Blepharospasm in a Multiplex African-American Pedigree
Ontology highlight
ABSTRACT: Blepharospasm (BSP) is a late-onset focal dystonia characterized by involuntary contractions of the orbicularis oculi muscles. Genetics plays an important role on the pathogenesis of BSP, especially in hereditary BSP families. In this project, a large African-American pedigree with BSP was phenotypically characterized and its relationship with known common dystonia genes was investigated with Sanger sequencing on dystonia genes such as THAP1, TOR1A and GNAL. And whole-exome sequencing (EXOME) of the proband was performed to identify all other dystonia-associated genes for potentially pathogenic SVs. A novel THAP1 SV (c.314T>C, p.L105S) was identified in the family, however, this SV did not co-segregate with blepharospasm in the pedigree. No pathogenic or likely pathogenic SVs in other dystonia-associated genes were identified with whole-exome sequencing. The current study makes available phenotype data and summary genotype data of n=12 family members (mutation absent/heterozygous for THAP1); whole exome sequencing data of one (het) subject are available through public SRA.
SECONDARY ACCESSION(S): PRJNA341750PRJNA341751
REPOSITORIES: dbGaP
Similar Datasets
Project description:The Human Induced Pluripotent Stem Cells Initiative (HipSci) is generating a large, high-quality reference panel of human IPSC lines. This is a pilot submission of mass-spectrometry analyses from 18 induced pluripotent stem cell lines generated by the HipSci project. This submission includes also data for two embryonic stem cell lines, and one reference sample comprising a mixture of 42 IPSC lines. Associated BioSamples accessions: <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2397999">SAMEA2397999</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2398167">SAMEA2398167</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2398916">SAMEA2398916</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2397948"> SAMEA2397948 </a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2399112">SAMEA2399112</a>,<a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2399257">SAMEA2399257</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2398553">SAMEA2398553</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2398821">SAMEA2398821</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2398316">SAMEA2398316</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2469778">SAMEA2469778</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2399037">SAMEA2399037</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2398656">SAMEA2398656</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2398428">SAMEA2398428</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2469777">SAMEA2469777</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2397959">SAMEA2397959</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2398442">SAMEA2398442</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2398024">SAMEA2398024</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2398450">SAMEA2398450</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA3402864">SAMEA3402864</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA3110364">SAMEA3110364</a>
2016-06-06 | PXD003903 | Pride
Project description:<p>Primary torsin dystonias (PTD) are a group of movement disorders characterized by twisting muscle contractures, where dystonia is the only clinical sign (except for tremor) and there is no evidence of neuronal degeneration or an acquired cause. Eleven genes have been mapped for primary dystonia including DYT1 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=1861" target="_blank">TOR1A</a>), <a href="https://www.ncbi.nlm.nih.gov/gene/1862" target="_blank">DYT2</a>, DYT4 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=10382" target="_blank">TUBB4A</a>), DYT6 (<a href="https://www.ncbi.nlm.nih.gov/gene/55145" target="_blank">THAP1</a>), <a href="https://www.ncbi.nlm.nih.gov/gene/?term=1866" target="_blank">DYT7</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/?term=93983" target="_blank">DYT13</a>,, <a href="https://www.ncbi.nlm.nih.gov/gene/?term=100216344" target="_blank">DYT17</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/?term=100885773" target="_blank">DYT21</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/?term=25792" target="_blank">CIZ1</a>, DYT24 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=63982" target="_blank">ANO3</a>), and DYT25 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=2774" target="_blank">GNAL</a>); however, only 3 genes (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=1861" target="_blank">TOR1A</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/55145" target="_blank">THAP1</a>, and <a href="https://www.ncbi.nlm.nih.gov/gene/?term=2774" target="_blank">GNAL</a>) have mutations in early onset dystonia patients. Each is inherited as an autosomal dominant trait but with reduced penetrance, meaning that individuals can carry the mutation but do not show clinical symptoms.</p> <p>The most common form of PTD is adult onset focal accounting for about 90% of all cases of dystonia with a prevalence estimated at 30/100,000 in the general population. A small percentage of focal cases are due to mutations in <a href="https://www.ncbi.nlm.nih.gov/gene/?term=25792" target="_blank">CIZ1</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/?term=63982" target="_blank">ANO3</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/55145" target="_blank">THAP1</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/?term=10382" target="_blank">TUBB4A</a>, and <a href="https://www.ncbi.nlm.nih.gov/gene/?term=2774" target="_blank">GNAL</a>, but the vast majority is unaccounted for and is most likely multigenic or multifactorial. In this grant, focusing on early onset PTD, we will uncover genes that influence the penetrance of DYT1 (<a href="https://www.ncbi.nlm.nih.gov/gene/?term=1861" target="_blank">TOR1A</a>) dystonia through GWAS and exome sequencing studies. We will identify other genes for early onset PTD using exome sequencing and determine whether variants within the identified early onset PTD genes or the pathways associated with these genes contribute to susceptibility in the most prevalent form of PTD, focal dystonia, using a case:control association study. The proposed research will identify novel PTD risk factors and genes, which in turn should reveal shared and intersecting pathways leading to a better understanding of the molecular basis of PTD and provide the underpinnings for developing new treatments. Additionally, insight into the factors that modulate disease penetrance would be a first step in determine whether these could be modified leading to a reduced incidence of the disease. </p>
| phs001733 | dbGaP
Project description:The overarching project goal was to describe proteome differences between long- and normal-living C.elegans worms. The associated publications are http://www.ncbi.nlm.nih.gov/pubmed/24555535 http://www.ncbi.nlm.nih.gov/pubmed/24002365
2015-05-13 | PXD002161 | Pride
Project description:<p>The objective of the Time-Dependent Proteome Study, was to evaluate changes in the proteome and phosphoproteome when there is a delay in freezing tissues following sample (tumor) excision. The biospecimens used are from patient-derived ovarian cancer tumors.<br><a href="http://www.ncbi.nlm.nih.gov/pubmed/24719451" target="_blank">Ref: Mertins P et al., (2014) Mol Cell Proteomics, Apr 9. E-Publication</a><br><a href="http://www.ncbi.nlm.nih.gov/pubmed/25670172" target="_blank">Ref: Gajadhar, A.S., et al., (2015) Cancer Res. Apr 1;75(7):1495-503. Epub 2015 Feb 10.</a></p><ul><li>Dataset imported into MassIVE from <a href="https://cptac-data-portal.georgetown.edu/cptac/s/S013">https://cptac-data-portal.georgetown.edu/cptac/s/S013</a> on 11/05/18</li></ul>
2018-11-05 | MSV000083107 | MassIVE
Project description:<p>We recruited 1,521 women from the Old Order Amish (OOA) population of Lancaster County, Pennsylvania, with the primary goal of identifying genetic factors that influence mammographic density. All women were between the ages of 40 and 88 years, with a mean of 54 years. Additional study design details, including eligibility criteria, are described elsewhere (Douglas et al., <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=19029399">2008</a>).</p> <p>The present-day OOA of Lancaster County are the descendants of approximately 550 individuals from central Western Europe who immigrated to the U.S. in the early eighteenth century. All living individuals derive from a single, 14-generation pedigree (Lee et al., <a href="http://www.ncbi.nlm.nih.gov/pubmed/?term=20433770">2010</a>). Although the OOA are a genetically closed founder population, allele frequencies and LD profiles are remarkably similar between the OOA and U.S. participants in the International HapMap project (HapMap CEU) for common SNPs (MAF>/=5%) (Van Hout et al., <a href="http://www.ncbi.nlm.nih.gov/pubmed?cmd=DetailsSearch&term=19697356[PMID]">2010</a>).</p> <p>We recently completed genome-wide linkage and association analyses of mammographic density, including dense and non-dense areas of the breast and the ratio of dense to total area of the breast. Summary-level data from our GWAS are available here and through the Marker of DEnsity (MODE) Consortium.</p>
| phs000604.v1.p1 | EGA
Project description:Effective molecular diagnosis of congenital diseases hinges on comprehensive genomic analysis, traditionally reliant on various methodologies specific to each variant type — whole exome or genome sequencing for single nucleotide variants (SNVs), array CGH for copy-number variants (CNVs), and microscopy for structural variants (SVs). We introduce a novel, integrative approach combining exome sequencing with chromosome conformation capture, termed Exo-C. This method enables the concurrent identification of SNVs in clinically relevant genes and SVs across the genome and allows analysis of heterozygous and mosaic carriers. Enhanced with targeted long-read sequencing, Exo-C evolves into a cost-efficient solution capable of resolving complex SVs at base-pair accuracy. Through several case studies, we demonstrate how Exo-C's multifaceted application can effectively uncover diverse causative variants and elucidate disease mechanisms in patients with rare disorders.
2024-01-24 | GSE253950 | GEO
Project description:Suicidal behavior (SB) has a complex etiology of genes, environment or both. One of the genetic components in SB could be copy number variations (CNVs), since CNVs are implicated in a range of neurodevelopmental disorders. However, a recently published genome-wide and case-control study failed to observe a significant role of CNVs in SB (see E-MTAB-3519). Here we complement those initial observations by conducting a brief CNV-association study, for the first time in a family-based trio-sample with severe suicide attempt (SA) outcome in offspring (n=660 trios; the \GISS\ sample, see http://www.ncbi.nlm.nih.gov/pubmed/23422793 and refs therein). For association testing, we here used the FBAT-CNV methodology (http://www.ncbi.nlm.nih.gov/pubmed/18228561), which allows for CNV association testing directly on the raw intensity values (Illumina \log R ratio\), evaluating any type of CNVs (e.g. de novo or inherited) without reliance on CNV calling algorithms and robust to control selection biases. Here we have deposited these raw logR-values for 88,450 on-chip CNV-loci of the HumanOmni1-Quad_v1 chip, arranged in a standard pedigree format used as input for FBAT-CNV analysis in SVS software (goldenhelix.com): column 1 is the family ID, column 2 is the Subject type (1 = offspring, 2 = mother, 3 = father), column 3 is the father ID (? for missing), column 4 is the mother ID (? for missing), column 5 is the sex (1 = female, 0 = male), column 6 is the affection status (1 = suicide attempt, 0 = not affected) and columns 7 and onward are the logR-values for each CNV-loci as is listed in the header row. We observed experiment-wide significant association (P ≤ 5.6 x 10-7) of two proximal CNVs at chromosome 14 (Illumina markers cnvi0108946 and cnvi0118308, with NCBI 36.3 start positions 22794779 and 22582820). However, these CNV-associations mapped to T-cell receptor regions, and therefore most likely reflect inter-individual variation in somatic rearrangements occurring in white blood cells (as our source of DNA was blood), rather than association with SA. In conclusion, our results did not suggest any major role of CNVs in SA etiology, in line with the results of the recent case-control study (see E-MTAB-3519).
2015-10-30 | E-MTAB-3744 | biostudies-arrayexpress
Project description:The Human Induced Pluripotent Stem Cells Initiative (HipSci) is generating a large, high-quality reference panel of human IPSC lines. This is a pilot submission of mass-spectrometry analyses from 18 induced pluripotent stem cell lines generated by the HipSci project. This submission includes also data for two embryonic stem cell lines, and one reference sample comprising a mixture of 42 IPSC lines. Associated BioSamples accessions: <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2397999">SAMEA2397999</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2398167">SAMEA2398167</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2398916">SAMEA2398916</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2397948"> SAMEA2397948 </a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2399112">SAMEA2399112</a>,<a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2399257">SAMEA2399257</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2398553">SAMEA2398553</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2398821">SAMEA2398821</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2398316">SAMEA2398316</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2469778">SAMEA2469778</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2399037">SAMEA2399037</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2398656">SAMEA2398656</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2398428">SAMEA2398428</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2469777">SAMEA2469777</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2397959">SAMEA2397959</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2398442">SAMEA2398442</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2398024">SAMEA2398024</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA2398450">SAMEA2398450</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA3402864">SAMEA3402864</a>, <a href="http://www.ebi.ac.uk/biosamples/sample/SAMEA3110364">SAMEA3110364</a>
2016-07-24 | MSV000080004 | MassIVE
Project description:Structural variants (SVs) involving enhancer hijacking can disrupt chromatin topologies to cause oncogene activation in cancer genomes, yet the molecular determinants for the transcriptional output of enhancer hijacking remain largely unknown. We developed a multimodal approach to integrate genome sequencing, chromosome conformation, and sequence-based deep learning for quantitative analysis of transcriptional effects and structural reorganization imposed by SVs in leukemic genomes. We identified candidate pathogenic SVs including recurrent t(5;14) translocations that cause the hijacking of BCL11B enhancers for oncogenic activation of TLX3-dependent transcriptional programs. By engineering patient-associated t(5;14) in isogenic leukemia cells, we uncovered an uncharacterized mechanism whereby DNA methylation serves as an epigenetic barrier to enhancer hijacking and loss of epigenetic barrier is a molecular determinant for the transcriptional output of pathogenic SVs. Hence, leveraging the epigenetic barriers of SV-mediated oncogenic programs may provide new opportunities to reprogram gene regulation as epigenetic therapies in human disease.
2023-04-25 | GSE199694 | GEO
Project description:Structural variants (SVs) involving enhancer hijacking can disrupt chromatin topologies to cause oncogene activation in cancer genomes, yet the molecular determinants for the transcriptional output of enhancer hijacking remain largely unknown. We developed a multimodal approach to integrate genome sequencing, chromosome conformation, and sequence-based deep learning for quantitative analysis of transcriptional effects and structural reorganization imposed by SVs in leukemic genomes. We identified candidate pathogenic SVs including recurrent t(5;14) translocations that cause the hijacking of BCL11B enhancers for oncogenic activation of TLX3-dependent transcriptional programs. By engineering patient-associated t(5;14) in isogenic leukemia cells, we uncovered an uncharacterized mechanism whereby DNA methylation serves as an epigenetic barrier to enhancer hijacking and loss of epigenetic barrier is a molecular determinant for the transcriptional output of pathogenic SVs. Hence, leveraging the epigenetic barriers of SV-mediated oncogenic programs may provide new opportunities to reprogram gene regulation as epigenetic therapies in human disease.
2023-04-25 | GSE199693 | GEO