13 results on '"Sumit Punj"'
Search Results
2. P110: The influence of monogenic kidney disorders on the risk of kidney transplant rejection
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Jing Xie, Sumit Punj, Philippe Gauthier, Hossein Tabriziani, Matt Moyer, and Lisa Vincent
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Genetics ,QH426-470 ,Medicine - Published
- 2023
- Full Text
- View/download PDF
3. P108: Kidney features in patients with a molecular diagnosis of Birt-Hogg-Dubé syndrome: A case series
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Kathryn Curry, Meg Hager, Akash Anand, Maggie Westermeyer, Emily Hendricks, Tessa Pitman, Kathleen Collett, Quinn Stein, and Sumit Punj
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Genetics ,QH426-470 ,Medicine - Published
- 2023
- Full Text
- View/download PDF
4. P109: Heterozygous loss-of-function variants in IFT140 are associated with polycystic kidney disease
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Dinah Clark, Karen Phaik Har Lim, Lili Li, Lisa Vincent, Jing Xie, Yuan Xue, and Sumit Punj
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Genetics ,QH426-470 ,Medicine - Published
- 2023
- Full Text
- View/download PDF
5. TAOK1 is associated with neurodevelopmental disorder and essential for neuronal maturation and cortical development
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Mari Rossi, Melissa K. Gabriel, Rolph Pfundt, Ange Line Bruel, Sonal Mahida, Daniel Groepper, Kristin W. Barañano, Tjitske Kleefstra, Saskia Brulleman, Charlotte de Konink, Angelika Erwin, Aida Telegrafi, Kristin Lindstrom, Amy Blevins, Marjon van Slegtenhorst, Katherine G. Langley, David A. Koolen, Geeske M. van Woerden, Anna Chassevent, Louisa Kalsner, A. Micheil Innes, Ype Elgersma, David R. FitzPatrick, Kristin G. Monaghan, Allison Goodwin, Ben Distel, Karen W. Gripp, Alice S. Brooks, Natasha Shur, Fatima Rehman, Rossella Avagliano Trezza, Amanda Noyes, Melanie Bos, Jane Juusola, Gwynna de Geus, Jennifer B. Humberson, Andrew O.M. Wilkie, Jessica Hoffman, Marleen Simon, David Johnson, Róisín McCormack, Sumit Punj, Maria J. Guillen Sacoto, Julie Fleischer, Eduardo Calpena, Arthur Sorlin, Allison Schreiber, Clinical Genetics, Neurosciences, Medical Biochemistry, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
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MAP Kinase Signaling System ,Biology ,Mice ,03 medical and health sciences ,Neurodevelopmental disorder ,Intellectual Disability ,Intellectual disability ,Genetics ,medicine ,Animals ,Humans ,Missense mutation ,cortical development ,Amino Acids ,Protein kinase A ,Research Articles ,Genetics (clinical) ,Loss function ,030304 developmental biology ,2. Zero hunger ,0303 health sciences ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,MAP kinase kinase kinase ,Muscular hypotonia ,neurodevelopmental disorders ,030305 genetics & heredity ,medicine.disease ,in utero electroporation ,TAOK1 ,Muscle Hypotonia ,Neuroscience ,functional genomics ,Function (biology) ,Research Article - Abstract
Thousand and one amino‐acid kinase 1 (TAOK1) is a MAP3K protein kinase, regulating different mitogen‐activated protein kinase pathways, thereby modulating a multitude of processes in the cell. Given the recent finding of TAOK1 involvement in neurodevelopmental disorders (NDDs), we investigated the role of TAOK1 in neuronal function and collected a cohort of 23 individuals with mostly de novo variants in TAOK1 to further define the associated NDD. Here, we provide evidence for an important role for TAOK1 in neuronal function, showing that altered TAOK1 expression levels in the embryonic mouse brain affect neural migration in vivo, as well as neuronal maturation in vitro. The molecular spectrum of the identified TAOK1 variants comprises largely truncating and nonsense variants, but also missense variants, for which we provide evidence that they can have a loss of function or dominant‐negative effect on TAOK1, expanding the potential underlying causative mechanisms resulting in NDD. Taken together, our data indicate that TAOK1 activity needs to be properly controlled for normal neuronal function and that TAOK1 dysregulation leads to a neurodevelopmental disorder mainly comprising similar facial features, developmental delay/intellectual disability and/or variable learning or behavioral problems, muscular hypotonia, infant feeding difficulties, and growth problems., In this study we expand the cohort of individuals with a neurodevelopmental disorder, carrying a de novo variant in TAOK1 (a), thereby further defining the neurodevelopmental disorder caused by TAOK1 malfunctioning. Using both in vivo (b) and in vitro (c) functional assays, we provide evidence that increased as well as decreased levels of TAOK1 cause disruption of neuronal development, showing that TAOK1 plays an important role in neuronal function. Additionally, our data suggests that both gain of function as well as loss of function mutations are potentially causative for the TAOK1‐related neurodevelopmental disorder.
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- 2021
6. Genotype-phenotype correlation at codon 1740 ofSETD2
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Bernt Popp, Shelby Romoser, Lara Menzies, Stacey A. Bélanger, Alireza Radmanesh, Kimberly A. Aldinger, Jennifer Keller-Ramey, Janice Baker, Jane A. Hurst, William B. Dobyns, Schahram Akbarian, Sébastien Jacquemont, Jan Maarten Cobben, Larissa Kerecuk, Kelly Radtke, Joseph T. Shieh, Khadije Jizi, Ian A. Glass, Patrick Watts, Nicola Foulds, Jerica Lenberg, Sumit Punj, George E. Hoganson, Nancy J. Mendelsohn, Rachel Rabin, Ina Sorge, Katarzyna A. Ellsworth, Katharina Löhner, Manuela Siekmeyer, Jennifer Burton, Leah Dowsett, John A. Bernat, Hannah Bombei, John Pappas, Henny H. Lemmink, Francis H. Sansbury, Ingrid M. Wentzensen, Kirsty McWalter, Deborah Osio, Pamela Trapane, Hermine E. Veenstra-Knol, General Paediatrics, Paediatric Genetics, and ANS - Complex Trait Genetics
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Male ,Microcephaly ,Mutation, Missense ,Biology ,Nervous System Malformations ,Epigenesis, Genetic ,Histone H3 ,Loss of Function Mutation ,Tubulin ,SETD2 ,Intellectual Disability ,Genetics ,medicine ,Humans ,Missense mutation ,Genetic Predisposition to Disease ,histone modification ,Epigenetics ,AUTISM ,Child ,Codon ,Genetic Association Studies ,Genetics (clinical) ,Loss function ,HYPB/SETD2 ,MARK ,IDENTIFICATION ,MUTATIONS ,METHYLATION ,Infant ,Histone-Lysine N-Methyltransferase ,Methylation ,neurodevelopmental ,medicine.disease ,Histone ,genotype phenotype ,Neurodevelopmental Disorders ,Child, Preschool ,biology.protein ,Female ,clinical genetics - Abstract
The SET domain containing 2, histone lysine methyltransferase encoded by SETD2 is a dual-function methyltransferase for histones and microtubules and plays an important role for transcriptional regulation, genomic stability, and cytoskeletal functions. Specifically, SETD2 is associated with trimethylation of histone H3 at lysine 36 (H3K36me3) and methylation of α-tubulin at lysine 40. Heterozygous loss of function and missense variants have previously been described with Luscan-Lumish syndrome (LLS), which is characterized by overgrowth, neurodevelopmental features, and absence of overt congenital anomalies. We have identified 15 individuals with de novo variants in codon 1740 of SETD2 whose features differ from those with LLS. Group 1 consists of 12 individuals with heterozygous variant c.5218C>T p.(Arg1740Trp) and Group 2 consists of 3 individuals with heterozygous variant c.5219G>A p.(Arg1740Gln). The phenotype of Group 1 includes microcephaly, profound intellectual disability, congenital anomalies affecting several organ systems, and similar facial features. Individuals in Group 2 had moderate to severe intellectual disability, low normal head circumference, and absence of additional major congenital anomalies. While LLS is likely due to loss of function of SETD2, the clinical features seen in individuals with variants affecting codon 1740 are more severe suggesting an alternative mechanism, such as gain of function, effects on epigenetic regulation, or posttranslational modification of the cytoskeleton. Our report is a prime example of different mutations in the same gene causing diverging phenotypes and the features observed in Group 1 suggest a new clinically recognizable syndrome uniquely associated with the heterozygous variant c.5218C>T p.(Arg1740Trp) in SETD2.
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- 2020
7. Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder
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Nicole Fleischer, Grace M. Anbouba, Vandana Shashi, Thomas Meitinger, Damara Ortiz, Sumedha Ghate, Caleb Bupp, Maria J. Guillen Sacoto, Tiana M. Scott, Juliane Winkelmann, Felix Distelmaier, Sarah R Green, Dirk Klee, Carolyn R Serbinski, Lea Velsher, Michael T. Zimmermann, Meriel McEntagart, Gretchen Parsons, Patrick Yap, Evan H. Baugh, David S. Wargowski, Juan C Del Rey Jimenez, Anne K Olsen, Amy Armstrong-Javors, Victoria Mok Siu, Andrew Green, Nikita R. Dsouza, Elisabeth Graf, Sumit Punj, Matias Wagner, Anna Cereda, Naomi Meeks, Barbro Stadheim, Kirsty McWalter, Ingrid M. Wentzensen, Bert Callewaert, Rhonda E. Schnur, Emily Lancaster, Laurie A. Demmer, G. Bradley Schaefer, Kristin Lindstrom, Maria Iascone, Gonzalo Alonso Ramos-Rivera, Loren D M Pena, Amber Begtrup, Richard E. Person, Harrison Moore, Ameni Kdissa, Eric W. Klee, Dana Mittag, Jana Švantnerová, Ingrid Bader, Theresa Brunet, Johannes A. Mayr, Michael Zech, Jennifer A. Sullivan, Margot A. Cousin, Katharina Mayerhanser, Dagmar Wieczorek, Ralitza H. Gavrilova, and Daryl A. Scott
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Male ,Genotype ,ACETYLATION ,Autism Spectrum Disorder ,Chromosomal Proteins, Non-Histone ,autism ,Biology ,Pediatrics ,Whole Exome Sequencing ,Article ,Frameshift mutation ,Autism ,Developmental Delay ,Histone Acetylation ,Msl3 ,X-linked ,DOMAIN ,Genes, X-Linked ,MSL COMPLEX ,Intellectual Disability ,Intellectual disability ,Exome Sequencing ,medicine ,Medicine and Health Sciences ,Missense mutation ,Humans ,Exome ,Genetics (clinical) ,Exome sequencing ,MOF ,Genetics ,MSL3 ,MUTATIONS ,TRANSCRIPTIONAL REGULATION ,Macrocephaly ,histone acetylation ,Non-Histone ,medicine.disease ,ddc ,Chromosomal Proteins ,DNA-Binding Proteins ,developmental delay ,Phenotype ,Genes ,Autism spectrum disorder ,Female ,medicine.symptom ,DECAY ,DOSAGE COMPENSATION - Abstract
PURPOSE: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). METHODS: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. RESULTS: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. CONCLUSION: Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.
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- 2021
8. NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism
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Kun Xia, Samantha Ayres, Amber Begtrup, Danielle Karlowicz, Raphael Bernier, Ahood Alsulaiman, Frédéric Bilan, Rebecca Hernan, Elena Savva, Fowzan S. Alkuraya, Ingrid M. Wentzensen, Mohammad A. Al-Muhaizea, Audrey Labalme, Sumit Punj, Jenny Meylan Merlini, Evan E. Eichler, Lucile Letienne-Cejudo, Alexia Boizot, Natasha J Brown, Emily Bryant, Senwei Tan, Wendy K. Chung, Bin Yu, Inken Dreyer, Maria J. Guillen Sacoto, Jieqiong Tan, Hilde Peeters, Xiangbin Jia, Inge Lore Ruiz-Arana, Brina Daniels, Elizabeth A. Sellars, Linda Pons, Jianjun Ou, Rujia Dai, Guodong Chen, Gaetan Lesca, Lindsay Rhodes, Anne chun-hui Tsai, Chao Chen, Marie T. McDonald, Linda Laux, Kendra Hoekzema, Hui Guo, Christina Fagerberg, Bradley Schaefer, Huidan Wu, Rhonda E. Schnur, Qiumeng Zhang, Federico Santoni, Qian Pan, Rose B. McGee, Lucia Bartoloni, Brigitte Gilbert-Dussardier, Zhengmao Hu, Charlotte Brasch-Andersen, Dhamidhu Eratne, Valerie Slegesky, and Lori A. Carpenter
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Male ,Autism Spectrum Disorder ,Gene Expression ,Variable Expression ,Mice ,0302 clinical medicine ,Neurodevelopmental disorder ,Genotype-phenotype distinction ,Pregnancy ,Intellectual disability ,Protein Isoforms ,RNA, Small Interfering ,Child ,de novo variants ,Genetics (clinical) ,Cerebral Cortex ,Mice, Knockout ,Neurons ,0303 health sciences ,Learning Disabilities ,Phenotype ,Pedigree ,Autism spectrum disorder ,Female ,Neuroglia ,Adolescent ,Genotype ,autism spectrum disorder ,genotype-phenotype correlation ,Biology ,Article ,03 medical and health sciences ,Young Adult ,Intellectual Disability ,Genetics ,medicine ,Animals ,Humans ,Loss function ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,disruptive variant ,medicine.disease ,neurodevelopmental disorder ,NCKAP1 ,HEK293 Cells ,Mutation ,Autism ,Transcriptome ,Neuroscience ,030217 neurology & neurosurgery - Abstract
NCKAP1/NAP1 regulates neuronal cytoskeletal dynamics and is essential for neuronal differentiation in the developing brain. Deleterious variants in NCKAP1 have been identified in individuals with autism spectrum disorder (ASD) and intellectual disability; however, its clinical significance remains unclear. To determine its significance, we assemble genotype and phenotype data for 21 affected individuals from 20 unrelated families with predicted deleterious variants in NCKAP1. This includes 16 individuals with de novo (n = 8), transmitted (n = 6), or inheritance unknown (n = 2) truncating variants, two individuals with structural variants, and three with potentially disruptive de novo missense variants. We report a de novo and ultra-rare deleterious variant burden of NCKAP1 in individuals with neurodevelopmental disorders which needs further replication. ASD or autistic features, language and motor delay, and variable expression of intellectual or learning disability are common clinical features. Among inherited cases, there is evidence of deleterious variants segregating with neuropsychiatric disorders. Based on available human brain transcriptomic data, we show that NCKAP1 is broadly and highly expressed in both prenatal and postnatal periods and demostrate enriched expression in excitatory neurons and radial glias but depleted expression in inhibitory neurons. Mouse in utero electroporation experiments reveal that Nckap1 loss of function promotes neuronal migration during early cortical development. Combined, these data support a role for disruptive NCKAP1 variants in neurodevelopmental delay/autism, possibly by interfering with neuronal migration early in cortical development.
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- 2020
9. Mosaicism in ASXL3-related syndrome: Description of five patients from three families
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Katrina Prescott, Anna Platt, Sumit Punj, Meena Balasubramanian, Deciphering Developmental Disorders Study, Schaida Schirwani, Sahar Mansour, Natalie Hauser, and Natalie Canham
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0301 basic medicine ,Male ,Developmental Disabilities ,Germline mosaicism ,Disease ,030105 genetics & heredity ,Saliva sample ,Biology ,Germline ,03 medical and health sciences ,Neurodevelopmental disorder ,Genetics ,medicine ,Humans ,Child ,Gene ,Genetics (clinical) ,Mechanism (biology) ,Mosaicism ,General Medicine ,medicine.disease ,Pedigree ,genomic DNA ,030104 developmental biology ,Child, Preschool ,Mutation ,Female ,Transcription Factors - Abstract
De novo pathogenic variants in the additional sex combs-like 3 (ASXL3) gene cause a rare multi-systemic neurodevelopmental disorder. There is growing evidence that germline and somatic mosaicism are more common and play a greater role in genetic disorders than previously acknowledged. There is one previous report of ASXL3-related syndrome caused by de novo pathogenic variants in two siblings suggesting gonadal mosaicism. In this report, we present five patients with ASXL3-related syndrome, describing two families comprising two non-twin siblings harbouring apparent de novo pathogenic variants in ASXL3. Parents were clinically unaffected and there was no evidence of mosaicism from genomic DNA on exome-trio data, suggesting germline mosaicism in one of the parents. We also describe clinical details of a patient with typical features of ASXL3-related syndrome and mosaic de novo pathogenic variant in ASXL3 in 30-35% of both blood and saliva sample on trio-exome sequencing. We expand the known genetic basis of ASXL3-related syndromes and discuss mosaicism as a disease mechanism in five patients from three unrelated families. The findings of this report highlight the importance of taking gonadal mosaicism into consideration when counselling families regarding recurrence risk. We also discuss postzygotic mosaicism as a cause of fully penetrant ASXL3-related syndrome.
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- 2020
10. Preconception Carrier Screening by Genome Sequencing: Results from the Clinical Laboratory
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Jennifer H. Huang, Marian J. Gilmore, Peggy D. Robertson, Dana Kostiner Simpson, Alan F. Rope, Patricia Himes, Amiee Potter, Allison L. Creason, Laura M. Amendola, Yassmine Akkari, Tia L. Kauffman, Michael O. Dorschner, C. Sue Richards, Jennifer Schleit, Deborah A. Nickerson, Benjamin S. Wilfond, Christine Pak, Gail P. Jarvik, Fei Yang, Jacob A. Reiss, Sumit Punj, and Katrina A.B. Goddard
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0301 basic medicine ,Male ,medicine.medical_specialty ,Heterozygote ,DNA Copy Number Variations ,RNA Splicing ,Genomics ,030105 genetics & heredity ,DNA sequencing ,Article ,03 medical and health sciences ,Pregnancy ,Genetics ,medicine ,Missense mutation ,Humans ,Disease ,Genetic Predisposition to Disease ,Genetic Testing ,RNA, Messenger ,Gene ,Genetics (clinical) ,Whole Genome Sequencing ,business.industry ,Clinical Laboratory Techniques ,Introns ,030104 developmental biology ,Targeted Mutation ,Haplotypes ,Hereditary hemochromatosis ,Mutation ,Medical genetics ,Female ,Preconception Care ,Carrier screening ,business - Abstract
Advances in sequencing technologies permit the analysis of a larger selection of genes for preconception carrier screening. The study was designed as a sequential carrier screen using genome sequencing to analyze 728 gene-disorder pairs for carrier and medically actionable conditions in 131 women and their partners (n = 71) who were planning a pregnancy. We report here on the clinical laboratory results from this expanded carrier screening program. Variants were filtered and classified using the latest American College of Medical Genetics and Genomics (ACMG) guideline; only pathogenic and likely pathogenic variants were confirmed by orthologous methods before being reported. Novel missense variants were classified as variants of uncertain significance. We reported 304 variants in 202 participants. Twelve carrier couples (12/71 couples tested) were identified for common conditions; eight were carriers for hereditary hemochromatosis. Although both known and novel variants were reported, 48% of all reported variants were missense. For novel splice-site variants, RNA-splicing assays were performed to aid in classification. We reported ten copy-number variants and five variants in non-coding regions. One novel variant was reported in F8, associated with hemophilia A; prenatal testing showed that the male fetus harbored this variant and the neonate suffered a life-threatening hemorrhage which was anticipated and appropriately managed. Moreover, 3% of participants had variants that were medically actionable. Compared with targeted mutation screening, genome sequencing improves the sensitivity of detecting clinically significant variants. While certain novel variant interpretation remains challenging, the ACMG guidelines are useful to classify variants in a healthy population.
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- 2018
11. Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine
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Robert C. Green, Katrina A.B. Goddard, Gail P. Jarvik, Laura M. Amendola, Paul S. Appelbaum, Jonathan S. Berg, Barbara A. Bernhardt, Leslie G. Biesecker, Sawona Biswas, Carrie L. Blout, Kevin M. Bowling, Kyle B. Brothers, Wylie Burke, Charlisse F. Caga-anan, Arul M. Chinnaiyan, Wendy K. Chung, Ellen W. Clayton, Gregory M. Cooper, Kelly East, James P. Evans, Stephanie M. Fullerton, Levi A. Garraway, Jeremy R. Garrett, Stacy W. Gray, Gail E. Henderson, Lucia A. Hindorff, Ingrid A. Holm, Michelle Huckaby Lewis, Carolyn M. Hutter, Pasi A. Janne, Steven Joffe, David Kaufman, Bartha M. Knoppers, Barbara A. Koenig, Ian D. Krantz, Teri A. Manolio, Laurence McCullough, Jean McEwen, Amy McGuire, Donna Muzny, Richard M. Myers, Deborah A. Nickerson, Jeffrey Ou, Donald W. Parsons, Gloria M. Petersen, Sharon E. Plon, Heidi L. Rehm, J. Scott Roberts, Dan Robinson, Joseph S. Salama, Sarah Scollon, Richard R. Sharp, Brian Shirts, Nancy B. Spinner, Holly K. Tabor, Peter Tarczy-Hornoch, David L. Veenstra, Nikhil Wagle, Karen Weck, Benjamin S. Wilfond, Kirk Wilhelmsen, Susan M. Wolf, Julia Wynn, Joon-Ho Yu, Michelle Amaral, Laura Amendola, Samuel J. Aronson, Shubhangi Arora, Danielle R. Azzariti, Greg S. Barsh, E.M. Bebin, Barbara B. Biesecker, Brian L. Brown, Amber A. Burt, Peter H. Byers, Muge G. Calikoglu, Sara J. Carlson, Nizar Chahin, Kurt D. Christensen, Wendy Chung, Allison L. Cirino, Ellen Clayton, Laura K. Conlin, Greg M. Cooper, David R. Crosslin, James V. Davis, Kelly Davis, Matthew A. Deardorff, Batsal Devkota, Raymond De Vries, Pamela Diamond, Michael O. Dorschner, Noreen P. Dugan, Dmitry Dukhovny, Matthew C. Dulik, Kelly M. East, Edgar A. Rivera-Munoz, Barbara Evans, Jessica Everett, Nicole Exe, Zheng Fan, Lindsay Z. Feuerman, Kelly Filipski, Candice R. Finnila, Kristen Fishler, Bob Ghrundmeier, Karen Giles, Marian J. Gilmore, Zahra S. Girnary, Katrina Goddard, Steven Gonsalves, Adam S. Gordon, Michele C. Gornick, William M. Grady, David E. Gray, Robert Green, Robert S. Greenwood, Amanda M. Gutierrez, Paul Han, Ragan Hart, Patrick Heagerty, Naomi Hensman, Susan M. Hiatt, Patricia Himes, Fuki M. Hisama, Carolyn Y. Ho, Lily B. Hoffman-Andrews, Celine Hong, Martha J. Horike-Pyne, Sara Hull, Seema Jamal, Brian C. Jensen, Steve Joffe, Jennifer Johnston, Dean Karavite, Tia L. Kauffman, Dave Kaufman, Whitley Kelley, Jerry H. Kim, Christine Kirby, William Klein, Bartha Knoppers, Sek Won Kong, Ian Krantz, Joel B. Krier, Neil E. Lamb, Michele P. Lambert, Lan Q. Le, Matthew S. Lebo, Alexander Lee, Kaitlyn B. Lee, Niall Lennon, Michael C. Leo, Kathleen A. Leppig, Katie Lewis, Michelle Lewis, Neal I. Lindeman, Nicole Lockhart, Bob Lonigro, Edward J. Lose, Philip J. Lupo, Laura Lyman Rodriguez, Frances Lynch, Kalotina Machini, Calum MacRae, Daniel S. Marchuk, Josue N. Martinez, Aaron Masino, Heather M. McLaughlin, Carmit McMullen, Piotr A. Mieczkowski, Jeff Miller, Victoria A. Miller, Rajen Mody, Sean D. Mooney, Elizabeth G. Moore, Elissa Morris, Michael Murray, David Ng, Nelly M. Oliver, Will Parsons, Donald L. Patrick, Jeffrey Pennington, Denise L. Perry, Gloria Petersen, Sharon Plon, Katie Porter, Bradford C. Powell, Sumit Punj, Carmen Radecki Breitkopf, Robin A. Raesz-Martinez, Wendy H. Raskind, Dean A. Reigar, Jacob A. Reiss, Carla A. Rich, Carolyn Sue Richards, Christine Rini, Scott Roberts, Peggy D. Robertson, Jill O. Robinson, Marguerite E. Robinson, Myra I. Roche, Edward J. Romasko, Elisabeth A. Rosenthal, Joseph Salama, Maria I. Scarano, Jennifer Schneider, Christine E. Seidman, Bryce A. Seifert, Brian H. Shirts, Lynette M. Sholl, Javed Siddiqui, Elian Silverman, Shirley Simmons, Janae V. Simons, Debra Skinner, Elena Stoffel, Natasha T. Strande, Shamil Sunyaev, Virginia P. Sybert, Jennifer Taber, Deanne M. Taylor, Christian R. Tilley, Ashley Tomlinson, Susan Trinidad, Ellen Tsai, Peter Ubel, Eliezer M. Van Allen, Jason L. Vassy, Pankaj Vats, Victoria L. Vetter, Raymond D. Vries, Sarah A. Walser, Rebecca C. Walsh, Allison Werner-Lin, Jana Whittle, Ben Wilfond, Kirk C. Wilhelmsen, Yaping Yang, Carol Young, and Brian J. Zikmund-Fisher
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0301 basic medicine ,Adult ,Evidence-based practice ,Biomedical Research ,Best practice ,Exploratory research ,MEDLINE ,Genomics ,Computational biology ,030105 genetics & heredity ,Bioinformatics ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Population Groups ,Genetics ,Medicine ,Genomic medicine ,Humans ,Genetics(clinical) ,Exome ,Child ,Genetics (clinical) ,Exome sequencing ,Medical education ,Clinical Trials as Topic ,business.industry ,Genome, Human ,Correction ,High-Throughput Nucleotide Sequencing ,Human genetics ,United States ,3. Good health ,National Human Genome Research Institute (U.S.) ,030104 developmental biology ,Cardiovascular Diseases ,Evidence-Based Practice ,Human genome ,business ,Psychology ,Software - Abstract
Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine.
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- 2016
12. Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium
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Jonathan S. Berg, Aleksandar Milosavljevic, Carrie Horton, Ragan Hart, Michael O. Dorschner, Michelle D. Amaral, Ronak Y. Patel, Matthew S. Lebo, Carolyn Sue Richards, Greg M. Cooper, Joseph Salama, Gail P. Jarvik, Kevin M. Bowling, Jeffrey Ou, Sharon E. Plon, Matthew C. Dulik, Leslie G. Biesecker, Arezou A. Ghazani, Natasha T. Strande, Jennifer J. Johnston, Laura M. Amendola, Rajarshi Ghosh, Robert C. Green, Yassmine Akkari, Yaping Yang, Laura K. Conlin, Sawona Biswas, Heidi L. Rehm, Michael C. Leo, Heather M. McLaughlin, Christine Pak, and Sumit Punj
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0301 basic medicine ,medicine.medical_specialty ,Biomedical Research ,Evidence-based practice ,Concordance ,MEDLINE ,Exploratory research ,Guidelines as Topic ,Genomics ,Computational biology ,030105 genetics & heredity ,Bioinformatics ,Article ,03 medical and health sciences ,Genetics ,Humans ,Medicine ,Exome ,Genetics(clinical) ,Genetic Testing ,Genetics (clinical) ,Genetic testing ,Incidental Findings ,medicine.diagnostic_test ,Genome, Human ,Molecular pathology ,business.industry ,Interpretation (philosophy) ,Genetic Variation ,High-Throughput Nucleotide Sequencing ,Correction ,Sequence Analysis, DNA ,United States ,Human genetics ,3. Good health ,030104 developmental biology ,Data Interpretation, Statistical ,Evidence-Based Practice ,Mutation ,Medical genetics ,Laboratories ,business ,Software - Abstract
Evaluating the pathogenicity of a variant is challenging given the plethora of types of genetic evidence that laboratories consider. Deciding how to weigh each type of evidence is difficult, and standards have been needed. In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for the assessment of variants in genes associated with Mendelian diseases. Nine molecular diagnostic laboratories involved in the Clinical Sequencing Exploratory Research (CSER) consortium piloted these guidelines on 99 variants spanning all categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign). Nine variants were distributed to all laboratories, and the remaining 90 were evaluated by three laboratories. The laboratories classified each variant by using both the laboratory's own method and the ACMG-AMP criteria. The agreement between the two methods used within laboratories was high (K-alpha = 0.91) with 79% concordance. However, there was only 34% concordance for either classification system across laboratories. After consensus discussions and detailed review of the ACMG-AMP criteria, concordance increased to 71%. Causes of initial discordance in ACMG-AMP classifications were identified, and recommendations on clarification and increased specification of the ACMG-AMP criteria were made. In summary, although an initial pilot of the ACMG-AMP guidelines did not lead to increased concordance in variant interpretation, comparing variant interpretations to identify differences and having a common framework to facilitate resolution of those differences were beneficial for improving agreement, allowing iterative movement toward increased reporting consistency for variants in genes associated with monogenic disease.
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- 2016
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13. Anti-androgen flutamide suppresses hepatocellular carcinoma cell proliferation via the aryl hydrocarbon receptor mediated induction of transforming growth factor-β1
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Hyo Sang Jang, Sumit Punj, Siva Kumar Kolluri, Edmond F. O’Donnell, Nancy I. Kerkvliet, Prasad Rao Kopparapu, William H. Bisson, and Daniel C. Koch
- Subjects
Cancer Research ,Aryl hydrocarbon receptor nuclear translocator ,Carcinoma, Hepatocellular ,Pharmacology ,Flutamide ,Transforming Growth Factor beta1 ,chemistry.chemical_compound ,Prostate cancer ,Genetics ,medicine ,Humans ,Molecular Biology ,Transcription factor ,Cell Proliferation ,biology ,Liver Neoplasms ,Androgen Antagonists ,Hep G2 Cells ,respiratory system ,medicine.disease ,Aryl hydrocarbon receptor ,respiratory tract diseases ,Androgen receptor ,Mechanism of action ,chemistry ,Receptors, Aryl Hydrocarbon ,biology.protein ,medicine.symptom ,Transforming growth factor - Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and a member of the basic helix-loop-helix PER/ARNT/SIM family of chemosensors and developmental regulators. The AhR is widely known as a mediator of dioxin toxicity; however, it also suppresses cancer cell proliferation and recent findings have implicated its role as a tumor suppressor. We conducted a chemical library screen to identify nontoxic AhR ligands with anti-cancer effects and discovered flutamide (Eulexin) as a putative AhR ligand. Flutamide is an androgen receptor (AR) antagonist approved by the United States Food and Drug Administration for the treatment of prostate cancer. We found that flutamide inhibited the growth of several cancer cell lines independent of AR status, and that suppression of AhR expression reversed the anti-proliferative effects of flutamide. We investigated the AhR-dependent mechanism of action of flutamide in human hepatocellular carcinoma cells and identified that transforming growth factor-β1 (TGF-β1) is induced by flutamide in an AhR-dependent manner. In contrast, the potent AhR agonist 2,3,7,8-Tetrachlorodibenzo-p-dioxin had no effect on TGF-β1 expression, indicating the ligand specificity of AhR activation. We also determined that TGF-β1 induction is required for the AhR-dependent growth inhibitory effects of flutamide. Therefore, flutamide may be effective in AhR-positive cancers that are sensitive to TGF-β1 signaling, such as hepatocellular carcinoma.
- Published
- 2014
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