DOCSLIB.ORG

Immunodeficiency Next-Generation Sequencing Panels

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Immunodeficiency Next-Generation Sequencing Panels IMMUNODEFICIENCY NEXT-GENERATION SEQUENCING PANELS Mail: One Gustave L. Levy Place, Box 1497 CLIA #: 33D2097541 Specimens: 1428 Madison Ave, Atran Bldg, Rm 2-25 T: 800-298-6470 1 New YorK, NY 10029 F: 212-241-0139 www.sema4genomics.com Mail: One Gustave L. Levy Place, Box 1497 CLIA #: 33D2097541 Specimens: 1428 Madison Ave, Atran Bldg, Rm 2-25 T: 800-298-6470 2 New YorK, NY 10029 F: 212-241-0139 www.sema4genomics.com Table of Contents GENETIC TESTING FOR IMMUNODEFICIENCY 4 GENETICS 4 INDICATIONS 4 TESTING METHODS, SENSITIVITY, AND LIMITATIONS 4 TURNAROUND TIME 7 SPECIMEN AND SHIPPING REQUIREMENTS 7 CUSTOMER SERVICES AND GENETIC COUNSELING 8 THE COMPREHENSIVE IMMUNODEFIENCY PANEL 9 PRIMARY IMMUNODEFIENCY (PID) SUBPANEL 22 INFLAMMATORY BOWEL DISEASE (IBD) SUBPANEL 32 SEVERE COMBINED IMMUNODEFICIENCY (SCID) SUBPANEL 36 REFERENCES 38 DISCLAIMER 46 Mail: One Gustave L. Levy Place, Box 1497 CLIA #: 33D2097541 Specimens: 1428 Madison Ave, Atran Bldg, Rm 2-25 T: 800-298-6470 3 New YorK, NY 10029 F: 212-241-0139 www.sema4genomics.com Genetic Testing for IMMUNODEFICIENCY Inherited disorders of the immune system include over 300 Known diseases in the world with prevalence rates of more than 1 in 1,000 in the US (Joshi, et al 2009). Genetic defects constitute the vast majority and are the main driver of immunological diseases with diagnosable causes (Zhernakova, et al 2009). Symptoms and severity range from mild increases in susceptibility to infection and gastrointestinal disorders to the inability to survive in non-sterile environments. Sema4 utilizes Agilent SureSelectQXT target enrichment library prep with Illumina NovaSeq NGS platform to detect clinically significant variants in immunodeficiency-related genes selected based on available evidence to date. The genes in this panel and subpanels were curated based on careful consideration of literature review, active physician input, and comparison against existing tests. The Comprehensive Panel includes 250 genes with the following subpanels: Primary Immunodeficiency (PID; 206), Inflammatory Bowel Disease (IBD; 59), and Severe Combined Immunodeficiency (SCID; 26). Our results aim to pinpoint the genetic basis of a patient’s immunological disease thereby aiding physicians when developing healthcare plans and allowing genetic counselors to advise the patient in family planning and carrier status relative risK for family members. Genetics The disorders included in this panel may be inherited in an autosomal dominant (AD), autosomal recessive (AR), X-linKed (XL), or isolated cases (IC) manner. For genes displaying an AD mode of inheritance, an affected parent carrying the mutated gene has a 50% chance of passing the variant on to an offspring, regardless of gender. Some of these genes are not fully penetrant, meaning that an individual may have a mutated gene but not display any of the signs/symptoms of the disorder. Additionally, these disorders may have variable expressivity indicating that individuals carrying the same pathogenic variant may display differing features and/or differing severity. For diseases with AR inheritance, the risk for a couple who are both carriers to have a child affected with the disease is 25% for each pregnancy. The parents of an affected child are most often obligate carriers (heterozygotes) and each carry one mutant allele (unless a de novo mutation occurs). An X-linKed inheritance means that the risK of a male offspring with the disorder will be 50% if the mother carries an XL mutation. Depending on the X-inactivation pattern of the gene, a mother and her daughters may rarely be affected. Although X-linKed diseases are normally transmitted from mother to son, transmission of an X-linKed mutation will occur from an affected father to each daughter, but will not occur from father to son. An IC mode of inheritance indicates no prior family history. Indications 1. Clinical status: to confirm a clinical diagnosis in an affected patient, in an individual with unKnown status (no screening/evaluation), or in unaffected relatives of an affected patient (all screening/evaluations(s) normal). The purpose of the test may be diagnostic, carrier testing, familial follow-up on a known family variant, or prenatal testing for known variant(s). 2. Treatment: to clarify the cause of an individual’s immunodeficiency and/or inflammatory bowel disease, provide information on the likelihood of related health issues, and guide treatment. 3. Family risK: to establish risK to other family members and future generations. For patients with a suspected syndrome or disorder, please consider single gene sequencing or associated subpanels prior to ordering the coMprehensive panel. Testing Methods, Sensitivity, and LiMitations Next Generation Sequencing (NGS) (Analytical Detection Rate >95%) Agilent SureSelectTM QXT technology is used with a custom capture library to target the exonic regions and intron/exon splice junctions of the relevant genes, as well as a number of UTR, intronic or promoter regions that Mail: One Gustave L. Levy Place, Box 1497 CLIA #: 33D2097541 Specimens: 1428 Madison Ave, Atran Bldg, Rm 2-25 T: 800-298-6470 4 New YorK, NY 10029 F: 212-241-0139 www.sema4genomics.com contain previously reported mutations. Samples are pooled and sequenced on the Illumina NovaSeq platform in the Xp workflow, using 100 bp paired-end reads. The sequencing data are analyzed using a custom bioinformatics algorithm designed and validated in-house. In our validation, average coverage was greater than 200X per sample with >99.9% of regions covered at greater than 20X. The coding exons and splice junctions of the Known protein-coding RefSeq genes are assessed for the average depth of coverage (minimum of 20X) and data quality threshold values. Most exons not meeting a minimum of >20X read depth across the exon are further analyzed by Sanger sequencing. Please note that several genomic regions present difficulties in mapping or obtaining read depth >20X. These regions include, but are not limited to, UTRs, promoters, and deep intronic areas. In addition, a mutation(s) in a gene not included on the panel could be present in this patient. The following regions (hg19 coordinates) have been excluded due to lacK of amenability to NGS or Sanger sequencing, high GC content, high homology, lacK of Known clinically significant variants, or overlap with repetitive regions: C4A chr6:31959812-31960020, C4A chr6:31962010-31962172, C4A chr6:31968818-31968943, C4A chr6:31964594-31964849, C4A chr6:31961479-31961613, C4A chr6:31961681- 31961774, C4A chr6:31962717-31962791, C4A chr6:31962870-31962982, C4A chr6:31963095-31963327, C4A chr6:31949873-31949960, C4A chr6:31950070-31950291, C4A chr6:31950483-31950707, C4A chr6:31950894- 31950987, C4A chr6:31951043-31951154, C4A chr6:31951350-31951455, C4A chr6:31951603-31951722, C4A chr6:31951838-31951966, C4A chr6:31952041-31952196, C4A chr6:31958957-31959095, C4A chr6:31959172- 31959374, C4A chr6:31959497-31959702, C4A chr6:31960151-31960332, C4A chr6:31960561-31960710, C4A chr6:31960855-31960952, C4A chr6:31961190-31961410, C4A chr6:31965470-31965552, C4A chr6:31966579- 31966695, C4A chr6:31966770-31966979, C4A chr6:31967071-31967184, C4A chr6:31967252-31967349, C4A chr6:31969086-31969198, C4A chr6:31969261-31969382, C4A chr6:31969542-31969648, C4A chr6:31969888- 31970043, C4A chr6:31970164-31970328, C4A chr6:31962263-31962495, C4A chr6:31963484-31963582, C4A chr6:31963720-31963899, C4A chr6:31963972-31964111, C4A chr6:31964909-31965099, C4B chr6:31992550- 31992758, C4B chr6:32001555-32001680, C4B chr6:31997331-31997586, C4B chr6:31992235-31992440, C4B chr6:31996458-31996637, C4B chr6:31994217-31994351, C4B chr6:31994419-31994512, C4B chr6:31995455- 31995529, C4B chr6:31995608-31995720, C4B chr6:31995833-31996065, C4B chr6:31982611-31982698, C4B chr6:31982808-31983029, C4B chr6:31983221-31983445, C4B chr6:31983632-31983725, C4B chr6:31983781- 31983892, C4B chr6:31984088-31984193, C4B chr6:31984341-31984460, C4B chr6:31984576-31984704, C4B chr6:31984779-31984934, C4B chr6:31991695-31991833, C4B chr6:31991910-31992112, C4B chr6:31992889- 31993070, C4B chr6:31993299-31993448, C4B chr6:31993593-31993690, C4B chr6:31993928-31994148, C4B chr6:31998207-31998289, C4B chr6:31999316-31999432, C4B chr6:31999507-31999716, C4B chr6:31999808- 31999921, C4B chr6:31999989-32000086, C4B chr6:32001823-32001935, C4B chr6:32001998-32002119, C4B chr6:32002279-32002385, C4B chr6:32002625-32002780, C4B chr6:32002901-32003065, C4B chr6:31995001- 31995233, C4B chr6:31994748-31994910, C4B chr6:31996222-31996320, C4B chr6:31996710-31996849, C4B chr6:31997646-31997836, CCDC40 chr17:78010450-78010501, CFHR1 chr1:196788963-196789043, CFHR1 chr1:196799618-196799823, CFHR3 chr1:196759163-196759368, CORO1A chr16:30200169-30200296, CSF2RA chrX:1422142-1422266, CYBB chrX:37656945-37657156, DCLRE1C chr10:14966805-14967016, DUOX2 chr15:45403297-45403486, IKBKG chrX:153792522-153792687, IKBKG chrX:153784368-153784602, IKBKG chrX:153786735-153786876, IKBKG chrX:153788610-153788785, IKBKG chrX:153791013-153791179, IKBKG chrX:153792162-153792246, IKBKG chrX:153791762-153791927, IKBKG chrX:153789891-153790010, IRAK4 chr12:44178044-44178050, NCF1 chr7:74203371-74203515, NCF1 chr7:74202316-74202443, NCF1 chr7:74199516-74199656, NCF1 chr7:74197270-74197415, NCF1 chr7:74191601-74191704, NCF1 chr7:74197856-74197986, NCF1 chr7:74193591-74193779, NCF1 chr7:74202891-74203059, NCF1 chr7:74193416-74193514, NCF1 chr7:74195114-74195192, NCF1 chr7:74188367-74188461, PMS2 chr7:6026378-6027262, PMS2 chr7:6017207-6017432,
Load more

Recommended publications
  • IDF Patient & Family Handbook
    Immune Deficiency Foundation Patient & Family Handbook for Primary Immunodeficiency Diseases This book contains general medical information which cannot be applied safely to any individual case. Medical knowledge and practice can change rapidly. Therefore, this book should not be used as a substitute for professional medical advice. FIFTH EDITION COPYRIGHT 1987, 1993, 2001, 2007, 2013 IMMUNE DEFICIENCY FOUNDATION Copyright 2013 by Immune Deficiency Foundation, USA. REPRINT 2015 Readers may redistribute this article to other individuals for non-commercial use, provided that the text, html codes, and this notice remain intact and unaltered in any way. The Immune Deficiency Foundation Patient & Family Handbook may not be resold, reprinted or redistributed for compensation of any kind without prior written permission from the Immune Deficiency Foundation. If you have any questions about permission, please contact: Immune Deficiency Foundation, 110 West Road, Suite 300, Towson, MD 21204, USA; or by telephone at 800-296-4433. Immune Deficiency Foundation Patient & Family Handbook for Primary Immunodeficency Diseases 5th Edition This publication has been made possible through a generous grant from Baxalta Incorporated Immune Deficiency Foundation 110 West Road, Suite 300 Towson, MD 21204 800-296-4433 www.primaryimmune.org [email protected] EDITORS R. Michael Blaese, MD, Executive Editor Francisco A. Bonilla, MD, PhD Immune Deficiency Foundation Boston Children’s Hospital Towson, MD Boston, MA E. Richard Stiehm, MD M. Elizabeth Younger, CPNP, PhD University of California Los Angeles Johns Hopkins Los Angeles, CA Baltimore, MD CONTRIBUTORS Mark Ballow, MD Joseph Bellanti, MD R. Michael Blaese, MD William Blouin, MSN, ARNP, CPNP State University of New York Georgetown University Hospital Immune Deficiency Foundation Miami Children’s Hospital Buffalo, NY Washington, DC Towson, MD Miami, FL Francisco A.
    [Show full text]
  • IDF Guide to Hematopoietic Stem Cell Transplantation
    Guide to Hematopoietic Stem Cell Transplantation Immune Deficiency Foundation Guide to Hematopoietic Stem Cell Transplantation This publication contains general medical information that cannot be applied safely to any individual case. Medical knowledge and practice can change rapidly. Therefore, this publication should not be used as a substitute for professional medical advice. In all cases, patients and caregivers should consult their healthcare providers. Each patient’s condition and treatment are unique. Copyright 2018 by Immune Deficiency Foundation, USA Readers may redistribute this guide to other individuals for non-commercial use, provided that the text, html codes, and this notice remain intact and unaltered in any way. Immune Deficiency Foundation Guide to Hematopoietic Stem Cell Transplantation may not be resold, reprinted or redistributed for compensation of any kind without prior written permission from the Immune Deficiency Foundation (IDF). If you have any questions about permission, please contact: Immune Deficiency Foundation, 110 West Road, Suite 300, Towson, MD 21204, USA, or by telephone: 800-296-4433. For more information about IDF, go to: www.primaryimmune.org. This publication has been made possible through the IDF SCID Initiative and the SCID, Angels for Life Foundation. Acknowledgements The Immune Deficiency Foundation would like to thank the organizations and individuals who helped make this publication possible and contributed to the development of the Immune Deficiency Foundation Guide to Hematopoietic Stem
    [Show full text]
  • Noelia Díaz Blanco
    Effects of environmental factors on the gonadal transcriptome of European sea bass (Dicentrarchus labrax), juvenile growth and sex ratios Noelia Díaz Blanco Ph.D. thesis 2014 Submitted in partial fulfillment of the requirements for the Ph.D. degree from the Universitat Pompeu Fabra (UPF). This work has been carried out at the Group of Biology of Reproduction (GBR), at the Department of Renewable Marine Resources of the Institute of Marine Sciences (ICM-CSIC). Thesis supervisor: Dr. Francesc Piferrer Professor d’Investigació Institut de Ciències del Mar (ICM-CSIC) i ii A mis padres A Xavi iii iv Acknowledgements This thesis has been made possible by the support of many people who in one way or another, many times unknowingly, gave me the strength to overcome this "long and winding road". First of all, I would like to thank my supervisor, Dr. Francesc Piferrer, for his patience, guidance and wise advice throughout all this Ph.D. experience. But above all, for the trust he placed on me almost seven years ago when he offered me the opportunity to be part of his team. Thanks also for teaching me how to question always everything, for sharing with me your enthusiasm for science and for giving me the opportunity of learning from you by participating in many projects, collaborations and scientific meetings. I am also thankful to my colleagues (former and present Group of Biology of Reproduction members) for your support and encouragement throughout this journey. To the “exGBRs”, thanks for helping me with my first steps into this world. Working as an undergrad with you Dr.
    [Show full text]
  • Dyskeratosis Congenita Precision Panel Overview Indications Clinical
    Dyskeratosis Congenita Precision Panel Overview Dyskeratosis Congenita (DKC) is a rare, progressive bone marrow failure syndrome characterized by reticulated skin hyperpigmentation, nail dystrophy and oral leukoplakia. Patients usually present with symptoms of skin hyperpigmentation and nail changes during the first decade of life. It is caused by germline mutations in genes regulating telomere maintenance, resulting in very short telomeres. DKC is a genetically heterogeneous with X-linked recessive form being the most common, autosomal dominant and autosomal recessive subtypes based on different patters of inheritance. Early mortality is associated with bone marrow failure, infections, lung and pulmonary complications as well as malignancy. The Igenomix Dyskeratosis Congenita Precision Panel can be used for an accurate and directed diagnosis as well as differential diagnosis of reticulate pigmentary disorders ultimately leading to a better management and prognosis of the disease. It provides a comprehensive analysis of the genes involved in this disease using next-generation sequencing (NGS) to fully understand the spectrum of relevant genes involved. Indications The Igenomix Dyskeratosis Congenita Precision Panel is used for patients with a clinical diagnosis or suspicion with or without the following symptoms: ‐ Abnormal skin pigmentation (tan-to-gray hyperpigmented or hypopigmented macules and patches) ‐ Nail dystrophy ‐ Skin atrophy and telangiectasia ‐ Alopecia of the skin, eyebrows and eyelashes ‐ Mucosal leukoplakia ‐ Bone marrow failure ‐ Dental manifestations Clinical Utility The clinical utility of this panel is: ‐ The genetic and molecular confirmation for an accurate clinical diagnosis of a symptomatic patient. 1 ‐ Early initiation of treatment involving a multidisciplinary team in the form of hematopoietic stem cell transplantation as well as medical care to prevent complications and early surveillance of malignancy.
    [Show full text]
  • The Hematological Complications of Alcoholism
    The Hematological Complications of Alcoholism HAROLD S. BALLARD, M.D. Alcohol has numerous adverse effects on the various types of blood cells and their functions. For example, heavy alcohol consumption can cause generalized suppression of blood cell production and the production of structurally abnormal blood cell precursors that cannot mature into functional cells. Alcoholics frequently have defective red blood cells that are destroyed prematurely, possibly resulting in anemia. Alcohol also interferes with the production and function of white blood cells, especially those that defend the body against invading bacteria. Consequently, alcoholics frequently suffer from bacterial infections. Finally, alcohol adversely affects the platelets and other components of the blood-clotting system. Heavy alcohol consumption thus may increase the drinker’s risk of suffering a stroke. KEY WORDS: adverse drug effect; AODE (alcohol and other drug effects); blood function; cell growth and differentiation; erythrocytes; leukocytes; platelets; plasma proteins; bone marrow; anemia; blood coagulation; thrombocytopenia; fibrinolysis; macrophage; monocyte; stroke; bacterial disease; literature review eople who abuse alcohol1 are at both direct and indirect. The direct in the number and function of WBC’s risk for numerous alcohol-related consequences of excessive alcohol increases the drinker’s risk of serious Pmedical complications, includ- consumption include toxic effects on infection, and impaired platelet produc- ing those affecting the blood (i.e., the the bone marrow; the blood cell pre- tion and function interfere with blood cursors; and the mature red blood blood cells as well as proteins present clotting, leading to symptoms ranging in the blood plasma) and the bone cells (RBC’s), white blood cells from a simple nosebleed to bleeding in marrow, where the blood cells are (WBC’s), and platelets.
    [Show full text]
  • Structures, Functions, and Mechanisms of Filament Forming Enzymes: a Renaissance of Enzyme Filamentation
    Structures, Functions, and Mechanisms of Filament Forming Enzymes: A Renaissance of Enzyme Filamentation A Review By Chad K. Park & Nancy C. Horton Department of Molecular and Cellular Biology University of Arizona Tucson, AZ 85721 N. C. Horton ([email protected], ORCID: 0000-0003-2710-8284) C. K. Park ([email protected], ORCID: 0000-0003-1089-9091) Keywords: Enzyme, Regulation, DNA binding, Nuclease, Run-On Oligomerization, self-association 1 Abstract Filament formation by non-cytoskeletal enzymes has been known for decades, yet only relatively recently has its wide-spread role in enzyme regulation and biology come to be appreciated. This comprehensive review summarizes what is known for each enzyme confirmed to form filamentous structures in vitro, and for the many that are known only to form large self-assemblies within cells. For some enzymes, studies describing both the in vitro filamentous structures and cellular self-assembly formation are also known and described. Special attention is paid to the detailed structures of each type of enzyme filament, as well as the roles the structures play in enzyme regulation and in biology. Where it is known or hypothesized, the advantages conferred by enzyme filamentation are reviewed. Finally, the similarities, differences, and comparison to the SgrAI system are also highlighted. 2 Contents INTRODUCTION…………………………………………………………..4 STRUCTURALLY CHARACTERIZED ENZYME FILAMENTS…….5 Acetyl CoA Carboxylase (ACC)……………………………………………………………………5 Phosphofructokinase (PFK)……………………………………………………………………….6
    [Show full text]
  • Orphanet Report Series Rare Diseases Collection
    Marche des Maladies Rares – Alliance Maladies Rares Orphanet Report Series Rare Diseases collection DecemberOctober 2013 2009 List of rare diseases and synonyms Listed in alphabetical order www.orpha.net 20102206 Rare diseases listed in alphabetical order ORPHA ORPHA ORPHA Disease name Disease name Disease name Number Number Number 289157 1-alpha-hydroxylase deficiency 309127 3-hydroxyacyl-CoA dehydrogenase 228384 5q14.3 microdeletion syndrome deficiency 293948 1p21.3 microdeletion syndrome 314655 5q31.3 microdeletion syndrome 939 3-hydroxyisobutyric aciduria 1606 1p36 deletion syndrome 228415 5q35 microduplication syndrome 2616 3M syndrome 250989 1q21.1 microdeletion syndrome 96125 6p subtelomeric deletion syndrome 2616 3-M syndrome 250994 1q21.1 microduplication syndrome 251046 6p22 microdeletion syndrome 293843 3MC syndrome 250999 1q41q42 microdeletion syndrome 96125 6p25 microdeletion syndrome 6 3-methylcrotonylglycinuria 250999 1q41-q42 microdeletion syndrome 99135 6-phosphogluconate dehydrogenase 67046 3-methylglutaconic aciduria type 1 deficiency 238769 1q44 microdeletion syndrome 111 3-methylglutaconic aciduria type 2 13 6-pyruvoyl-tetrahydropterin synthase 976 2,8 dihydroxyadenine urolithiasis deficiency 67047 3-methylglutaconic aciduria type 3 869 2A syndrome 75857 6q terminal deletion 67048 3-methylglutaconic aciduria type 4 79154 2-aminoadipic 2-oxoadipic aciduria 171829 6q16 deletion syndrome 66634 3-methylglutaconic aciduria type 5 19 2-hydroxyglutaric acidemia 251056 6q25 microdeletion syndrome 352328 3-methylglutaconic
    [Show full text]
  • Practice Parameter for the Diagnosis and Management of Primary Immunodeficiency
    Practice parameter Practice parameter for the diagnosis and management of primary immunodeficiency Francisco A. Bonilla, MD, PhD, David A. Khan, MD, Zuhair K. Ballas, MD, Javier Chinen, MD, PhD, Michael M. Frank, MD, Joyce T. Hsu, MD, Michael Keller, MD, Lisa J. Kobrynski, MD, Hirsh D. Komarow, MD, Bruce Mazer, MD, Robert P. Nelson, Jr, MD, Jordan S. Orange, MD, PhD, John M. Routes, MD, William T. Shearer, MD, PhD, Ricardo U. Sorensen, MD, James W. Verbsky, MD, PhD, David I. Bernstein, MD, Joann Blessing-Moore, MD, David Lang, MD, Richard A. Nicklas, MD, John Oppenheimer, MD, Jay M. Portnoy, MD, Christopher R. Randolph, MD, Diane Schuller, MD, Sheldon L. Spector, MD, Stephen Tilles, MD, Dana Wallace, MD Chief Editor: Francisco A. Bonilla, MD, PhD Co-Editor: David A. Khan, MD Members of the Joint Task Force on Practice Parameters: David I. Bernstein, MD, Joann Blessing-Moore, MD, David Khan, MD, David Lang, MD, Richard A. Nicklas, MD, John Oppenheimer, MD, Jay M. Portnoy, MD, Christopher R. Randolph, MD, Diane Schuller, MD, Sheldon L. Spector, MD, Stephen Tilles, MD, Dana Wallace, MD Primary Immunodeficiency Workgroup: Chairman: Francisco A. Bonilla, MD, PhD Members: Zuhair K. Ballas, MD, Javier Chinen, MD, PhD, Michael M. Frank, MD, Joyce T. Hsu, MD, Michael Keller, MD, Lisa J. Kobrynski, MD, Hirsh D. Komarow, MD, Bruce Mazer, MD, Robert P. Nelson, Jr, MD, Jordan S. Orange, MD, PhD, John M. Routes, MD, William T. Shearer, MD, PhD, Ricardo U. Sorensen, MD, James W. Verbsky, MD, PhD GlaxoSmithKline, Merck, and Aerocrine; has received payment for lectures from Genentech/ These parameters were developed by the Joint Task Force on Practice Parameters, representing Novartis, GlaxoSmithKline, and Merck; and has received research support from Genentech/ the American Academy of Allergy, Asthma & Immunology; the American College of Novartis and Merck.
    [Show full text]
  • Mackenzie's Mission Gene & Condition List
    Mackenzie’s Mission Gene & Condition List What conditions are being screened for in Mackenzie’s Mission? Genetic carrier screening offered through this research study has been carefully developed. It is focused on providing people with information about their chance of having children with a severe genetic condition occurring in childhood. The screening is designed to provide genetic information that is relevant and useful, and to minimise uncertain and unclear information. How the conditions and genes are selected The Mackenzie’s Mission reproductive genetic carrier screen currently includes approximately 1300 genes which are associated with about 750 conditions. The reason there are fewer conditions than genes is that some genetic conditions can be caused by changes in more than one gene. The gene list is reviewed regularly. To select the conditions and genes to be screened, a committee comprised of experts in genetics and screening was established including: clinical geneticists, genetic scientists, a genetic pathologist, genetic counsellors, an ethicist and a parent of a child with a genetic condition. The following criteria were developed and are used to select the genes to be included: • Screening the gene is technically possible using currently available technology • The gene is known to cause a genetic condition • The condition affects people in childhood • The condition has a serious impact on a person’s quality of life and/or is life-limiting o For many of the conditions there is no treatment or the treatment is very burdensome for the child and their family. For some conditions very early diagnosis and treatment can make a difference for the child.
    [Show full text]
  • Mackenzie's Mission Gene & Condition List
    Mackenzie’s Mission Gene & Condition List What conditions are being screened for in Mackenzie’s Mission? Genetic carrier screening offered through this research study has been carefully developed. It is focused on providing people with information about their chance of having children with a severe genetic condition occurring in childhood. The screening is designed to provide genetic information that is relevant and useful, and to minimise uncertain and unclear information. How the conditions and genes are selected The Mackenzie’s Mission reproductive genetic carrier screen currently includes approximately 1300 genes which are associated with about 750 conditions. The reason there are fewer conditions than genes is that some genetic conditions can be caused by changes in more than one gene. The gene list is reviewed regularly. To select the conditions and genes to be screened, a committee comprised of experts in genetics and screening was established including: clinical geneticists, genetic scientists, a genetic pathologist, genetic counsellors, an ethicist and a parent of a child with a genetic condition. The following criteria were developed and are used to select the genes to be included: • Screening the gene is technically possible using currently available technology • The gene is known to cause a genetic condition • The condition affects people in childhood • The condition has a serious impact on a person’s quality of life and/or is life-limiting o For many of the conditions there is no treatment or the treatment is very burdensome for the child and their family. For some conditions very early diagnosis and treatment can make a difference for the child.
    [Show full text]
  • Whole Exome Sequencing Gene Package Intellectual Disability, Version 9.1, 31-1-2020
    Whole Exome Sequencing Gene package Intellectual disability, version 9.1, 31-1-2020 Technical information DNA was enriched using Agilent SureSelect DNA + SureSelect OneSeq 300kb CNV Backbone + Human All Exon V7 capture and paired-end sequenced on the Illumina platform (outsourced). The aim is to obtain 10 Giga base pairs per exome with a mapped fraction of 0.99. The average coverage of the exome is ~50x. Duplicate and non-unique reads are excluded. Data are demultiplexed with bcl2fastq Conversion Software from Illumina. Reads are mapped to the genome using the BWA-MEM algorithm (reference: http://bio-bwa.sourceforge.net/). Variant detection is performed by the Genome Analysis Toolkit HaplotypeCaller (reference: http://www.broadinstitute.org/gatk/). The detected variants are filtered and annotated with Cartagenia software and classified with Alamut Visual. It is not excluded that pathogenic mutations are being missed using this technology. At this moment, there is not enough information about the sensitivity of this technique with respect to the detection of deletions and duplications of more than 5 nucleotides and of somatic mosaic mutations (all types of sequence changes). HGNC approved Phenotype description including OMIM phenotype ID(s) OMIM median depth % covered % covered % covered gene symbol gene ID >10x >20x >30x A2ML1 {Otitis media, susceptibility to}, 166760 610627 66 100 100 96 AARS1 Charcot-Marie-Tooth disease, axonal, type 2N, 613287 601065 63 100 97 90 Epileptic encephalopathy, early infantile, 29, 616339 AASS Hyperlysinemia,
    [Show full text]
  • The Genetics and Clinical Manifestations of Telomere Biology Disorders Sharon A
    REVIEW The genetics and clinical manifestations of telomere biology disorders Sharon A. Savage, MD1, and Alison A. Bertuch, MD, PhD2 3 Abstract: Telomere biology disorders are a complex set of illnesses meric sequence is lost with each round of DNA replication. defined by the presence of very short telomeres. Individuals with classic Consequently, telomeres shorten with aging. In peripheral dyskeratosis congenita have the most severe phenotype, characterized blood leukocytes, the cells most extensively studied, the rate 4 by the triad of nail dystrophy, abnormal skin pigmentation, and oral of attrition is greatest during the first year of life. Thereafter, leukoplakia. More significantly, these individuals are at very high risk telomeres shorten more gradually. When the extent of telo- of bone marrow failure, cancer, and pulmonary fibrosis. A mutation in meric DNA loss exceeds a critical threshold, a robust anti- one of six different telomere biology genes can be identified in 50–60% proliferative signal is triggered, leading to cellular senes- of these individuals. DKC1, TERC, TERT, NOP10, and NHP2 encode cence or apoptosis. Thus, telomere attrition is thought to 1 components of telomerase or a telomerase-associated factor and TINF2, contribute to aging phenotypes. 5 a telomeric protein. Progressively shorter telomeres are inherited from With the 1985 discovery of telomerase, the enzyme that ex- generation to generation in autosomal dominant dyskeratosis congenita, tends telomeric nucleotide repeats, there has been rapid progress resulting in disease anticipation. Up to 10% of individuals with apparently both in our understanding of basic telomere biology and the con- acquired aplastic anemia or idiopathic pulmonary fibrosis also have short nection of telomere biology to human disease.
    [Show full text]