found 27 (20.6%) cases. Trisomy 18 was detected most frequently among abnormal karyotypes. The detection rate of SNP array was significantly higher than that of traditional chromosome karyotype analysis.SNP array detected 15 (11.5%) cases of submicroscopic abnormalities that karyotype analysis did not find. The most common CNV was the 22q11.2 microdeletion. For both analyses, the overall detection rates were significantly higher in the complex TE group than in the isolated TE group. The incremental yield of chromosomal abnormalities in fetuses with unilateral TE (22.0%) was higher than in fetuses with bilateral TE (19.8%), but this difference was not statistically significant.Abnormal chromosomes were most frequently detected in fetuses with TE plus cardiovascular system abnormalities.Fetal TE is related to chromosomal microdeletion or microduplication. Prenatal diagnosis is recommended for fetuses with TE, and CMA testing is preferred. CMA can improve the detection rate of chromosomal abnormalities associated with fetal TE, especially in pregnancies with complex TE.
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