The Experts below are selected from a list of 25893 Experts worldwide ranked by ideXlab platform
Stephanie L Bielas - One of the best experts on this subject based on the ideXlab platform.
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de novo dominant asxl3 mutations alter h2a deubiquitination and transcription in bainbridge ropers syndrome
Human Molecular Genetics, 2016Co-Authors: Anshika Srivastava, K C Ritesh, Yao Chang Tsan, Rosy Liao, Catherine E Keegan, Mark C Hannibal, Fengyun Su, Arul M. Chinnaiyan, Donna M Martin, Stephanie L BielasAbstract:: De novo truncating mutations in Additional sex combs-like 3 (ASXL3) have been identified in individuals with Bainbridge-Ropers syndrome (BRS), characterized by failure to thrive, global developmental delay, feeding problems, hypotonia, dysmorphic features, profound speech delays and intellectual disability. We identified three novel de novo heterozygous truncating variants distributed across ASXL3, outside the original cluster of ASXL3 mutations previously described for BRS. Primary skin fibroblasts established from a BRS patient were used to investigate the functional impact of pathogenic variants. ASXL3 mRNA transcripts from the mutated allele are prone to nonsense-mediated decay, and expression of ASXL3 is reduced. We found that ASXL3 interacts with BAP1, a hydrolase that removes mono-ubiquitin from histone H2A lysine 119 (H2AK119Ub1) as a component of the Polycomb repressive deubiquitination (PR-DUB) complex. A significant increase in H2AK119Ub1 was observed in ASXL3 patient fibroblasts, highlighting an important functional role for ASXL3 in PR-DUB mediated deubiquitination. Transcriptomes of ASXL3 patient and control fibroblasts were compared to investigate the impact of chromatin changes on transcriptional regulation. Out of 564 significantly differentially expressed Genes (DEGs) in ASXL3 patient fibroblasts, 52% were upregulated and 48% downregulated. DEGs were enriched in molecular processes impacting transcriptional regulation, development and proliferation, consistent with the features of BRS. This is the first Single Gene Disorder linked to defects in deubiquitination of H2AK119Ub1 and suggests an important role for dynamic regulation of H2A mono-ubiquitination in transcriptional regulation and the pathophysiology of BRS.
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de novo dominant asxl3 mutations alter h2a deubiquitination and transcription in bainbridge ropers syndrome
Human Molecular Genetics, 2016Co-Authors: Anshika Srivastava, K C Ritesh, Yao Chang Tsan, Rosy Liao, Catherine E Keegan, Mark C Hannibal, Fengyun Su, Arul M. Chinnaiyan, Donna M Martin, Stephanie L BielasAbstract:: De novo truncating mutations in Additional sex combs-like 3 (ASXL3) have been identified in individuals with Bainbridge-Ropers syndrome (BRS), characterized by failure to thrive, global developmental delay, feeding problems, hypotonia, dysmorphic features, profound speech delays and intellectual disability. We identified three novel de novo heterozygous truncating variants distributed across ASXL3, outside the original cluster of ASXL3 mutations previously described for BRS. Primary skin fibroblasts established from a BRS patient were used to investigate the functional impact of pathogenic variants. ASXL3 mRNA transcripts from the mutated allele are prone to nonsense-mediated decay, and expression of ASXL3 is reduced. We found that ASXL3 interacts with BAP1, a hydrolase that removes mono-ubiquitin from histone H2A lysine 119 (H2AK119Ub1) as a component of the Polycomb repressive deubiquitination (PR-DUB) complex. A significant increase in H2AK119Ub1 was observed in ASXL3 patient fibroblasts, highlighting an important functional role for ASXL3 in PR-DUB mediated deubiquitination. Transcriptomes of ASXL3 patient and control fibroblasts were compared to investigate the impact of chromatin changes on transcriptional regulation. Out of 564 significantly differentially expressed Genes (DEGs) in ASXL3 patient fibroblasts, 52% were upregulated and 48% downregulated. DEGs were enriched in molecular processes impacting transcriptional regulation, development and proliferation, consistent with the features of BRS. This is the first Single Gene Disorder linked to defects in deubiquitination of H2AK119Ub1 and suggests an important role for dynamic regulation of H2A mono-ubiquitination in transcriptional regulation and the pathophysiology of BRS.
Richard T. Scott - One of the best experts on this subject based on the ideXlab platform.
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Development and validation of concurrent preimplantation Genetic diagnosis for Single Gene Disorders and comprehensive chromosomal aneuploidy screening without whole genome amplification.
Fertility and sterility, 2015Co-Authors: R.s. Zimmerman, Richard T. Scott, Anastasia Fedick, Chaim Jalas, Xin Tao, Julia G. Kim, Russell J. Pepe, L.e. Northrop, Nathan R. TreffAbstract:Objective To develop a novel and robust protocol for multifactorial preimplantation Genetic testing of trophectoderm biopsies using quantitative polymerase chain reaction (qPCR). Design Prospective and blinded. Setting Not applicable. Patient(s) Couples indicated for preimplantation Genetic diagnosis (PGD). Intervention(s) None. Main Outcome Measure(s) Allele dropout (ADO) and failed amplification rate, genotyping consistency, chromosome screening success rate, and clinical outcomes of qPCR-based screening. Result(s) The ADO frequency on a Single cell from a fibroblast cell line was 1.64% (18/1,096). When two or more cells were tested, the ADO frequency dropped to 0.02% (1/4,426). The rate of amplification failure was 1.38% (55/4,000) overall, with 2.5% (20/800) for Single cells and 1.09% (35/3,200) for samples that had two or more cells. Among 152 embryos tested in 17 cases by qPCR-based PGD and CCS, 100% were successfully given a diagnosis, with 0% ADO or amplification failure. Genotyping consistency with reference laboratory results was >99%. Another 304 embryos from 43 cases were included in the clinical application of qPCR-based PGD and CCS, for which 99.7% (303/304) of the embryos were given a definitive diagnosis, with only 0.3% (1/304) having an inconclusive result owing to recombination. In patients receiving a transfer with follow-up, the pregnancy rate was 82% (27/33). Conclusion(s) This study demonstrates that the use of qPCR for PGD testing delivers consistent and more reliable results than existing methods and that Single Gene Disorder PGD can be run concurrently with CCS without the need for additional embryo biopsy or whole genome amplification.
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evaluation of targeted next Generation sequencing based preimplantation Genetic diagnosis of monogenic disease
Fertility and Sterility, 2013Co-Authors: Nathan R. Treff, Anastasia Fedick, X Tao, Batsal Devkota, Deanne Taylor, Richard T. ScottAbstract:Objective To investigate the applicability of next-Generation sequencing (NGS) to preimplantation Genetic diagnosis (PGD); to evaluate semiconductor-based NGS for Genetic analysis of human embryos. Design Blinded. Setting Academic center for reproductive medicine. Patient(s) Six couples at risk of transmitting Single-Gene Disorders to their offspring. Intervention(s) None. Main Outcome Measure(s) Embryonic genotype consistency of NGS with two independent conventional methods of PGD. Result(s) NGS provided 100% equivalent PGD diagnoses of compound point mutations and small deletions and insertions compared with both reference laboratory– and internally developed quantitative polymerase chain reaction (qPCR)–based analyses. Furthermore, NGS Single-Gene Disorder screening could be performed in parallel with qPCR-based comprehensive chromosome screening. Conclusion(s) NGS can provide blastocyst PGD results with a high level of consistency with established methodologies. This study and its design could serve as a model for further development of this important and emerging technology.
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Trophectoderm biopsy for Single-Gene Disorder preimplantation Genetic diagnosis (PGD) is significantly more reliable than day 3 blastomere biopsy
Fertility and Sterility, 2011Co-Authors: Eric J. Forman, K.m. Ferry, N.-a. Gueye, R.d. Smith, John R. Stevens, Richard T. ScottAbstract:TROPHECTODERM BIOPSY FOR Single-Gene Disorder PREIMPLANTATION GeneTIC DIAGNOSIS (PGD) IS SIGNIFICANTLYMORE RELIABLE THAN DAY 3 BLASTOMERE BIOPSY. E. J. Forman, K. M. Ferry, N.-A. Gueye, R. D. Smith, J. Stevens, R. T. Scott, Jr. Reproductive Endocrinology & Infertility, Reproductive Medicine Associates of New Jersey, Morristown, NJ; Obstetrics, Gynecology and Reproductive Sciences, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ; Fertility Laboratories of Colorado, Lone Tree, CO.
Anshika Srivastava - One of the best experts on this subject based on the ideXlab platform.
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de novo dominant asxl3 mutations alter h2a deubiquitination and transcription in bainbridge ropers syndrome
Human Molecular Genetics, 2016Co-Authors: Anshika Srivastava, K C Ritesh, Yao Chang Tsan, Rosy Liao, Catherine E Keegan, Mark C Hannibal, Fengyun Su, Arul M. Chinnaiyan, Donna M Martin, Stephanie L BielasAbstract:: De novo truncating mutations in Additional sex combs-like 3 (ASXL3) have been identified in individuals with Bainbridge-Ropers syndrome (BRS), characterized by failure to thrive, global developmental delay, feeding problems, hypotonia, dysmorphic features, profound speech delays and intellectual disability. We identified three novel de novo heterozygous truncating variants distributed across ASXL3, outside the original cluster of ASXL3 mutations previously described for BRS. Primary skin fibroblasts established from a BRS patient were used to investigate the functional impact of pathogenic variants. ASXL3 mRNA transcripts from the mutated allele are prone to nonsense-mediated decay, and expression of ASXL3 is reduced. We found that ASXL3 interacts with BAP1, a hydrolase that removes mono-ubiquitin from histone H2A lysine 119 (H2AK119Ub1) as a component of the Polycomb repressive deubiquitination (PR-DUB) complex. A significant increase in H2AK119Ub1 was observed in ASXL3 patient fibroblasts, highlighting an important functional role for ASXL3 in PR-DUB mediated deubiquitination. Transcriptomes of ASXL3 patient and control fibroblasts were compared to investigate the impact of chromatin changes on transcriptional regulation. Out of 564 significantly differentially expressed Genes (DEGs) in ASXL3 patient fibroblasts, 52% were upregulated and 48% downregulated. DEGs were enriched in molecular processes impacting transcriptional regulation, development and proliferation, consistent with the features of BRS. This is the first Single Gene Disorder linked to defects in deubiquitination of H2AK119Ub1 and suggests an important role for dynamic regulation of H2A mono-ubiquitination in transcriptional regulation and the pathophysiology of BRS.
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de novo dominant asxl3 mutations alter h2a deubiquitination and transcription in bainbridge ropers syndrome
Human Molecular Genetics, 2016Co-Authors: Anshika Srivastava, K C Ritesh, Yao Chang Tsan, Rosy Liao, Catherine E Keegan, Mark C Hannibal, Fengyun Su, Arul M. Chinnaiyan, Donna M Martin, Stephanie L BielasAbstract:: De novo truncating mutations in Additional sex combs-like 3 (ASXL3) have been identified in individuals with Bainbridge-Ropers syndrome (BRS), characterized by failure to thrive, global developmental delay, feeding problems, hypotonia, dysmorphic features, profound speech delays and intellectual disability. We identified three novel de novo heterozygous truncating variants distributed across ASXL3, outside the original cluster of ASXL3 mutations previously described for BRS. Primary skin fibroblasts established from a BRS patient were used to investigate the functional impact of pathogenic variants. ASXL3 mRNA transcripts from the mutated allele are prone to nonsense-mediated decay, and expression of ASXL3 is reduced. We found that ASXL3 interacts with BAP1, a hydrolase that removes mono-ubiquitin from histone H2A lysine 119 (H2AK119Ub1) as a component of the Polycomb repressive deubiquitination (PR-DUB) complex. A significant increase in H2AK119Ub1 was observed in ASXL3 patient fibroblasts, highlighting an important functional role for ASXL3 in PR-DUB mediated deubiquitination. Transcriptomes of ASXL3 patient and control fibroblasts were compared to investigate the impact of chromatin changes on transcriptional regulation. Out of 564 significantly differentially expressed Genes (DEGs) in ASXL3 patient fibroblasts, 52% were upregulated and 48% downregulated. DEGs were enriched in molecular processes impacting transcriptional regulation, development and proliferation, consistent with the features of BRS. This is the first Single Gene Disorder linked to defects in deubiquitination of H2AK119Ub1 and suggests an important role for dynamic regulation of H2A mono-ubiquitination in transcriptional regulation and the pathophysiology of BRS.
George J Dover - One of the best experts on this subject based on the ideXlab platform.
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SS disease is not a Single Gene Disorder
Blood, 2002Co-Authors: George J DoverAbstract:In SS disease CNS damage is found in a continuum of clinical settings: normal (no ischemic changes), silent strokes (MRI changes without symptoms), transient ischemic episodes, and clinical strokes (either ischemic or hemorrhagic). Four to eight percent of children with SS disease have clinical
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Sickle cell disease: no longer a Single Gene Disorder.
Current Opinion in Pediatrics, 2001Co-Authors: David H K Chui, George J DoverAbstract:Patients who are homozygous for the sickle hemoglobin mutation can present with remarkably different clinical courses, varying from death in childhood, to recurrent painful vasoocclusive crises and multiple organ damage in adults, to being relatively well even until old age. Increasing numbers of Genetic loci have now been identified that can modulate sickle cell disease phenotype, from nucleotide motifs within the beta-globin Gene cluster, to Genes located on different chromosomes. With recent success of the human genome project, it is anticipated that many more Genetic modifiers of sickle cell disease will be discovered that can lead to the development of more effective therapeutic approaches. The multigenic origin of the variable phenotype in sickle cell disease will serve as a paradigm for the study of variation in phenotypes of all Single Gene Disorders in man.
Nathan R. Treff - One of the best experts on this subject based on the ideXlab platform.
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Development and validation of concurrent preimplantation Genetic diagnosis for Single Gene Disorders and comprehensive chromosomal aneuploidy screening without whole genome amplification.
Fertility and sterility, 2015Co-Authors: R.s. Zimmerman, Richard T. Scott, Anastasia Fedick, Chaim Jalas, Xin Tao, Julia G. Kim, Russell J. Pepe, L.e. Northrop, Nathan R. TreffAbstract:Objective To develop a novel and robust protocol for multifactorial preimplantation Genetic testing of trophectoderm biopsies using quantitative polymerase chain reaction (qPCR). Design Prospective and blinded. Setting Not applicable. Patient(s) Couples indicated for preimplantation Genetic diagnosis (PGD). Intervention(s) None. Main Outcome Measure(s) Allele dropout (ADO) and failed amplification rate, genotyping consistency, chromosome screening success rate, and clinical outcomes of qPCR-based screening. Result(s) The ADO frequency on a Single cell from a fibroblast cell line was 1.64% (18/1,096). When two or more cells were tested, the ADO frequency dropped to 0.02% (1/4,426). The rate of amplification failure was 1.38% (55/4,000) overall, with 2.5% (20/800) for Single cells and 1.09% (35/3,200) for samples that had two or more cells. Among 152 embryos tested in 17 cases by qPCR-based PGD and CCS, 100% were successfully given a diagnosis, with 0% ADO or amplification failure. Genotyping consistency with reference laboratory results was >99%. Another 304 embryos from 43 cases were included in the clinical application of qPCR-based PGD and CCS, for which 99.7% (303/304) of the embryos were given a definitive diagnosis, with only 0.3% (1/304) having an inconclusive result owing to recombination. In patients receiving a transfer with follow-up, the pregnancy rate was 82% (27/33). Conclusion(s) This study demonstrates that the use of qPCR for PGD testing delivers consistent and more reliable results than existing methods and that Single Gene Disorder PGD can be run concurrently with CCS without the need for additional embryo biopsy or whole genome amplification.
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evaluation of targeted next Generation sequencing based preimplantation Genetic diagnosis of monogenic disease
Fertility and Sterility, 2013Co-Authors: Nathan R. Treff, Anastasia Fedick, X Tao, Batsal Devkota, Deanne Taylor, Richard T. ScottAbstract:Objective To investigate the applicability of next-Generation sequencing (NGS) to preimplantation Genetic diagnosis (PGD); to evaluate semiconductor-based NGS for Genetic analysis of human embryos. Design Blinded. Setting Academic center for reproductive medicine. Patient(s) Six couples at risk of transmitting Single-Gene Disorders to their offspring. Intervention(s) None. Main Outcome Measure(s) Embryonic genotype consistency of NGS with two independent conventional methods of PGD. Result(s) NGS provided 100% equivalent PGD diagnoses of compound point mutations and small deletions and insertions compared with both reference laboratory– and internally developed quantitative polymerase chain reaction (qPCR)–based analyses. Furthermore, NGS Single-Gene Disorder screening could be performed in parallel with qPCR-based comprehensive chromosome screening. Conclusion(s) NGS can provide blastocyst PGD results with a high level of consistency with established methodologies. This study and its design could serve as a model for further development of this important and emerging technology.