Genetic Analysis of Limb Malformation Disorders: Freeman Sheldon Syndrome Exome Sequencing Study (LMD-FSS)
Ontology highlight
ABSTRACT: The overall goal of this project is to investigate the etiology and pathogenesis of malformations (i.e., birth defects) of the limb, concentrating on abnormalities of limb patterning such as limb deficiency/duplications and multiple congenital contractures. The exome sequences of four unrelated individuals were obtained by massively parallel DNA sequencing. The three individuals were affected with Freeman Sheldon syndrome (OMIM: 193700).
SECONDARY ACCESSION(S): PRJNA74829PRJNA74827
REPOSITORIES: dbGaP
Similar Datasets
Project description:<p>The overall goal of this project is to investigate the etiology and pathogenesis of malformations (i.e., birth defects) of the limb, concentrating on abnormalities of limb patterning such as limb deficiency/duplications and multiple congenital contractures.</p> <p>The exome sequences of four unrelated individuals were obtained by massively parallel DNA sequencing. The three individuals were affected with Freeman Sheldon syndrome (OMIM: <a href="http://www.ncbi.nlm.nih.gov/omim/193700">193700</a>).</p>
| phs000204.v1.p1 | EGA
Project description:<p>The overall goal of this project is to investigate the etiology and pathogenesis of malformations (i.e., birth defects) of the limb, concentrating on abnormalities of limb patterning such as limb deficiency/duplications and multiple congenital contractures.</p> <p>The exome sequences of two siblings and two unrelated individuals were obtained by massively parallel DNA sequencing. The four individuals were affected with Miller syndrome (OMIM: <a href="http://www.ncbi.nlm.nih.gov/omim/263750">263750</a>).</p> <p>Additionally, the whole-genome sequences of a family of four were obtained with the method of Complete Genomics Incorporated (CGI). The two offspring were both affected with Miller syndrome and is the same sibling pair mentioned previously from whom exome sequences were also obtained.</p>
| phs000244 | dbGaP
Project description:<p>The overall goal of this project is to investigate the etiology and pathogenesis of malformations (i.e., birth defects) of the limb, concentrating on abnormalities of limb patterning such as limb deficiency/duplications and multiple congenital contractures.</p> <p>The exome sequences of two siblings and two unrelated individuals were obtained by massively parallel DNA sequencing. The four individuals were affected with Miller syndrome (OMIM: <a href="http://www.ncbi.nlm.nih.gov/omim/263750">263750</a>).</p> <p>Additionally, the whole-genome sequences of a family of four were obtained with the method of Complete Genomics Incorporated (CGI). The two offspring were both affected with Miller syndrome and is the same sibling pair mentioned previously from whom exome sequences were also obtained.</p>
| phs000244.v1.p1 | EGA
Project description:<p>The ultimate purpose of this research is to identify genes causing hereditary disorders. We are scaling a new approach to identify the candidate genes and gene mutations that underlie rare human Mendelian (a set of primary tenets relating to the transmission of hereditary characteristics from parent to child) diseases by using exome (protein coding segments of DNA) resequencing.</p> <p>The exome sequences of ten unrelated individuals with a diagnosis of Kabuki Syndrome (OMIM: <a href="http://www.ncbi.nlm.nih.gov/omim/147920" target="_blank">147920</a>) were obtained by massively parallel DNA sequencing.</p>
| phs000295 | dbGaP
Project description:<p>The ultimate purpose of this research is to identify genes causing hereditary disorders. We are scaling a new approach to identify the candidate genes and gene mutations that underlie rare human Mendelian (a set of primary tenets relating to the transmission of hereditary characteristics from parent to child) diseases by using exome (protein coding segments of DNA) resequencing.</p> <p>The exome sequences of ten unrelated individuals with a diagnosis of Kabuki Syndrome (OMIM: <a href="http://www.ncbi.nlm.nih.gov/omim/147920" target="_blank">147920</a>) were obtained by massively parallel DNA sequencing.</p>
| phs000295.v1.p1 | EGA
Project description:[original title] Identification of recurrent microdeletion on 17q23.2 flanked by segmental duplications associated with heart defects and limb abnormalities. Segmental duplications, are known to mediate non-allelic homologous recombination and have been suggested to be hotspots in chromosome evolution and human genomic instability. We report the identification by microarray-based comparative genomic hybridization (aCGH) of seven individuals with microdeletions of 17q23.1q23.2. The clinical information obtained from six individuals for whom medical records were available showed common features including mild to moderate developmental delay, postnatal growth retardation, eye anomalies, heart defects and hand/foot/limb abnormalities. The presence in the deletion region of TBX2 and TBX4, transcription factors belonging to a family of genes implicated in a variety of developmental pathways including those of heart and limb, suggests that these genes may play an important role in the phenotype of this emerging syndrome.
2010-12-31 | GSE19932 | GEO
Project description:[original title] Identification of recurrent microdeletion on 17q23.2 flanked by segmental duplications associated with heart defects and limb abnormalities. Segmental duplications, are known to mediate non-allelic homologous recombination and have been suggested to be hotspots in chromosome evolution and human genomic instability. We report the identification by microarray-based comparative genomic hybridization (aCGH) of seven individuals with microdeletions of 17q23.1q23.2. The clinical information obtained from six individuals for whom medical records were available showed common features including mild to moderate developmental delay, postnatal growth retardation, eye anomalies, heart defects and hand/foot/limb abnormalities. The presence in the deletion region of TBX2 and TBX4, transcription factors belonging to a family of genes implicated in a variety of developmental pathways including those of heart and limb, suggests that these genes may play an important role in the phenotype of this emerging syndrome. aCGH control vs. patient, total of 7 patients Lowest normalized log2 ratio = patient 1: -1.99; patient 2: -1.87; patient 3: -2.16; patient 4: -2.11; patient 5: -1.974802452; patient 6: -2.23; patient 7: -1.36.
2010-12-31 | E-GEOD-19932 | biostudies-arrayexpress
Project description:Mammalian genomes are organized into megabase-scale topologically associated domains (TADs) that have been proposed to represent large regulatory units. Here we demonstrate that disruption of TADs can cause rewiring of long-range regulatory architecture and result in pathogenic phenotypes. We show that distinct human limb malformations are caused by deletions, inversions, or duplications altering the structure of the TAD-spanning WNT6/IHH/EPHA4/PAX3 locus. Using CRISPR/Cas genome editing, we generated mice with corresponding rearrangements. Both in mouse limb tissue and patient-derived fibroblasts, disease-relevant structural changes cause ectopic interactions between promoters and non-coding DNA, and a cluster of limb enhancers normally associated with Epha4 is misplaced relative to TAD boundaries and drives ectopic limb expression of another gene in the locus. Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome. RNA-seq profile of developing distal limbs of mutants and WT animals at E11.5
2015-05-08 | E-GEOD-66377 | biostudies-arrayexpress
Project description:Mammalian genomes are organized into megabase-scale topologically associated domains (TADs) that have been proposed to represent large regulatory units. Here we demonstrate that disruption of TADs can cause rewiring of long-range regulatory architecture and result in pathogenic phenotypes. We show that distinct human limb malformations are caused by deletions, inversions, or duplications altering the structure of the TAD-spanning WNT6/IHH/EPHA4/PAX3 locus. Using CRISPR/Cas genome editing, we generated mice with corresponding rearrangements. Both in mouse limb tissue and patient-derived fibroblasts, disease-relevant structural changes cause ectopic interactions between promoters and non-coding DNA, and a cluster of limb enhancers normally associated with Epha4 is misplaced relative to TAD boundaries and drives ectopic limb expression of another gene in the locus. Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome. Circular Chromosome Conformation Capture (4C seq) at the WNT6/IHH/EPHA4/PAX3 locus in human adult fibroblasts (HAF) of adult patients and controls
2015-05-08 | E-GEOD-66378 | biostudies-arrayexpress
Project description:Mammalian genomes are organized into megabase-scale topologically associated domains (TADs) that have been proposed to represent large regulatory units. Here we demonstrate that disruption of TADs can cause rewiring of long-range regulatory architecture and result in pathogenic phenotypes. We show that distinct human limb malformations are caused by deletions, inversions, or duplications altering the structure of the TAD-spanning WNT6/IHH/EPHA4/PAX3 locus. Using CRISPR/Cas genome editing, we generated mice with corresponding rearrangements. Both in mouse limb tissue and patient-derived fibroblasts, disease-relevant structural changes cause ectopic interactions between promoters and non-coding DNA, and a cluster of limb enhancers normally associated with Epha4 is misplaced relative to TAD boundaries and drives ectopic limb expression of another gene in the locus. Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome. Circular Chromosome Conformation Capture (4C seq) at the Wnt6/Ihh/Epha4/Pax3 locus in developing distal limbs of mutants and WT animals at E11.5
2015-05-08 | E-GEOD-66379 | biostudies-arrayexpress