Medical Genetics Commons^™

Hypotonia And Intellectual Disability Without Dysmorphic Features In A Patient With Pign-Related Disease., Isabelle Thiffault, Britton Zuccarelli, Holly Welsh, Xuan Yuan, Emily Farrow, Lee Zellmer, Neil Miller, Sarah Soden, Ahmed Abdelmoity, Robert A Brodsky, Carol Saunders

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BACKGROUND: Defects in the human glycosylphosphatidylinositol anchor biosynthetic pathway are associated with inherited glycosylphosphatidylinositol (GPI)-deficiencies characterized by a broad range of clinical phenotypes including multiple congenital anomalies, dysmorphic faces, developmental delay, hypotonia, and epilepsy. Biallelic variants in PIGN, encoding phosphatidylinositol-glycan biosynthesis class N have been recently associated with multiple congenital anomalies hypotonia seizure syndrome.

CASE PRESENTATION: Our patient is a 2 year old male with hypotonia, global developmental delay, and focal epilepsy. Trio whole-exome sequencing revealed heterozygous variants in PIGN, c.181G > T (p.Glu61*) and c.284G > A (p.Arg95Gln). Analysis of FLAER and anti-CD59 by flow-cytometry demonstrated a shift in this patient's …

Clinical Pharmacogenetics Implementation Consortium Guideline (Cpic) For Cyp2d6 And Cyp2c19 Genotypes And Dosing Of Tricyclic Antidepressants: 2016 Update., J K. Hicks, K Sangkuhl, J J. Swen, V L. Ellingrod, D J. Müller, K Shimoda, J R. Bishop, E D. Kharasch, T C. Skaar, Andrea Gaedigk, H M. Dunnenberger, T E. Klein, K E. Caudle, J C. Stingl

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No abstract provided.

Genomic Contraindications For Heart Transplantation., Danton S. Char, Gabriel Lázaro-Muñoz, Aliessa Barnes, David Magnus, Michael J. Deem, John Lantos

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Genome sequencing raises new ethical challenges. Decoding the genome produces new forms of diagnostic and prognostic information; however, the information is often difficult to interpret. The connection between most genetic variants and their phenotypic manifestations is not understood. This scenario is particularly true for disorders that are not associated with an autosomal genetic variant. The analytic uncertainty is compounded by moral uncertainty about how, exactly, the results of genomic testing should influence clinical decisions. In this Ethics Rounds, we present a case in which genomic findings seemed to play a role in deciding whether a patient was to be listed …

Impact Of Cyp2d6 Genotype On Amitriptyline Efficacy For The Treatment Of Diabetic Peripheral Neuropathy: A Pilot Study., Mamoonah Chaudhry, Marco Alessandrini, Jacobus Rademan, Tyren M. Dodgen, Francois E. Steffens, Danie G. Van Zyl, Andrea Gaedigk, Michael S. Pepper

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AIM: Therapy with low-dose amitriptyline is commonly used to treat painful diabetic peripheral neuropathy. There is a knowledge gap, however, regarding the role of variable CYP2D6-mediated drug metabolism and side effects (SEs). We aimed to generate pilot data to demonstrate that SEs are more frequent in patients with variant CYP2D6 alleles.

METHOD: To that end, 31 randomly recruited participants were treated with low-dose amitriptyline for painful diabetic peripheral neuropathy and their CYP2D6 gene sequenced.

RESULTS: Patients with predicted normal or ultra-rapid metabolizer phenotypes presented with less SEs compared with individuals with decreased CYP2D6 activity.

CONCLUSION: Hence, CYP2D6 genotype contributes to …

Fine-Mapping The Mhc Locus In Juvenile Idiopathic Arthritis (Jia) Reveals Genetic Heterogeneity Corresponding To Distinct Adult Inflammatory Arthritic Diseases., A Hinks, J Bowes, J Cobb, H C. Ainsworth, M C. Marion, M E. Comeau, M Sudman, B Han, Juvenile Arthritis Consortium For Immunochip, Mara L. Becker, J F. Bohnsack, P I W De Bakker, J P. Haas, M Hazen, D J. Lovell, P A. Nigrovic, E Nordal, M Punnaro, A M. Rosenberg, M Rygg, S L. Smith, C A. Wise, V Videm, L R. Wedderburn, A Yarwood, R S M Yeung, S Prahalad, C D. Langefeld, S Raychaudhuri, S D. Thompson, W Thomson

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OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides.

METHODS: Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. …

In Vivo Characterization Of Cyp2d6*12, *29 And *84 Using Dextromethorphan As A Probe Drug: A Case Report., Andrea Gaedigk, Greyson P. Twist, Emily G. Farrow, Jennifer Lowry, Sarah E. Soden, Neil A. Miller

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CYP2D6*84 was first described in a Black South African subject, however, its function remains unknown. Astrolabe, a probabilistic scoring tool developed in our laboratory to call genotypes from whole genome sequence, identified CYP2D6*84 in a trio. The father presented with intermediate metabolism when challenged with the CYP2D6 probe drug dextromethorphan (DM/dextrorphan [DX] = 0.0839). Since his second allele, CYP2D6*12, is nonfunctional, the observed activity is derived by CYP2D6*84. This finding suggests that the allele's hallmark P267H causes decreased activity toward DM and that this allele should receive a value of 0.5 for Activity Score calculations. The mother's DM/DX of 0.0543 …

Metabolic And Molecular Insights Into An Essential Role Of Nicotinamide Phosphoribosyltransferase., Li Q. Zhang, Leon Van Haandel, Min Xiong, Peixin Huang, Daniel P. Heruth, Chengpeng Bi, R Gaedigk, Xun Jiang, Ding-You Li, Gerald Wyckoff, Dmitry N. Grigoryev, Li Gao, Linheng Li, Min Wu, J Steven Leeder, Shui Qing Ye

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Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein implicated in the pathogenesis of acute respiratory distress syndrome, aging, cancer, coronary heart diseases, diabetes, nonalcoholic fatty liver disease, obesity, rheumatoid arthritis, and sepsis. However, the underlying molecular mechanisms of NAMPT in these physiological and pathological processes are not fully understood. Here, we provide experimental evidence that a Nampt gene homozygous knockout (Nampt-/-) resulted in lethality at an early stage of mouse embryonic development and death within 5-10 days in adult mice accompanied by a 25.24±2.22% body weight loss, after the tamoxifen induction of NamptF/F × Cre mice. These results substantiate that Nampt …

Mucopolysaccharidosis Type I Newborn Screening: Best Practices For Diagnosis And Management., Lorne A. Clarke, Andrea M. Atherton, Barbara K. Burton, Debra L. Day-Salvatore, Paige Kaplan, Nancy D. Leslie, C Ronald Ronald Scott, David W. Stockton, Janet A. Thomas, Joseph Muenzer

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No abstract provided.

Genetic Drivers Of Kidney Defects In The Digeorge Syndrome., Esther Lopez-Rivera, Yangfan P. Liu, Miguel Verbitsky, Blair R. Anderson, Valentina P. Capone, Edgar A. Otto, Zhonghai Yan, Adele Mitrotti, Jeremiah Martino, Nicholas J. Steers, David A. Fasel, Katarina Vukojevic, Rong Deng, Silvia E. Racedo, Qingxue Liu, Max Werth, Rik Westland, Asaf Vivante, Gabriel S. Makar, Monica Bodria, Matthew G. Sampson, Christopher E. Gillies, Virginia Vega-Warner, Mariarosa Maiorana, Donald S. Petrey, Barry Honig, Vladimir J. Lozanovski, Rémi Salomon, Laurence Heidet, Wassila Carpentier, Dominique Gaillard, Alba Carrea, Loreto Gesualdo, Daniele Cusi, Claudia Izzi, Francesco Scolari, Joanna A E Van Wijk, Adela Arapovic, Mirna Saraga-Babic, Marijan Saraga, Nenad Kunac, Ali Samii, Donna M. Mcdonald-Mcginn, Terrence B. Crowley, Elaine H. Zackai, Dorota Drozdz, Monika Miklaszewska, Marcin Tkaczyk, Przemyslaw Sikora, Maria Szczepanska, Malgorzata Mizerska-Wasiak, Grazyna Krzemien, Agnieszka Szmigielska, Marcin Zaniew, John M. Darlow, Prem Puri, David Barton, Emilio Casolari, Susan L. Furth, Bradley A. Warady, Zoran Gucev, Hakon Hakonarson, Hana Flogelova, Velibor Tasic, Anna Latos-Bielenska, Anna Materna-Kiryluk, Landino Allegri, Craig S. Wong, Iain A Drummond, Vivette D'Agati, Akira Imamoto, Jonathan M. Barasch, Friedhelm Hildebrandt, Krzysztof Kiryluk, Richard P. Lifton, Bernice E. Morrow, Cecile Jeanpierre, Virginia E. Papaioannou, Gian Marco Ghiggeri, Ali G. Gharavi, Nicholas Katsanis, Simone Sanna-Cherchi

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BACKGROUND: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown.

METHODS: We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice.

RESULTS: We identified heterozygous deletions of 22q11.2 in 1.1% …

Surrogate Pregnancy After Prenatal Diagnosis Of Spina Bifida., Lynnette J. Mazur, Mary Kay Kisthardt, Helen H. Kim, Laura M. Rosas, John Lantos

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Some pregnancies today involve infertile individuals or couples who contract with a fertile woman to carry a pregnancy for them. The woman who carries the pregnancy is referred to as a "gestational carrier." The use of such arrangements is increasing. Most of the time, these arrangements play out as planned; sometimes, however, problems arise. This article discusses a case in which a fetal diagnosis of spina bifida led the infertile couple to request that the gestational carrier terminate the pregnancy, and the gestational carrier did not wish to do so. Experts in the medical and legal issues surrounding surrogacy discuss …

Metronidazole Metabolism In Neonates And The Interplay Between Ontogeny And Genetic Variation., Laura A. Wang, Daniel Gonzalez, J Steven Leeder, Rachel F. Tyndale, Robin E. Pearce, Daniel K. Benjamin, Gregory L. Kearns, Michael Cohen-Wolkowiez, Best Pharmaceuticals For Children Act-Pediatric Trials Network Steering Committee

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No abstract provided.

Newborn Sequencing In Genomic Medicine And Public Health., Jonathan S. Berg, Pankaj B. Agrawal, Donald B. Bailey, Alan H. Beggs, Steven E. Brenner, Amy M. Brower, Julie A. Cakici, Ozge Ceyhan-Birsoy, Kee Chan, Flavia Chen, Robert J. Currier, Dmitry Dukhovny, Robert C. Green, Julie Harris-Wai, Ingrid A. Holm, Brenda Iglesias, Galen Joseph, Stephen F. Kingsmore, Barbara A. Koenig, Pui-Yan Kwok, John Lantos, J Steven Leeder, Megan A. Lewis, Amy L. Mcguire, Laura V. Milko, Sean D. Mooney, Richard B. Parad, Stacey Pereira, Josh E. Petrikin, Bradford C. Powell, Cynthia M. Powell, Jennifer M. Puck, Heidi L. Rehm, Neil Risch, Myra Roche, Joseph T. Shieh, Narayanan Veeraraghavan, Michael S. Watson, Laurel K. Willig, Timothy W. Yu, Tiina Urv, Anastasia L. Wise

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The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing …

Biochemical And Biophysical Methods For Analysis Of Poly(Adp-Ribose) Polymerase 1 And Its Interactions With Chromatin., Maggie H. Chassé, Uma M. Muthurajan, Nicholas J. Clark, Michael A. Kramer, Srinivas Chakravarthy, Thomas Irving, Karolin Luger

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Poly (ADP-Ribose) Polymerase I (PARP-1) is a first responder to DNA damage and participates in the regulation of gene expression. The interaction of PARP-1 with chromatin and DNA is complex and involves at least two different modes of interaction. In its enzymatically inactive state, PARP-1 binds native chromatin with similar affinity as it binds free DNA ends. Automodification of PARP-1 affects interaction with chromatin and DNA to different extents. Here we describe a series of biochemical and biophysical techniques to quantify and dissect the different binding modes of PARP-1 with its various substrates. The techniques listed here allow for high …

Prediction Of Cyp2d6 Phenotype From Genotype Across World Populations., Andrea Gaedigk, Katrin Sangkuhl, Michelle Whirl-Carrillo, Teri Klein, J Steven Leeder

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PURPOSE: Owing to its highly polymorphic nature and major contribution to the metabolism and bioactivation of numerous clinically used drugs, CYP2D6 is one of the most extensively studied drug-metabolizing enzymes and pharmacogenes. CYP2D6 alleles confer no, decreased, normal, or increased activity and cause a wide range of activity among individuals and between populations. However, there is no standard approach to translate diplotypes into predicted phenotype.

METHODS: We exploited CYP2D6 allele-frequency data that have been compiled for Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines (>60,000 subjects, 173 reports) in order to estimate genotype-predicted phenotype status across major world populations based on …

A Novel Compound-Heterozygous Epithelial Cell Adhesion Molecule Mutation In Tufting Enteropathy., Valentina Shakhnovich, Darrell Dinwiddie, Amber Hildreth, Thomas M. Attard, Stephen Kingsmore

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No abstract provided.

Novel Hla-Dp Region Susceptibility Loci Associated With Severe Acute Gvhd., Rakesh K. Goyal, S J. Lee, T Wang, M Trucco, M Haagenson, S R. Spellman, M Verneris, R E. Ferrell

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Despite HLA allele matching, significant acute GvHD remains a major barrier to successful unrelated donor BMT. We conducted a genome-wide association study (GWAS) to identify recipient and donor genes associated with the risk of acute GvHD. A case-control design (grade III-IV versus no acute GvHD) and pooled GWA approach was used to study European-American recipients with hematological malignancies who received myeloablative conditioning non-T-cell-depleted first transplantation from HLA-A, -B, -C, -DRB1, -DQB1 allele level (10/10) matched unrelated donors. DNA samples were divided into three pools and tested in triplicate using the Affymetrix Genome-wide SNP Array 6.0. We identified three novel susceptibility …

Immunodeficiency-Associated Lymphoid Hyperplasia As A Cause Of Intussusception In A Case Of Activated Pi3k-Δ Syndrome., Daniel Mettman, Isabelle Thiffault, Chitra Dinakar, Carol J. Saunders

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Activated PI3K-δ syndrome refers to a recently described primary immunodeficiency syndrome consisting of recurrent sinopulmonary infections, lymphadenopathy, mucosal lymphoid aggregates, increased susceptibility to Epstein-Barr virus and cytomegalovirus, and increased incidence of B-cell lymphomas. Variants in PIK3CD, which encodes the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform, enhance membrane association and kinase activity, resulting in increased signal transduction through the PI3K-Akt pathway. Whole-exome sequencing revealed a pathogenic PIK3CD variant in a patient with history of immunologic impairment, recurrent sinopulmonary infections, and lymphoid hyperplasia presenting as intussusception. This case illustrates that while lymphoid hyperplasia secondary to immunodeficiency is most often unsurprising and …

Mc-Ppea As A New And More Potent Inhibitor Of Clp-Induced Sepsis And Pulmonary Inflammation Than Fk866., Peixin Huang, Mark W Lee, Keivan Sadrerafi, Daniel P. Heruth, Li Q. Zhang, Dev Maulik, Shui Qing Ye

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Our previous study indicated that overexpression of nicotinamide phosphoribosyltransferase (NAMPT) aggravated acute lung injury, while knockdown of NAMPT expression attenuated ventilator-induced lung injury. Recently, we found that meta-carborane-butyl-3-(3-pyridinyl)-2E-propenamide (MC-PPEA, MC4), in which the benzoylpiperidine moiety of FK866 has been replaced by a carborane, displayed a 100-fold increase in NAMPT inhibition over FK866. Here, we determined the effects of MC4 and FK866 on cecal ligation and puncture (CLP) surgery-induced sepsis in C57BL/6J mice. MC4 showed stronger inhibitory effects than FK866 on CLP-induced mortality, serum tumor necrosis factor α (TNFα) levels, pulmonary myeloperoxidase activity, alveolar injury, and interleukin 6 and interleukin1β messenger …