19 results on '"Sumit Punj"'
Search Results
2. COL4A4 variant recently identified: lessons learned in variant interpretation—a case report
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Jenelle Cocorpus, Megan M Hager, Corinne Benchimol, Vanesa Bijol, Fadi Salem, Sumit Punj, Laura Castellanos, Pamela Singer, Christine B Sethna, and Abby Basalely
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Case report ,Alport syndrome ,COL4A4 ,Genetic testing ,Variant interpretations ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Abstract Background Alport syndrome is a hereditary kidney disease characterized by hematuria and proteinuria. Although there have been reports of autosomal dominant COL4A4 variants, this is likely an underdiagnosed condition. Improved access to affordable genetic testing has increased the diagnosis of Alport syndrome. As genetic testing becomes ubiquitous, it is imperative that clinical nephrologists understand the benefits and challenges associated with clinical genetic testing. Case Presentation We present a family of Mexican descent with a heterozygous COL4A4 variant (c.5007delC, ClinVar accession numbers: SCV001580980.2, SCV001993731.1) not previously discussed in detail in the literature. The proband received a biopsy diagnosis suggestive of Fabry disease 18 years after she first developed hematuria and progressed to chronic kidney disease stage III. One year later, the proband was provisionally diagnosed with Alport syndrome after a variant of uncertain significance in the COL4A4 gene was identified following targeted family variant testing of her daughter. Upon review of the medical histories of the proband’s children and niece, all but one had the same variant. Of the four with the variant, three display clinical symptoms of hematuria, and/or proteinuria. The youngest of the four, only months old, has yet to exhibit clinical symptoms. Despite these findings there was a considerable delay in synthesizing this data, as patients were tested in different commercial genetic testing laboratories. Subsequently, understanding this family’s inheritance pattern, family history, and clinical symptoms, as well as the location of the COL4A4 variant resulted in the upgrade of the variant’s classification. Although the classification of this variant varied among different clinical genetic testing laboratories, the consensus was that this variant is likely pathogenic. Conclusions This COL4A4 variant (c.5007delC) not yet discussed in detail in the literature is associated with Alport syndrome. The inheritance pattern is suggestive of autosomal dominant inheritance. This report highlights the intricacies of variant interpretation and classification, the siloed nature of commercial genetic testing laboratories, and the importance of a thorough family history for proper variant interpretation. Additionally, the cases demonstrate the varied clinical presentations of Alport syndrome and suggest the utility of early screening, diagnosis, monitoring, and treatment.
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- 2022
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3. Isolated benign persistent proteinuria with novel association of CUBN (cubilin) variants
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Vivian Shi, Quinn Stein, Dinah Clark, Sumit Punj, Robin Kremsdorf, and Mohammed Faizan
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cubilin gene ,genetic testing ,kidney ,monogenic ,persistent proteinuria ,Medicine ,Medicine (General) ,R5-920 - Abstract
Key Clinical Message We present two siblings with persistent proteinuria and normal kidney function, each carrying the same compound heterozygous variants in the CUBN gene. The CUBN‐related phenotype appears to be dependent upon both variant type and the domain site within the gene. Knowledge of CUBN status may allow for avoidance of invasive testing.
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- 2023
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4. 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
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5. 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
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6. 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
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7. Benzimidazoisoquinolines: a new class of rapidly metabolized aryl hydrocarbon receptor (AhR) ligands that induce AhR-dependent Tregs and prevent murine graft-versus-host disease.
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Sumit Punj, Prasad Kopparapu, Hyo Sang Jang, Jessica L Phillips, Jamie Pennington, Diana Rohlman, Edmond O'Donnell, Patrick L Iversen, Siva Kumar Kolluri, and Nancy I Kerkvliet
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Medicine ,Science - Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that plays multiple roles in regulation of immune and inflammatory responses. The ability of certain AhR ligands to induce regulatory T cells (Tregs) has generated interest in developing AhR ligands for therapeutic treatment of immune-mediated diseases. To this end, we designed a screen for novel Treg-inducing compounds based on our understanding of the mechanisms of Treg induction by the well-characterized immunosuppressive AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We screened a ChemBridge small molecule library and identified 10-chloro-7H-benzimidazo[2,1-a]benzo[de]Iso-quinolin-7-one (10-Cl-BBQ) as a potent AhR ligand that was rapidly metabolized and not cytotoxic to proliferating T cells. Like TCDD,10-Cl-BBQ altered donor CD4(+) T cell differentiation during the early stages of a graft versus host (GVH) response resulting in expression of high levels of CD25, CTLA-4 and ICOS, as well as several genes associated with Treg function. The Treg phenotype required AhR expression in the donor CD4(+) T cells. Foxp3 was not expressed in the AhR-induced Tregs implicating AhR as an independent transcription factor for Treg induction. Structure-activity studies showed that unsubstituted BBQ as well as 4, 11-dichloro-BBQ were capable of inducing AhR-Tregs. Other substitutions reduced activation of AhR. Daily treatment with 10-Cl-BBQ during the GVH response prevented development of GVH disease in an AhR-dependent manner with no overt toxicity. Together, our data provide strong support for development of select BBQs that activate the AhR to induce Tregs for treatment of immune-mediated diseases.
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- 2014
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8. 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
9. 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
10. 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
11. 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
12. A case for expanding carrier testing to include actionable X‐linked disorders
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Deborah A. Nickerson, James V. Davis, Jennifer L. Schneider, Mari J. Gilmore, Benjamin S. Wilfond, Pat Himes, Jacob A. Reiss, Laura M. Amendola, C. Sue Richards, Tia L. Kauffman, Carmit K. McMullen, Yassmine Akkari, Gail P. Jarvik, Amiee Potter, Sumit Punj, Alan F. Rope, and Katrina A.B. Goddard
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Pregnancy ,business.industry ,expanded carrier screening ,Case Report ,General Medicine ,Case Reports ,030204 cardiovascular system & hematology ,Carrier testing ,medicine.disease ,Bioinformatics ,informed decision making ,3. Good health ,03 medical and health sciences ,X‐linked ,0302 clinical medicine ,Mutation (genetic algorithm) ,Medicine ,030212 general & internal medicine ,business ,Carrier screening - Abstract
Key Clinical Message A research study utilizing whole‐genome sequence analysis for preconception carrier screening provided a genome‐first detection of a severe de novo Factor VIII mutation in a woman with implications for pregnancy management and life‐saving interventions of her newborn son, and a challenge to the existing paradigm regarding carrier testing.
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- 2018
13. 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
14. Lessons Learned From A Study Of Genomics-Based Carrier Screening For Reproductive Decision Making
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Stephanie A. Kraft, C. Sue Richards, John F. Dickerson, Tia L. Kauffman, Carmit K. McMullen, Benjamin S. Wilfond, Alan F. Rope, Gail P. Jarvik, Kevin Lutz, Elizabeth V. Clarke, Patricia Himes, Marian J. Gilmore, Michael C. Leo, Kathryn M. Porter, Sumit Punj, Frances L. Lynch, Jacob A. Reiss, Katrina A.B. Goddard, and Jennifer L. Schneider
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0301 basic medicine ,Male ,Genetic counseling ,Clinical Decision-Making ,Genomics ,030105 genetics & heredity ,Risk Assessment ,Article ,03 medical and health sciences ,Neonatal Screening ,Pregnancy ,Humans ,Reproductive decision ,Health policy ,Medical education ,Health Policy ,Genetic Carrier Screening ,Genetic Diseases, Inborn ,Infant, Newborn ,Medical decision making ,United States ,Health care delivery ,Reproductive Health ,Genomic information ,Female ,Health Services Research ,Preconception Care ,Psychology ,Carrier screening ,Delivery of Health Care - Abstract
Genomics-based carrier screening is one of many opportunities to use genomic information to inform medical decision making, but clinicians, health care delivery systems, and payers need to determine whether to offer screening and how to do so in an efficient, ethical way. To shed light on this issue, we conducted a study in the period 2014-17 to inform the design of clinical screening programs and guide further health services research. Many of our results have been published elsewhere; this article summarizes the lessons we learned from that study and offers policy insights. Our experience can inform understanding of the potential impact of expanded carrier screening services on health system workflows and workforces-impacts that depend on the details of the screening approach. We found limited patient or health system harms from expanded screening. We also found that some patients valued the information they learned from the process. Future policy discussions should consider the value of offering such expanded carrier screening in health delivery systems with limited resources.
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- 2018
15. 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.
- Published
- 2016
16. Benzimidazoisoquinolines: a new class of rapidly metabolized aryl hydrocarbon receptor (AhR) ligands that induce AhR-dependent Tregs and prevent murine graft-versus-host disease
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Siva Kumar Kolluri, Hyo Sang Jang, Jamie M. Pennington, Sumit Punj, Patrick L. Iversen, Diana Rohlman, Jessica Lynne Phillips, Prasad Rao Kopparapu, Edmond F. O’Donnell, and Nancy I. Kerkvliet
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medicine.medical_treatment ,Graft vs Host Disease ,lcsh:Medicine ,Ligands ,T-Lymphocytes, Regulatory ,Biochemistry ,Mice ,0302 clinical medicine ,Molecular Cell Biology ,Cytotoxic T cell ,Membrane Receptor Signaling ,IL-2 receptor ,Biomacromolecule-Ligand Interactions ,Receptor ,lcsh:Science ,0303 health sciences ,Multidisciplinary ,biology ,Clinical Pharmacology ,FOXP3 ,Signaling in Selected Disciplines ,respiratory system ,3. Good health ,030220 oncology & carcinogenesis ,Medicine ,Immunotherapy ,Immunologic Receptor Signaling ,Research Article ,Signal Transduction ,Drugs and Devices ,Immunology ,chemical and pharmacologic phenomena ,Immunopathology ,Immunological Signaling ,Structure-Activity Relationship ,03 medical and health sciences ,Immune system ,medicine ,Animals ,Biology ,Transcription factor ,030304 developmental biology ,Transplantation ,lcsh:R ,Immunologic Subspecialties ,Isoquinolines ,Aryl hydrocarbon receptor ,Kinetics ,Receptors, Aryl Hydrocarbon ,biology.protein ,Cancer research ,Benzimidazoles ,Clinical Immunology ,lcsh:Q - Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that plays multiple roles in regulation of immune and inflammatory responses. The ability of certain AhR ligands to induce regulatory T cells (Tregs) has generated interest in developing AhR ligands for therapeutic treatment of immune-mediated diseases. To this end, we designed a screen for novel Treg-inducing compounds based on our understanding of the mechanisms of Treg induction by the well-characterized immunosuppressive AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We screened a ChemBridge small molecule library and identified 10-chloro-7H-benzimidazo[2,1-a]benzo[de]Iso-quinolin-7-one (10-Cl-BBQ) as a potent AhR ligand that was rapidly metabolized and not cytotoxic to proliferating T cells. Like TCDD,10-Cl-BBQ altered donor CD4(+) T cell differentiation during the early stages of a graft versus host (GVH) response resulting in expression of high levels of CD25, CTLA-4 and ICOS, as well as several genes associated with Treg function. The Treg phenotype required AhR expression in the donor CD4(+) T cells. Foxp3 was not expressed in the AhR-induced Tregs implicating AhR as an independent transcription factor for Treg induction. Structure-activity studies showed that unsubstituted BBQ as well as 4, 11-dichloro-BBQ were capable of inducing AhR-Tregs. Other substitutions reduced activation of AhR. Daily treatment with 10-Cl-BBQ during the GVH response prevented development of GVH disease in an AhR-dependent manner with no overt toxicity. Together, our data provide strong support for development of select BBQs that activate the AhR to induce Tregs for treatment of immune-mediated diseases.
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- 2014
17. Identification and Isolation of an Azoreductase from Enterococcus faecium
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Sumit Punj, John G. Cooper, Evan Schwenk, Susan R. Macwana, and Gilbert H. John
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acpD ,FMN binding ,substrate specificity ,Enterococcus faecium ,Enterococcus faecalis ,Cofactor ,AzoEf1 ,Microbiology ,specific activity ,Residue (chemistry) ,chemistry.chemical_compound ,azoreductase ,biology ,AzoA ,Active site ,coenzyme preference ,General Medicine ,biology.organism_classification ,chemistry ,Biochemistry ,Methyl red ,biology.protein ,Specific activity - Abstract
Azo dyes are commonly used in many commercial industries. Some of the azo dyes can produce carcinogenic compounds after being metabolized by azoreductase. Several human intestinal microbiota possess azoreductase activity which plays an important role in the toxicity and mutagenicity of these azo dye compounds. The acpD gene product (AzoEf1) responsible for the azoreductase activity of Enterococcus faecium, an intestinal bacterium, was heterologously expressed, purified and characterized. The protein sequence shares 67% identity with the azoreductase from Enterococcus faecalis, AzoA. Although AzoEf1 possesses many commonalities with AzoA, there are differences in coenzyme preference, residues associated with FMN binding, substrate specificity, and specific activity. AzoEf1 utilized both NADH and NADPH for the reduction of azo dyes, and it contains a leucyl residue at position 104 and threonyl residue at position 19 which differ from AzoA at the active site. Its specific activity was 5095 &mu, M/min/mg and its catalytic efficiency for Methyl red reduction was lower than AzoA.
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- 2009
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18. Purification and Identification of an FMN-dependent NAD(P)H Azoreductase from Enterococcus faecalis
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Gilbert H. John and Sumit Punj
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azo bond ,biology ,Azoreductase ,Chemistry ,AzoA ,Electron donor ,General Medicine ,biology.organism_classification ,Enterococcus faecalis ,Cofactor ,chemistry.chemical_compound ,Affinity chromatography ,Biochemistry ,amine ,E. faecalis ,Methyl red ,NADH ,biology.protein ,azo dye ,NADPH ,Amine gas treating ,NAD+ kinase ,Polyacrylamide gel electrophoresis - Abstract
Azoreductases reduce the azo bond (N=N) in azo dyes to produce colorless amine products. Crude cell extracts from Enterococcus faecalis have been shown to utilize both NADH and NADPH as electron donors for azo dye reduction. An azoreductase was purified from E. faecalis by hydrophobic, anion exchange and affinity chromatography. The azoreductase activity of the purified preparation was tested on a polyacrylamide gel after electrophoresis under native conditions and the protein that decolorized the azo dye (Methyl Red) with both NADH and NADPH was identified by mass spectrometry to be AzoA. Previously, the heterologously expressed and purified AzoA was shown to utilize NADH only for the reduction of Methyl Red. However, AzoA purified from the wild-type organism was shown to utilize both coenzymes but with more than 180-fold preference for NADH over NADPH as an electron donor to reduce Methyl Red. Also, its specific activity was more than 150-fold higher than the previous study on AzoA when NADH was used as the electron donor. The catalytic efficiency for Methyl Red reduction by AzoA from E. faecalis was several orders of magnitude higher than other azoreductases that were purified from a heterologous source.
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- 2008
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19. Lessons Learned From A Study Of Genomics-Based Carrier Screening For Reproductive Decision Making.
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Wilfond BS, Kauffman TL, Jarvik GP, Reiss JA, Richards CS, McMullen C, Gilmore M, Himes P, Kraft SA, Porter KM, Schneider JL, Punj S, Leo MC, Dickerson JF, Lynch FL, Clarke E, Rope AF, Lutz K, and Goddard KAB
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- Female, Genetic Diseases, Inborn epidemiology, Health Services Research, Humans, Infant, Newborn, Male, Preconception Care methods, Pregnancy, Reproductive Health, Risk Assessment, United States, Clinical Decision-Making methods, Delivery of Health Care organization & administration, Genetic Carrier Screening methods, Genetic Diseases, Inborn diagnosis, Genomics, Neonatal Screening methods
- Abstract
Genomics-based carrier screening is one of many opportunities to use genomic information to inform medical decision making, but clinicians, health care delivery systems, and payers need to determine whether to offer screening and how to do so in an efficient, ethical way. To shed light on this issue, we conducted a study in the period 2014-17 to inform the design of clinical screening programs and guide further health services research. Many of our results have been published elsewhere; this article summarizes the lessons we learned from that study and offers policy insights. Our experience can inform understanding of the potential impact of expanded carrier screening services on health system workflows and workforces-impacts that depend on the details of the screening approach. We found limited patient or health system harms from expanded screening. We also found that some patients valued the information they learned from the process. Future policy discussions should consider the value of offering such expanded carrier screening in health delivery systems with limited resources.
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- 2018
- Full Text
- View/download PDF
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