Next Generation Mendelian Genetics: Kabuki Syndrome
Ontology highlight
ABSTRACT: 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. The exome sequences of ten unrelated individuals with a diagnosis of Kabuki Syndrome (OMIM: 147920) were obtained by massively parallel DNA sequencing.
SECONDARY ACCESSION(S): PRJNA74859PRJNA74857
REPOSITORIES: dbGaP
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| GapExchange_phs000295.v1.p1.xml | Xml | |||
| dbGaPEx2.1.5.xsd | Other | |||
| Study_Report.phs000295.Kabuki.v1.p1.MULTI.pdf | ||||
| manifest_phs000295.Kabuki.v1.p1.c1.KS.pdf | ||||
| datadict_v2.xsl | Other |
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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>
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Project description:Next Generation Mendelian Genetics: Hereditary Neurological Disorders
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Project description:<p>The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases.</p> <p>This dataset was obtained from exome analyses of people with hereditary neurologic disorders of unknown cause. </p>
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Project description:<p>The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases.</p> <p>Samples were collected from a single, multi-generational family with the same phenotype of exaggerated muscular development (muscular hypertrophy) and strength characterized by reduced fat pad thickness under the skin. All family members deny "body building" activities, and are so far negative for known gene mutation that have been identified as associated with excessive muscle development. All family members have examples of demonstrating extraordinary strength occurring both in childhood and old age. No negative associated phenotype traits with the muscle hypertrophy phenotype have been identified.</p>
| phs000541.v1.p1 | EGA
Project description:Retinoblastoma (RB, OMIM:180200) is the most common malignant childhood tumor of the eye with an estimated incidence between 1 in 16,000 and 1 in 18,000 live births [1,2]. RB is the first disease for which a genetic etiology of cancer has been described [3] being caused by mutations in the first tumor suppressor gene identified (RB1, Genbank accession # L11910). Mutations in both alleles of the RB1 gene are required for the development of this neoplasm [4], and, depending on the germ-line or somatic origin of the defect, a heritable or sporadic form can be distinguished. RB is unilateral in 60% of cases and only 15% of these are heritable [5]; in contrast, 40% of retinoblastomas are bilateral with risk of transmission to the offspring. Heritable retinoblastoma constitutes a cancer predisposition syndrome [6]. RB1 is located on chromosome 13 at band q14 and can be affected by a heterogeneous spectrum of genetic abnormalities, including chromosome translocation/deletion, genomic rearrangements, ranging from whole gene microdeletion to intragenic exons loss or duplication, and more than 900 different point mutations [7]. Mutational analysis is performed to search for the predisposing RB1 gene mutation in peripheral blood of patients with RB, but the molecular diagnosis requires several technical approaches to cover the entire field of oncogenic RB1 defects, frequently resulting in numerous, expensive and time consuming procedures. In particular, cytogenetic tools, such as classical chromosome investigations and Fluorescent In Situ Hybridization (FISH), in addition to Multiplex Ligation-dependent Probe Amplification (MLPA) technique, may account for detection of about 16% of RB1 abnormalities [8], while the remaining large amount of point mutations need to be investigated using sequencing analysis. Since the 1970s, Sanger sequencing has been recognized as the gold standard for mutation analysis in molecular diagnostics; however, its low-throughput, long turnaround time and overall cost [9] have called for new paradigms. Next Generation Sequencing (NGS) can massively sequence millions of DNA segments, promising low costs, increased workflow speed and enhanced sensitivity in mutation detection [9,10,11] On the other hand, conventional and molecular cytogenetic analysis, have been replaced by modern high-throughput investigations, such as array Comparative Genomic Hybridization (aCGH), that can reveal and measure cryptic genomic imbalances. In addition, aCGH can be focused on specific DNA segments or genes maximizing the resolution via a customized process. Based on these observations, we have recruited a cohort of retinoblastoma patients we previously investigated with conventional cytogenetics and MLPA. Patients diagnosed with RB but negative to the above standard screening have been tested with NGS to assess its ability in identifying RB causative mutations. On the other hand, patients positive to standard screening have been further investigated with RB1-custom array CGH analysis to characterize the genomic rearrangements with a better resolution compared to the conventional techniques. The complementary aCGH data set related to this study has also been deposited at ArrayExpress, under accession number E-MTAB-3492: https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-3492/
2015-10-31 | E-MTAB-3515 | biostudies-arrayexpress
Project description:<p>The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases.</p> <p>The research study procedures included the collection of a fasting blood sample, 2 medical history/life style questionnaires and a measurement of subjects' waist circumference that were completed many years ago. Blood samples were analyzed for metabolic markers including cholesterol, HDL, triglycerides and APOE. Genetic tests targeted known and novel genes and polymorphisms associated with carotid artery disease. </p>
| phs000538.v1.p1 | EGA
Project description:<p>The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases.</p> <p>Congenital Hyperinsulinism (CHI) is the most common cause of hypoglycemia in the newborn and it is due to mutations in 8 different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and UCP2). It is a heterogeneous disease with variable onset (birth to adulthood) and a persistent, intermittent, or transient course with possible later conversion to non-autoimmune diabetes. Although mutations in the two subunits of the KATP channel (ABCC8 and KCNJ11) account for 50% of the cases, the other half is still genetically unexplained. CHI can be inherited in a dominant or recessive and can also present as a 'de novo' mutation.</p> <p>We became part of this study when we submitted 8 DNA samples for exome sequencing, from patients with CHI of Caucasian ancestry, which had no mutations identified in ABCC8 or KCNJ1, with the goal to identify new mutations in known genes or new mutations in new genes or genetic variants.</p>
| phs000539.v1.p1 | EGA
Project description:<p>The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases.</p> <p>Neonatal diabetes mellitus (ND) is a rare form of monogenic diabetes (90,000-260,000 live births) that is diagnosed in the first 6 months of life. The disease has been classified as transient or permanent and although it can be inherited, more frequently is sporadic as a result of 'de novo' mutations. Defects in 12 genes have been found as responsible for the disease (defects in the paternally imprinted chromosomal region 6q24, IPF1, SLCA2A, INS, EIF2AK3, GCK, FOXP3, GLIS3, PTF1A, HNF1Beta, KCNJ11 and ABCC8). The two subunits of the ATP-sensitive K channel (ABCC8 and KCNJ11) and the insulin gene (INS), account for almost half of the cases and similar to CHI, the other half, remains genetically unexplained.</p> <p>We became part of this study when we submitted 4 DNA samples for exome sequencing, from patients with NDM of Caucasian ancestry, which had no mutations identified in ABCC8 or KCNJ1, with the goal to identify new mutations in known genes or new mutations or genetic variants in new genes.</p>
| phs000542.v1.p1 | EGA
Project description:<p>The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases.</p> <p>Familial hemophagocytic lymphohistiocytosis (fHLH) is a serious immune disorder that results from defective cytotoxic lymphocyte function. Autosomal recessive mutations in PFP1, UNC13D, STX11, STBP2, or RAB27, and hemizygous mutations in SH2D1A or BIRC4, account for known causes of the disease, but 30-70% of patients in North America lack a known genetic etiology. This project was designed to identify additional genetic abnormalities from HLH patients. </p> <p>The exome sequences of four unrelated individuals with a diagnosis of HLH, but without mutations in genes known to cause disease, were obtained by massively parallel DNA sequencing.</p>
| phs000537.v1.p1 | EGA
Project description:<p>The NHGRI Next Generation Mendelian Genetics project uses exome resequencing to identify variants in unsolved Mendelian diseases.</p> <p>Ehlers-Danlos syndrome Type VIII is a dominantly inherited connective tissue disorder that is distinguished from other forms of EDS by significant early-onset periodontal disease. Although the clinical phenotype is well delineated, the underlying molecular basis remains unknown. By studying a large family of affected and unaffected individuals with the EDS VIII by exome sequencing, we hope to identify unique regions of homology to assist in identifying the causative gene. </p>
| phs000540.v1.p1 | EGA