Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Biesecker Lab (NHGRI) Whole Genome Medical Sequencing for Gene Discovery

ABSTRACT:

We aim to use whole-genome medical sequencing (WGMS) to discover causative molecular lesions for a set of rare, severe phenotypes hypothesized to be caused by either somatic mutations, germline de nova heterozygous mutations, germline inherited recessive, or germline inherited dominant mutations in currently unknown or uncharacterized genes. The goal of this research is threefold: to identify causative sequence variants for disorders whose molecular etiology was previously unknown, to apply this insight to both the rare disorders under study and more common phenotypes, and to enhance the study of mutation on a genome-wide level.

PROVIDER: phs001348 | dbGaP |

SECONDARY ACCESSION(S): PRJNA381265PRJNA381266

REPOSITORIES: dbGaP

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	GapExchange_phs001348.v1.p1.xml	Xml
	dbGaPEx2.1.5.xsd	Other
	Study_Report.phs001348.GeneDiscovery_WGMS.v1.p1.MULTI.pdf	Pdf
	manifest_phs001348.GeneDiscovery_WGMS.v1.p1.c1.HMB.pdf	Pdf
	datadict_v2.xsl	Other

Items per page:

1 - 5 of 34

Similar Datasets

Germline ERCC6L2 mutations lead to impaired erythropoiesis and reshaping of the bone marrow niche

Project description:Despite the inclusion of inherited myeloid malignancies as a separate entity in the WHO Classification, our understanding of the etiology of familial leukemia remains limited. ERCC6L2-deficiency is a rare, life-threatening inherited condition that gives rise to bone marrow failure (BMF), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) resulting from germline mutations in DNA repair factor ERCC6L2. Here we employ a lentiviral shRNA approach to functionally characterize the impact of ERCC6L2 loss on hematopoietic stem/progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs). By combining cell culture assays and transcriptomic analysis of knockdown and ERCC6L2-mutated patient cells, we find that ERCC6L2-deficiency reduces HSPC clonogenic potential and delays erythropoiesis, while in MSCs it induces a significant lineage skewing, with increased osteogenesis and suppressed adipogenesis. Altogether, we demonstrate that ERCC6L2-deficiency impacts both hematopoietic and stromal compartments, and that our ex vivo model recapitulates patient phenotypes, providing a robust system to study germline mutations in hematological malignancies.

2022-09-26 | GSE190542 | GEO

Selective elimination of mitochondria mutations in the germline by genome editing

Project description:Currently there is no treatment for mitochondrial disease, a group of devastating inherited disorders caused by mutations in mitochondrial DNA (mtDNA). Here we report a strategy to prevent the germline transmission of mitochondrial diseases. This technique is based on the specific elimination of mutated mtDNA through the use of mitochondria targeted nucleases. Our approaches represent a potential therapeutic avenue for preventing the transgenerational transmission of human mitochondrial diseases caused by mutations in mtDNA. A total of 4 samples were analyzed. Test samples were compared to sex-matched reference samples.

2015-04-23 | E-GEOD-67371 | biostudies-arrayexpress

Insights into inherited thrombocytopenia resulting from mono-allelic germline mutations in ETV6 or RUNX1 using a human pluripotent stem cell model

Project description:Inherited thrombocytopenia results in low platelet counts and increased bleeding. Subsets of these patients have monoallelic germline mutations in ETV6 or RUNX1 and a heightened risk of developing hematologic malignancies. Utilizing CRISPR/Cas9, we compared the in vitro phenotype of hematopoietic progenitor cells and megakaryocytes derived from induced pluripotent stem cell (iPSC) lines harboring mutations in either ETV6 or RUNX1. Both mutant lines display phenotypes consistent with a platelet-bleeding disorder. Surprisingly, these cellular phenotypes were largely distinct. The ETV6-mutant iPSCs yield more hematopoietic progenitor cells and megakaryocytes, but the megakaryocytes are immature and less responsive to agonist stimulation. On the contrary, RUNX1-mutant iPSCs yield fewer hematopoietic progenitor cells and megakaryocytes, but the megakaryocytes are more responsive to agonist stimulation. However, both mutant iPSC lines display defects in proplatelet formation. Our work highlights that while patients harboring germline ETV6 or RUNX1 mutations have similar clinical phenotypes, the molecular mechanisms may be distinct.

2021-03-06 | GSE168326 | GEO

The Molecular Basis of Inherited Reproductive Disorders

Project description:The Molecular Basis of Inherited Reproductive Disorders

| PRJNA89533 | ENA

Homo sapiens

Project description:The Molecular Basis of Inherited Reproductive Disorders

| PRJNA157237 | ENA

A human mitochondrial DNA genetic bottleneck prevents mutational meltdown by purifying the early maternal germ line

Project description:Mitochondrial DNA (mtDNA) mutations cause inherited diseases and are implicated in the pathogenesis of common late-onset disorders, but it is not clear how they arise and propagate in the humans. Here we show that mtDNA mutations are present in primordial germ cells (PGCs) within healthy female human embryos. Close scrutiny revealed the signature of selection against non-synonymous variants in the protein-coding region, tRNA gene variants, and variants in specific regions of the non-coding D-loop. In isolated single PGCs we saw a profound reduction in the cellular mtDNA content, with discrete mitochondria containing ~5 mtDNA molecules during early germline development. Single cell deep mtDNA sequencing showed rare variants reaching higher heteroplasmy levels in later PGCs, consistent with the observed genetic bottleneck, and predicting >80% levels within isolated organelles. Genome-wide RNA-seq showed a progressive upregulation of genes involving mtDNA replication and transcription, linked to a transition from glycolytic to oxidative metabolism. The metabolic shift exposes deleterious mutations to selection at the organellar level during early germ cell development. In this way, the genetic bottleneck prevents the relentless accumulation of mtDNA mutations in the human population predicted by Muller’s ratchet. Mutations escaping this mechanism will, however, show massive shifts in heteroplasmy levels within one human generation, explaining the extreme phenotypic variation seen in human pedigrees with inherited mtDNA disorders.

2018-02-02 | GSE77882 | GEO

Selective elimination of mitochondria mutations in the germline by genome editing

2015-04-23 | GSE67371 | GEO

Homo sapiens

Project description:Germline and somatic mutations in neuronal migration disorders

| PRJNA397726 | ENA

MATN2 knock-down human immortalized podocytes LC-MS/MS

Project description:Basement membranes (BMs) are ubiquitous extracellular matrices whose composition remains elusive, limiting our understanding of BM regulation and function. By developing a bioinformatic and in vivo discovery pipeline, we define a network of over 220 human proteins localized to BMs. More than 100 BM-network genes associate with human phenotypes and by screening over 63,000 germline genomic sequences from families with rare disorders, we discovered novel predicted loss-of-function variants in MATN2. Biochemical analyses suggest that MATN2 interacts with many BM proteins, and we found that depletion of MATN2 affected levels of core BM components in human podocyte-derived extracellular matrix.

2022-05-31 | PXD029266 | Pride

NHGRI Mendelian Disorders Sequencing Centers

Project description:NHGRI Mendelian Disorders Sequencing Centers

| PRJNA158501 | ENA