Advances in genetic diagnosis of neurological disorders
|
|
- Samson Stokes
- 5 years ago
- Views:
Transcription
1 Acta Neurol Scand 2014: 129 (Suppl. 198): DOI: /ane John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA Review Article Advances in genetic diagnosis of neurological disorders Toft M. Advances in genetic diagnosis of neurological disorders. Acta Neurol Scand: 2014: 129 (Suppl. 198): John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Neurogenetics has developed enormously in recent years, and the genetic basis of human disorders is being unravelled rapidly. Many neurological disorders are Mendelian disorders, caused by mutations in genes involved in normal function of the brain, spinal cord, peripheral nerves or muscles. Due to high costs and time-consuming procedures, genetic tests have normally been performed late in the diagnostic process, when clinical examination and other tests have indicated a specific gene as the likely disease cause. Many neurological phenotypes are genetically very heterogeneous, and testing of all possible disease genes has been impossible. As a result, many patients with genetic neurological disorders have remained without a specific diagnosis, even when the disease is caused by mutations in known disease genes. Recent technological advances, in particular nextgeneration DNA sequencing techniques, have resulted in rapid identification of genes involved in Mendelian disorders and provided new possibilities for diagnostic genetic testing. The development of methods for coupling targeted capture and massively parallel DNA sequencing has made it possible to examine a large number of genes in a single reaction. Diagnostic genetic testing can today be performed by the use of gene panels and exome sequencing. This allows a more precise diagnosis of many neurological disorders, and genetic testing should now be considered earlier in the diagnostic procedure. M. Toft Department of Neurology, Oslo University Hospital Rikshospitalet, Oslo, Norway Key words: diagnostic test; genetic; sequencing M. Toft, Department of Neurology, Oslo University Hospital Rikshospitalet, P.O. Box 4950 Nydalen, N-0424 Oslo, Norway Tel.: Fax: mtoft@ous-hf.no Accepted for publication September 12, 2013 Introduction Many neurological disorders are caused by single mutations in genes involved in normal function of the brain, spinal cord, peripheral nerves or muscles. In addition to this, a large number of neurological disorders are so-called complex disorders, caused by a presumed interplay between several genetic and environmental factors. Over the past few years, the field of neurogenetics has developed rapidly and enabled a much greater understanding in the aetiology of many neurological disorders. Recent technological developments have led to an enormous increase in the identification of disease-related genes. These advances have allowed the determination of whole-genome structure and variation and examination of its impact on human phenotypes. Genome-wide association studies have provided information on how common genetic variability influences risk for the development of complex diseases. Furthermore, identification of rare disease-causing mutations has been followed by the discovery of novel biological pathways involved in disease pathogenesis. The purpose of this review is to give an introduction into the field of neurogenetics, and to discuss some of the recent advances in genetic technology. I will also discuss the implications these developments have on the use of genetic testing in the diagnostic process of neurological conditions. Mutations and genes In 1953, Crick and Watson identified the structure of DNA and showed that genetic information exists in the sequence of nucleotides on two 20
2 Genetics of neurological disorders strands of DNA (1). A gene is a sequence of DNA located on a chromosome, and the human genome contains more than 20,000 genes. The sequence of nucleotides in a gene is translated to a chain of amino acids, which in turn spontaneously fold into proteins. Before the human genome sequence was published in 2001, a limited number of disease-related genes had been identified and genetic testing was only performed for a very limited number of disorders. However, the completion of the Human Genome Project provided the necessary basis for the identification of disease genes as it provided an almost complete map of human genes (2). Only a little more than 1% of the human genome encodes genes. The remaining sequence has regulatory or largely unknown functions. Several million variants in the genome sequence exist in the human population. Despite this, more than 99.9% of two individual s genetic sequence is identical. The information in a gene is not always identical in two individuals, these alternative forms are called alleles. Spontaneous changes in genes, referred to as mutations, can give rise to new alleles with different properties. These new alleles can either be recessive or dominant. An individual s allele at a specific locus is called this person s genotype. A mutation is a permanent change in the nucleotide sequence or DNA structure. The consequence of a mutation on the function or amount of proteins is normally the molecular cause of a genetic disease. The vast majority of normally occurring genetic variants in the genome, so-called single-nucleotide polymorphisms (SNPs), are occurring in intronic regions that are not encoding amino acids. These variants therefore do not cause changes of protein sequence, but can influence regulatory elements and gene promoters and thus be involved in disease susceptibility. The most common form of mutations is point mutations caused by the substitution of a single nucleotide. On the protein level, this can cause a substitution of a single amino acid (missense mutation) or the introduction of a premature stop codon (nonsense mutation). Point mutations can also change splicing of exons or influence regulatory regions affecting gene expression. Structural mutations that are adding or deleting small sequences of nucleotides or large parts of chromosomes also exist. In addition, expansions of repeated sequence can also alter gene function and cause neurological disorders. Mutations can cause disease through different mechanisms. A common mechanism is that the mutation leads to a reduced or completely abolished function of the protein. This is typical for autosomal recessive disorders caused by defects of enzymes. Alternatively, the mutation causes disease by a gain of function, with increased protein activity or altered protein function for example in the form of protein aggregation. The genetics of neurological disorders The central nervous system is very complex, and normal function of neurons is depending on the correct performance of thousands of genes and their products. A large number of genetic disorders are therefore affecting functions of the nervous system. There are several different types of inherited genetic disorders, and neurological disease can be caused by all these different mechanisms. Chromosomal disorders This group of disorders is caused by structural mutations of one or several chromosomes. Chromosome abnormalities impair cell functions because of missing or extra chromosomal material (either whole chromosome or segments of chromosomes) or because a structural rearrangement interrupts a gene (3). Chromosome abnormalities are a relatively common cause of developmental disorders, occurring in 1 in 200 individuals. Chromosomal disorders are common syndromes with a complex phenotype and frequently involve intellectual disability. Thus, these syndromes are mostly diagnosed in childhood. However, neurologists are involved in the treatment for symptoms persisting into adulthood as epilepsy and spasticity. A diagnosis of a chromosomal disorder was traditionally based on cytogenetic testing using karyograms and fluorescent in situ hybridization (FISH). Due to recent advances in diagnostic techniques, including the development of arraybased comparative genomic hybridization (acgh), genomic copy number variations can be detected at a much higher resolution level than through traditional methods. This had led to the identification of a large number of chromosomal disorders in the last years. As an example, acgh has been applied to identify the molecular causes of several types of epilepsy (4). Mendelian disorders These disorders are caused by a mutation in a single gene and are therefore also known as monogenic disorders. In Mendelian disorders, 21
3 Toft one copy (for dominant genes) or two copies (for recessive genes) of the mutant gene inevitably lead to the development of the disease. Diseases with such simple inheritance patterns are each relatively rare and constitute a small proportion of all cases of neurological disease. However, the total frequency of all inherited neurological disorders is considerable. There are a many Mendelian neurological disorders, including neuropathies, myopathies, epilepsies, ataxias and other degenerative disorders of the brain and spinal cord. In 1993, one of the first molecular causes of a Mendelian disorder was found when an international consortium identified the gene causing Huntington s disease (5). Huntington s disease is caused by an expansion of a CAG trinucleotide repeat. A number of repeat disorders are caused by abnormal length of a repeated section within a gene, including Friedreich s ataxia, several spinocerebellar ataxias and myotonic dystrophy. Interestingly, a hexanucleotide repeat within the C9orf72 gene has recently been identified in a substantial proportion of both familial and sporadic forms of frontotemporal dementia and amyotrophic lateral sclerosis (6). This indicates that repeat disorders might be even more frequent than appreciated. The most common causes of Mendelian neurological disorders are however missense and nonsense mutations within the coding region of a gene. Many neurological phenotypes are genetically heterogeneous. Different mutations within a single gene can cause the same disease (allelic heterogeneity), and mutations in several different genes can be related to the same clinical expression (locus heterogeneity). For example, a large number of genes have been identified in neuropathies (7), myopathies (8) and ataxias (9). In addition to these more traditional genetic disorders, Mendelian forms of disorders that are normally occurring sporadically have also been identified. As an example, a proportion of patients with Parkinson s disease have inherited mutations in one of several disease genes (10). Even more complex is the aetiology of epilepsies, where a number of environmental causes are also known. In addition to improved diagnostic possibilities, these forms of disease have identified pathways that are involved in disease pathogenesis, providing information that is applicable also for the more common sporadic forms. Complex disorders Complex disorders are presumably caused by interplay between a large number of genetic, environmental and stochastic factors. Genome-wide association studies (GWAS) have identified large numbers of loci that contribute to the genetic basis of complex traits. For example, a large international study of multiple sclerosis, which included Norwegian participants, identified 29 new risk loci in addition to the more than 20 previously known loci (11). Many of the identified genes are involved in immune response, in particular differentiation of T-helper cells, further emphasizing the role of the immune system in the pathogenesis of multiple sclerosis. Despite the identification of many susceptibility genes for complex disorders, these genes collectively contribute very little to disease risk of each individual patient. We recently confirmed a number of disease associations in a large Scandinavian study of Parkinson s disease (12). However, the results from risk-profile analysis showed that the group of individuals with the largest number of risk alleles only had an about three times higher disease risk than individuals with few risk alleles. Thus, the most important contribution of genetic association studies is increased general insights, rather than individual predictions. There is therefore currently a very limited role for genetic testing of complex disorders. Nevertheless, detailed genetic and molecular characterizations might in the future translate into personalized and better treatment options for patients with these common disorders (13). Genetic testing today The neurological diagnostic process starts with the anamnesis followed by a clinical neurological and general examination. This is followed by a variable number of biochemical laboratory test, MRI or other imaging techniques, neurophysiological examinations and other diagnostic tests. Diagnostic genetic tests are being carried out by polymerase chain reaction (PCR) followed by analysis of known frequent mutations, capillary sequencing of known disease genes, or by testing of multiplications, deletions and repeat expansions within these genes (Fig. 1). An updated list of diagnostic genetic tests provided by Norwegian laboratories is available on Diagnostic genetic tests are relatively time-consuming and expensive. Thus, such tests have normally been performed late in the diagnostic process, when the clinical examination and other performed tests have indicated a mutation in a specific gene as the likely disease cause (Fig. 2A). As previously mentioned, many neurological phenotypes are genetically heterogeneous, and complex 22
4 Genetics of neurological disorders A B C Figure 1. Detection of genetic mutations. Different types of mutations have to be tested using different techniques. (A) Gel electrophoresis to separate DNA of different size, for example heterozygous trinucleotide repeat expansions. (B) DNA capillary sequencing to detect nucleotide exchanges. A homozygous point mutation is marked in the electropherogram with an asterix. (C) Semiquantitative PCR to detect deletions and multiplications. A heterozygous deletion in the two samples in the middle is demonstrated by a reduction in gene product by around 50%. A B Figure 2. Current and new strategies for genetic testing in myopathies. (A) Genetic testing of single mutations or genes is currently being performed late in the diagnostic process. (B) With the use of gene panels and exome sequencing, genetic testing of genetically heterogeneous phenotypes could be performed earlier in the diagnostic process. diagnostic algorithms have been proposed, as testing of all possible disease genes has been impossible (Fig. 3) (14). As a result, many patients with genetic neurological disorders have remained without a specific diagnosis, even when the disease is caused by mutations in known disease genes. Technological developments New genomic technologies developed in the last decade have provided unprecedented opportunities to perform large-scale analyses of an individual s genome. Microarray-based techniques as acgh and genome-wide SNP arrays have largely replaced cytogenetic testing. Recently, next-generation DNA sequencing platforms have become widely available, reducing the cost of DNA sequencing by several orders of magnitude compared with traditional capillary sequencing. The development of methods for coupling targeted capture and massively parallel DNA sequencing has made it possible to examine a large number of genes (gene panels) or nearly all of the coding parts of genes (exome sequencing) in a single reaction. Also, whole-genome sequencing is gradually becoming routine, but requires more bioinformatic resources. These advances have resulted in a rapid identification of genes involved in 23
5 Toft bioinformatics analyses than tests using a gene panel, and it increases the likelihood of findings that are unrelated to the neurological disorder. Thus, this technique has several additional ethical issues that must be addressed. Figure 3. Proposed diagnostic algorithm for Charcot Marie Tooth disease (CMT). In patients with suspected autosomal dominant neuropathy, this diagnostic algorithm has been proposed (modified from Li, Semin Neurol 2012). Similar algorithms have been proposed for autosomal recessive neuropathy. Mendelian diseases and provided new possibilities for diagnostic genetic testing (15). Genetic testing in the future The recent tremendous advances in sequencing technology now allow for much broader testing of disease genes than in the past. Several laboratories offer testing of gene panels, where a large number of genes related to a specific phenotype are tested in a single reaction. This is particularly interesting for genetically heterogeneous disorders, especially if other diagnostic tests are cumbersome and expensive. An example is myopathies, in which neurophysiological examinations and muscle biopsies are frequently being performed. For these disorders, genetic testing using gene panels should be considered earlier in the diagnostic process (Fig. 2B). This might result in a molecular diagnosis preventing the use of further diagnostic tests. A recent study using a gene panel to examine patients with hereditary spastic paraparesis identified the genetic cause in 25% of patients, even though the most common genetic form had already been excluded (16). In some patients with unknown familial disorders, complex phenotypes or atypical manifestations exome sequencing might be the test of choice. In exome sequencing, nearly all coding regions of genes are tested, and thus also previously unknown disease genes can be found using this method. Exome sequencing requires more Conclusions Today, diagnostic genetic testing of neurological disorders is normally performed late in the diagnostic process. Due to recent developments in sequencing technology, new genetic disease causes are identified almost on a daily basis. These technological advances also enable comprehensive genetic testing of large panels of candidate genes or the whole exome. This allows a more precise diagnosis of many neurological disorders, and genetic testing should be considered earlier in the diagnostic procedure. Acknowledgments Genetic studies in the author s research group are supported by grants from the Research Council of Norway and the South-Eastern Norway Regional Health Authority. Conflict of interest The author reports no financial conflict of interest. References 1. WATSON JD, CRICK FHC. Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid. Nature 1953;4356: LANDER ES, LINTON LM, BIRREN B et al. Initial sequencing and analysis of the human genome. Nature 2001; 409: BIESECKER LG, SPINNER NB. A genomic view of mosaicism and human disease. Nat Rev Genet 2013;14: MULLEY JC, MEFFORD HC. Epilepsy and the new cytogenetics. Epilepsia 2011;52: The Huntington s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington s disease chromosomes. Cell 1993;72: VAN LANGENHOVE T, VAN DER ZEE J, VAN BROECKHOVEN C. The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum. Ann Med 2012;44: BRAATHEN GJ. Genetic epidemiology of Charcot-Marie- Tooth disease. Acta Neurol Scand Suppl 2012;193:iv MERCURI E, MUNTONI F. Muscular dystrophies. Lancet 2013;381: HERSHESON J, HAWORTH A, HOULDEN H. The inherited ataxias: genetic heterogeneity, mutation databases, and future directions in research and clinical diagnostics. Hum Mutat 2012;33: HOULDEN H, SINGLETON AB. The genetics and neuropathology of Parkinson s disease. Acta Neuropathol 2012;124:
6 Genetics of neurological disorders 11. International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, SAWCER S et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011;476: PIHLSTRØM L, AXELSSON G, BJØRNARA KA et al. Supportive evidence for 11 loci from genome-wide association studies in Parkinson s disease. Neurobiol Aging, 2013;34:1708. e HARBO HF, MERO IL. From genes to characteristics of multiple sclerosis. Acta Neurol Scand Suppl 2012;195: LI J. Inherited neuropathies. Semin Neurol 2012;32: BAMSHAD MJ, NG SB, BIGHAM AW et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 2011;12: KUMAR KR, BLAIR NF, VANDEBONA H, et al. Targeted next generation sequencing in SPAST-negative hereditary spastic paraplegia. J Neurol 2013;260:
CURRENT GENETIC TESTING TOOLS IN NEONATAL MEDICINE. Dr. Bahar Naghavi
2 CURRENT GENETIC TESTING TOOLS IN NEONATAL MEDICINE Dr. Bahar Naghavi Assistant professor of Basic Science Department, Shahid Beheshti University of Medical Sciences, Tehran,Iran 3 Introduction Over 4000
More informationvariant led to a premature stop codon p.k316* which resulted in nonsense-mediated mrna decay. Although the exact function of the C19L1 is still
157 Neurological disorders primarily affect and impair the functioning of the brain and/or neurological system. Structural, electrical or metabolic abnormalities in the brain or neurological system can
More informationNon-Mendelian inheritance
Non-Mendelian inheritance Focus on Human Disorders Peter K. Rogan, Ph.D. Laboratory of Human Molecular Genetics Children s Mercy Hospital Schools of Medicine & Computer Science and Engineering University
More informationIntroduction to genetic variation. He Zhang Bioinformatics Core Facility 6/22/2016
Introduction to genetic variation He Zhang Bioinformatics Core Facility 6/22/2016 Outline Basic concepts of genetic variation Genetic variation in human populations Variation and genetic disorders Databases
More informationIntroduction to Genetics
Introduction to Genetics Table of contents Chromosome DNA Protein synthesis Mutation Genetic disorder Relationship between genes and cancer Genetic testing Technical concern 2 All living organisms consist
More informationCHROMOSOMAL MICROARRAY (CGH+SNP)
Chromosome imbalances are a significant cause of developmental delay, mental retardation, autism spectrum disorders, dysmorphic features and/or birth defects. The imbalance of genetic material may be due
More informationCentoXome FUTURE'S KNOWLEDGE APPLIED TODAY
CentoXome FUTURE'S KNOWLEDGE APPLIED TODAY More genetic information requires cutting-edge interpretation techniques Whole Exome Sequencing For certain patients the combination of symptoms does not allow
More informationProposal form for the evaluation of a genetic test for NHS Service Gene Dossier
Proposal form for the evaluation of a genetic test for NHS Service Gene Dossier Test Disease Population Triad Disease name Amyotrophic Lateral Sclerosis 10 (ALS10) and Amyotrophic Lateral Sclerosis 6 (ALS6)
More informationBenefits and pitfalls of new genetic tests
Benefits and pitfalls of new genetic tests Amanda Krause Division of Human Genetics, NHLS and University of the Witwatersrand Definition of Genetic Testing the analysis of human DNA, RNA, chromosomes,
More informationGenetics and Genomics in Medicine Chapter 8 Questions
Genetics and Genomics in Medicine Chapter 8 Questions Linkage Analysis Question Question 8.1 Affected members of the pedigree above have an autosomal dominant disorder, and cytogenetic analyses using conventional
More informationCentoXome FUTURE'S KNOWLEDGE APPLIED TODAY
CentoXome FUTURE'S KNOWLEDGE APPLIED TODAY More genetic information requires cutting-edge interpretation techniques Whole Exome Sequencing For some patients, the combination of symptoms does not allow
More informationBasic Definitions. Dr. Mohammed Hussein Assi MBChB MSc DCH (UK) MRCPCH
Basic Definitions Chromosomes There are two types of chromosomes: autosomes (1-22) and sex chromosomes (X & Y). Humans are composed of two groups of cells: Gametes. Ova and sperm cells, which are haploid,
More informationCorporate Medical Policy
Corporate Medical Policy Invasive Prenatal (Fetal) Diagnostic Testing File Name: Origination: Last CAP Review: Next CAP Review: Last Review: invasive_prenatal_(fetal)_diagnostic_testing 12/2014 3/2018
More informationWelcome to the Genetic Code: An Overview of Basic Genetics. October 24, :00pm 3:00pm
Welcome to the Genetic Code: An Overview of Basic Genetics October 24, 2016 12:00pm 3:00pm Course Schedule 12:00 pm 2:00 pm Principles of Mendelian Genetics Introduction to Genetics of Complex Disease
More informationChallenges of CGH array testing in children with developmental delay. Dr Sally Davies 17 th September 2014
Challenges of CGH array testing in children with developmental delay Dr Sally Davies 17 th September 2014 CGH array What is CGH array? Understanding the test Benefits Results to expect Consent issues Ethical
More informationSingle Gene (Monogenic) Disorders. Mendelian Inheritance: Definitions. Mendelian Inheritance: Definitions
Single Gene (Monogenic) Disorders Mendelian Inheritance: Definitions A genetic locus is a specific position or location on a chromosome. Frequently, locus is used to refer to a specific gene. Alleles are
More informationMEDICAL GENOMICS LABORATORY. Next-Gen Sequencing and Deletion/Duplication Analysis of NF1 Only (NF1-NG)
Next-Gen Sequencing and Deletion/Duplication Analysis of NF1 Only (NF1-NG) Ordering Information Acceptable specimen types: Fresh blood sample (3-6 ml EDTA; no time limitations associated with receipt)
More informationWhat s the Human Genome Project Got to Do with Developmental Disabilities?
What s the Human Genome Project Got to Do with Developmental Disabilities? Disclosures Neither speaker has anything to disclose. Phase Two: Interpretation Officially started in October 1990 Goals of the
More informationLecture 17: Human Genetics. I. Types of Genetic Disorders. A. Single gene disorders
Lecture 17: Human Genetics I. Types of Genetic Disorders A. Single gene disorders B. Multifactorial traits 1. Mutant alleles at several loci acting in concert C. Chromosomal abnormalities 1. Physical changes
More informationPsych 3102 Lecture 3. Mendelian Genetics
Psych 3102 Lecture 3 Mendelian Genetics Gregor Mendel 1822 1884, paper read 1865-66 Augustinian monk genotype alleles present at a locus can we identify this? phenotype expressed trait/characteristic can
More informationProteins. Length of protein varies from thousands of amino acids to only a few insulin only 51 amino acids
Proteins Protein carbon, hydrogen, oxygen, nitrogen and often sulphur Length of protein varies from thousands of amino acids to only a few insulin only 51 amino acids During protein synthesis, amino acids
More informationDan Koller, Ph.D. Medical and Molecular Genetics
Design of Genetic Studies Dan Koller, Ph.D. Research Assistant Professor Medical and Molecular Genetics Genetics and Medicine Over the past decade, advances from genetics have permeated medicine Identification
More informationChapter 1 : Genetics 101
Chapter 1 : Genetics 101 Understanding the underlying concepts of human genetics and the role of genes, behavior, and the environment will be important to appropriately collecting and applying genetic
More informationComputational Systems Biology: Biology X
Bud Mishra Room 1002, 715 Broadway, Courant Institute, NYU, New York, USA L#4:(October-0-4-2010) Cancer and Signals 1 2 1 2 Evidence in Favor Somatic mutations, Aneuploidy, Copy-number changes and LOH
More informationGaucher disease 3/22/2009. Mendelian pedigree patterns. Autosomal-dominant inheritance
Mendelian pedigree patterns Autosomal-dominant inheritance Autosomal dominant Autosomal recessive X-linked dominant X-linked recessive Y-linked Examples of AD inheritance Autosomal-recessive inheritance
More informationClinical Spectrum and Genetic Mechanism of GLUT1-DS. Yasushi ITO (Tokyo Women s Medical University, Japan)
Clinical Spectrum and Genetic Mechanism of GLUT1-DS Yasushi ITO (Tokyo Women s Medical University, Japan) Glucose transporter type 1 (GLUT1) deficiency syndrome Mutation in the SLC2A1 / GLUT1 gene Deficiency
More informationAssociation for Molecular Pathology Promoting Clinical Practice, Basic Research, and Education in Molecular Pathology
Association for Molecular Pathology Promoting Clinical Practice, Basic Research, and Education in Molecular Pathology 9650 Rockville Pike, Bethesda, Maryland 20814 Tel: 301-634-7939 Fax: 301-634-7990 Email:
More informationApproach to Mental Retardation and Developmental Delay. SR Ghaffari MSc MD PhD
Approach to Mental Retardation and Developmental Delay SR Ghaffari MSc MD PhD Introduction Objectives Definition of MR and DD Classification Epidemiology (prevalence, recurrence risk, ) Etiology Importance
More informationDOES THE BRCAX GENE EXIST? FUTURE OUTLOOK
CHAPTER 6 DOES THE BRCAX GENE EXIST? FUTURE OUTLOOK Genetic research aimed at the identification of new breast cancer susceptibility genes is at an interesting crossroad. On the one hand, the existence
More informationCytogenetics 101: Clinical Research and Molecular Genetic Technologies
Cytogenetics 101: Clinical Research and Molecular Genetic Technologies Topics for Today s Presentation 1 Classical vs Molecular Cytogenetics 2 What acgh? 3 What is FISH? 4 What is NGS? 5 How can these
More informationGenetics and Genomics: Applications to Developmental Disability
Tuesday, 12:30 2:00, B1 Objective: Genetics and Genomics: Applications to Developmental Disability Helga Toriello 616-234-2712 toriello@msu.edu Identify advances in clinical assessment and management of
More informationGenetic diagnosis of limb girdle muscular dystrophy type 2A, A Case Report
Genetic diagnosis of limb girdle muscular dystrophy type 2A, A Case Report Roshanak Jazayeri, MD, PhD Assistant Professor of Medical Genetics Faculty of Medicine, Alborz University of Medical Sciences
More informationGenetic Diseases. SCPA202: Basic Pathology
Genetic Diseases SCPA202: Basic Pathology Amornrat N. Jensen, Ph.D. Department of Pathobiology School of Science, Mahidol University amornrat.nar@mahidol.ac.th Genetic disease An illness caused by abnormalities
More informationChapter 15 Notes 15.1: Mendelian inheritance chromosome theory of inheritance wild type 15.2: Sex-linked genes
Chapter 15 Notes The Chromosomal Basis of Inheritance Mendel s hereditary factors were genes, though this wasn t known at the time Now we know that genes are located on The location of a particular gene
More informationAgro/Ansc/Bio/Gene/Hort 305 Fall, 2017 MEDICAL GENETICS AND CANCER Chpt 24, Genetics by Brooker (lecture outline) #17
Agro/Ansc/Bio/Gene/Hort 305 Fall, 2017 MEDICAL GENETICS AND CANCER Chpt 24, Genetics by Brooker (lecture outline) #17 INTRODUCTION - Our genes underlie every aspect of human health, both in function and
More informationGenetic Diseases. SCPA202: Basic Pathology
Genetic Diseases SCPA202: Basic Pathology Amornrat N. Jensen, Ph.D. Department of Pathobiology School of Science, Mahidol University amornrat.nar@mahidol.ac.th Genetic disease An illness caused by abnormalities
More informationpanel tests assessing multiple genes at the same time for the diagnosis of one or more related disorders
NGS tests panel tests assessing multiple genes at the same time for the diagnosis of one or more related disorders UKGTN website lists 13 laboratories offering a total of 56 panel test UKGTN listed panel
More informationMultiple Copy Number Variations in a Patient with Developmental Delay ASCLS- March 31, 2016
Multiple Copy Number Variations in a Patient with Developmental Delay ASCLS- March 31, 2016 Marwan Tayeh, PhD, FACMG Director, MMGL Molecular Genetics Assistant Professor of Pediatrics Department of Pediatrics
More informationPedigree Construction Notes
Name Date Pedigree Construction Notes GO TO à Mendelian Inheritance (http://www.uic.edu/classes/bms/bms655/lesson3.html) When human geneticists first began to publish family studies, they used a variety
More informationGenetics of Hereditary Spastic Paraplegia Dr. Arianna Tucci
Genetics of Hereditary Spastic Paraplegia 1 Clinical Research Fellow Institute of Neurology University College London Hereditary spastic paraplegia: definition Clinical designation for neurologic syndromes
More informationMEDICAL GENOMICS LABORATORY. Non-NF1 RASopathy panel by Next-Gen Sequencing and Deletion/Duplication Analysis of SPRED1 (NNP-NG)
Non-NF1 RASopathy panel by Next-Gen Sequencing and Deletion/Duplication Analysis of SPRED1 (NNP-NG) Ordering Information Acceptable specimen types: Blood (3-6ml EDTA; no time limitations associated with
More informationGenomic structural variation
Genomic structural variation Mario Cáceres The new genomic variation DNA sequence differs across individuals much more than researchers had suspected through structural changes A huge amount of structural
More informationGenetic Testing for Single-Gene and Multifactorial Conditions
Clinical Appropriateness Guidelines Genetic Testing for Single-Gene and Multifactorial Conditions EFFECTIVE DECEMBER 1, 2017 Appropriate.Safe.Affordable 2017 AIM Specialty Health 2069-1217 Table of Contents
More informationLab Activity Report: Mendelian Genetics - Genetic Disorders
Name Date Period Lab Activity Report: Mendelian Genetics - Genetic Disorders Background: Sometimes genetic disorders are caused by mutations to normal genes. When the mutation has been in the population
More informationGenomics and Genetics in Healthcare. By Mary Knutson, RN, MSN
Genomics and Genetics in Healthcare By Mary Knutson, RN, MSN Clinical Objectives Understand the importance of genomics to provide effective nursing care Integrate genetic knowledge and skills into nursing
More informationMRC-Holland MLPA. Description version 08; 30 March 2015
SALSA MLPA probemix P351-C1 / P352-D1 PKD1-PKD2 P351-C1 lot C1-0914: as compared to the previous version B2 lot B2-0511 one target probe has been removed and three reference probes have been replaced.
More informationAn Update on PGD: Where we are today
An Update on PGD: Where we are today Joyce Harper UCL Centre for PG&D and CRGH Institute for Womens Health University College London Overview What is PGD/PGS How we do it Disadvantages and advantages Future
More informationWhat is New in Genetic Testing. Steven D. Shapiro MS, DMD, MD
What is New in Genetic Testing Steven D. Shapiro MS, DMD, MD 18th Annual Primary Care Symposium Financial and Commercial Disclosure I have a no financial or commercial interest in my presentation. 2 Genetic
More informationHow many disease-causing variants in a normal person? Matthew Hurles
How many disease-causing variants in a normal person? Matthew Hurles Summary What is in a genome? What is normal? Depends on age What is a disease-causing variant? Different classes of variation Final
More informationJay M. Baraban MD, PhD January 2007 GENES AND BEHAVIOR
Jay M. Baraban MD, PhD jay.baraban@gmail.com January 2007 GENES AND BEHAVIOR Overview One of the most fascinating topics in neuroscience is the role that inheritance plays in determining one s behavior.
More informationOriginal Policy Date
MP 2.04.76 Genetic Counseling Medical Policy Section Medicine Issue 12:2013 Original Policy Date 12:2013 Last Review Status/Date Created Local Policy/ 12:2013 Return to Medical Policy Index Disclaimer
More informationCANCER GENETICS PROVIDER SURVEY
Dear Participant, Previously you agreed to participate in an evaluation of an education program we developed for primary care providers on the topic of cancer genetics. This is an IRB-approved, CDCfunded
More informationGenetics of Inclusion Body Myositis
Genetics of Inclusion Body Myositis Thomas Lloyd, MD, PhD Associate Professor of Neurology and Neuroscience Co-director, Johns Hopkins Myositis Center Sporadic IBM (IBM) Age at onset usually > 50 Prevalence
More informationThe Meaning of Genetic Variation
Activity 2 The Meaning of Genetic Variation Focus: Students investigate variation in the beta globin gene by identifying base changes that do and do not alter function, and by using several CD-ROM-based
More informationCS2220 Introduction to Computational Biology
CS2220 Introduction to Computational Biology WEEK 8: GENOME-WIDE ASSOCIATION STUDIES (GWAS) 1 Dr. Mengling FENG Institute for Infocomm Research Massachusetts Institute of Technology mfeng@mit.edu PLANS
More informationSequencing studies implicate inherited mutations in autism
NEWS Sequencing studies implicate inherited mutations in autism BY EMILY SINGER 23 JANUARY 2013 1 / 5 Unusual inheritance: Researchers have found a relatively mild mutation in a gene linked to Cohen syndrome,
More informationSNP Array NOTE: THIS IS A SAMPLE REPORT AND MAY NOT REFLECT ACTUAL PATIENT DATA. FORMAT AND/OR CONTENT MAY BE UPDATED PERIODICALLY.
SAMPLE REPORT SNP Array NOTE: THIS IS A SAMPLE REPORT AND MAY NOT REFLECT ACTUAL PATIENT DATA. FORMAT AND/OR CONTENT MAY BE UPDATED PERIODICALLY. RESULTS SNP Array Copy Number Variations Result: LOSS,
More informationSNP Array NOTE: THIS IS A SAMPLE REPORT AND MAY NOT REFLECT ACTUAL PATIENT DATA. FORMAT AND/OR CONTENT MAY BE UPDATED PERIODICALLY.
SAMPLE REPORT SNP Array NOTE: THIS IS A SAMPLE REPORT AND MAY NOT REFLECT ACTUAL PATIENT DATA. FORMAT AND/OR CONTENT MAY BE UPDATED PERIODICALLY. RESULTS SNP Array Copy Number Variations Result: GAIN,
More informationHuman Genetics of Tuberculosis. Laurent Abel Laboratory of Human Genetics of Infectious Diseases University Paris Descartes/INSERM U980
Human Genetics of Tuberculosis Laurent Abel Laboratory of Human Genetics of Infectious Diseases University Paris Descartes/INSERM U980 Human genetics in tuberculosis? Concept Epidemiological/familial
More informationIdentifying Mutations Responsible for Rare Disorders Using New Technologies
Identifying Mutations Responsible for Rare Disorders Using New Technologies Jacek Majewski, Department of Human Genetics, McGill University, Montreal, QC Canada Mendelian Diseases Clear mode of inheritance
More informationGenome 371, Autumn 2018 Quiz Section 9: Genetics of Cancer Worksheet
Genome 371, Autumn 2018 Quiz Section 9: Genetics of Cancer Worksheet All cancer is due to genetic mutations. However, in cancer that clusters in families (familial cancer) at least one of these mutations
More informationSALSA MLPA KIT P060-B2 SMA
SALSA MLPA KIT P6-B2 SMA Lot 111, 511: As compared to the previous version B1 (lot 11), the 88 and 96 nt DNA Denaturation control fragments have been replaced (QDX2). Please note that, in contrast to the
More informationDNA is the genetic material that provides instructions for what our bodies look like and how they function. DNA is packaged into structures called
DNA is the genetic material that provides instructions for what our bodies look like and how they function. DNA is packaged into structures called chromosomes. We have 23 pairs of chromosomes (for a total
More informationUnderstanding The Genetics of Diamond Blackfan Anemia
Understanding The Genetics of Diamond Blackfan Anemia Jason Farrar, MD jefarrar@ About Me Assistant Professor of Pediatrics at University of Arkansas for Medical Sciences & Arkansas Children s Hospital
More informationMRC-Holland MLPA. Description version 19;
SALSA MLPA probemix P6-B2 SMA Lot B2-712, B2-312, B2-111, B2-511: As compared to the previous version B1 (lot B1-11), the 88 and 96 nt DNA Denaturation control fragments have been replaced (QDX2). SPINAL
More information5/2/18. After this class students should be able to: Stephanie Moon, Ph.D. - GWAS. How do we distinguish Mendelian from non-mendelian traits?
corebio II - genetics: WED 25 April 2018. 2018 Stephanie Moon, Ph.D. - GWAS After this class students should be able to: 1. Compare and contrast methods used to discover the genetic basis of traits or
More informationGenetic diseases. - chromosomal disorders (aneuploidy) - mitochondrial inherited diseases (female lineage transmission)
Genetic diseases - chromosomal disorders (aneuploidy) - monogenic diseases (mendelian transmission) - mitochondrial inherited diseases (female lineage transmission) HOWEVER: interaction gene-environment
More informationThe Human Major Histocompatibility Complex
The Human Major Histocompatibility Complex 1 Location and Organization of the HLA Complex on Chromosome 6 NEJM 343(10):702-9 2 Inheritance of the HLA Complex Haplotype Inheritance (Family Study) 3 Structure
More informationEgypt 90 Million People Power Seven Thousands Year Culture 29 Governorates
Egypt 90 Million People Power Seven Thousands Year Culture 29 Governorates Recent advances in Molecular Medicine: Changing the practice of neurology Presentation by Nagwa Meguid, Prof. of Human Genetics
More informationEvolution of Genetic Testing. Joan Pellegrino MD Associate Professor of Pediatrics SUNY Upstate Medical University
Evolution of Genetic Testing Joan Pellegrino MD Associate Professor of Pediatrics SUNY Upstate Medical University Genetic Testing Chromosomal analysis Flourescent in situ hybridization (FISH) Chromosome
More informationGenetic Disorders. SCPA 501: General Pathology. Amornrat Naranuntarat Jensen
Genetic Disorders SCPA 501: General Pathology Amornrat Naranuntarat Jensen amornrat.nar@mahidol.ac.th Human has 46 chromosomes (23 pairs) Sex chromosomes Human genome contains approximately 3 billion base
More informationSharan Goobie, MD, MSc, FRCPC
Sharan Goobie, MD, MSc, FRCPC Chromosome testing in 2014 Presenter Disclosure: Sharan Goobie has no potential for conflict of interest with this presentation Objectives Review of standard genetic investigations
More informationThe Foundations of Personalized Medicine
The Foundations of Personalized Medicine Jeremy M. Berg Pittsburgh Foundation Professor and Director, Institute for Personalized Medicine University of Pittsburgh Personalized Medicine Physicians have
More informationWhole Exome Sequencing (WES) Whole Exome Sequencing. What Is Whole Exome Sequencing?
Whole Exome Sequencing (WES) Procedure(s) addressed by this policy: Exome (e.g., unexplained constitutional or heritable disorder or syndrome); sequence analysis Sequence analysis, each comparator exome
More informationExploding Genetic Knowledge in Developmental Disabilities. Disclosures. The Genetic Principle
Exploding Genetic Knowledge in Developmental Disabilities How to acquire the data and how to make use of it Elliott H. Sherr MD PhD Professor of Neurology & Pediatrics UCSF Disclosures InVitae: clinical
More informationPutative low penetrance or susceptibility variants: sodium channel genes in painful neuropathy as an example
Putative low penetrance or susceptibility variants: sodium channel genes in painful neuropathy as an example Carl Fratter 1 Kate Sergeant 1, Julie C Evans 1, Anneke Seller 1, David Bennett 2 1 Oxford Medical
More informationHands-On Ten The BRCA1 Gene and Protein
Hands-On Ten The BRCA1 Gene and Protein Objective: To review transcription, translation, reading frames, mutations, and reading files from GenBank, and to review some of the bioinformatics tools, such
More informationSEX-LINKED INHERITANCE. Dr Rasime Kalkan
SEX-LINKED INHERITANCE Dr Rasime Kalkan Human Karyotype Picture of Human Chromosomes 22 Autosomes and 2 Sex Chromosomes Autosomal vs. Sex-Linked Traits can be either: Autosomal: traits (genes) are located
More informationHuman Genetics 542 Winter 2018 Syllabus
Human Genetics 542 Winter 2018 Syllabus Monday, Wednesday, and Friday 9 10 a.m. 5915 Buhl Course Director: Tony Antonellis Jan 3 rd Wed Mapping disease genes I: inheritance patterns and linkage analysis
More informationMutational and phenotypical spectrum of phenylalanine hydroxylase deficiency in Denmark
Clin Genet 2016: 90: 247 251 Printed in Singapore. All rights reserved Short Report 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12692 Mutational and
More information22q11.2 DELETION SYNDROME. Anna Mª Cueto González Clinical Geneticist Programa de Medicina Molecular y Genética Hospital Vall d Hebrón (Barcelona)
22q11.2 DELETION SYNDROME Anna Mª Cueto González Clinical Geneticist Programa de Medicina Molecular y Genética Hospital Vall d Hebrón (Barcelona) Genomic disorders GENOMICS DISORDERS refers to those diseases
More informationGene Therapy. Definition: A disease resulting from a defect in individual genes. > 6000 inherited diseases 1:200 Births
Inherited Disease (AKA Genetic Disease): A disease that is caused by a defect in the genome and that, like other genetic features, can be passed from parents to offspring. Epigenetics: A heritable change
More informationThe Chromosomal Basis Of Inheritance
The Chromosomal Basis Of Inheritance Chapter 15 Objectives Explain the chromosomal theory of inheritance and its discovery. Explain why sex-linked diseases are more common in human males than females.
More informationBiology 2C03: Genetics What is a Gene?
Biology 2C03: Genetics What is a Gene? September 9 th, 2013 Model Organisms - E. coli - Yeast - Worms - Arabodopsis - Fruitflie - Mouse What is a Gene? - Define, recognize, describe and apply Mendel s
More informationProposal form for the evaluation of a genetic test for NHS Service Gene Dossier
Proposal form for the evaluation of a genetic test for NHS Service Gene Dossier Test Disease Population Triad Disease name Leber congenital amaurosis OMIM number for disease 204000 Disease alternative
More informationHuman Genetics 542 Winter 2017 Syllabus
Human Genetics 542 Winter 2017 Syllabus Monday, Wednesday, and Friday 9 10 a.m. 5915 Buhl Course Director: Tony Antonellis Module I: Mapping and characterizing simple genetic diseases Jan 4 th Wed Mapping
More informationIntroduction to the Genetics of Complex Disease
Introduction to the Genetics of Complex Disease Jeremiah M. Scharf, MD, PhD Departments of Neurology, Psychiatry and Center for Human Genetic Research Massachusetts General Hospital Breakthroughs in Genome
More informationTumor suppressor genes D R. S H O S S E I N I - A S L
Tumor suppressor genes 1 D R. S H O S S E I N I - A S L What is a Tumor Suppressor Gene? 2 A tumor suppressor gene is a type of cancer gene that is created by loss-of function mutations. In contrast to
More informationNOTES: : HUMAN HEREDITY
NOTES: 14.1-14.2: HUMAN HEREDITY Human Genes: The human genome is the complete set of genetic information -it determines characteristics such as eye color and how proteins function within cells Recessive
More informationClinical Genetics & Dementia
Clinical Genetics & Dementia Dr Nayana Lahiri Consultant in Clinical Genetics & Honorary Senior Lecturer Nayana.lahiri@nhs.net Aims of the Session To appreciate the potential utility of family history
More informationNGS in neurodegenerative disorders - our experience
Neurology Clinic, Clinical Center of Serbia Faculty of Medicine, University of Belgrade Belgrade, Serbia NGS in neurodegenerative disorders - our experience Marija Branković, MSc Belgrade, 2018 Next Generation
More informationMeiotic Mistakes and Abnormalities Learning Outcomes
Meiotic Mistakes and Abnormalities Learning Outcomes 5.6 Explain how nondisjunction can result in whole chromosomal abnormalities. (Module 5.10) 5.7 Describe the inheritance patterns for strict dominant
More informationPractical challenges that copy number variation and whole genome sequencing create for genetic diagnostic labs
Practical challenges that copy number variation and whole genome sequencing create for genetic diagnostic labs Joris Vermeesch, Center for Human Genetics K.U.Leuven, Belgium ESHG June 11, 2010 When and
More informationMRC-Holland MLPA. Description version 29; 31 July 2015
SALSA MLPA probemix P081-C1/P082-C1 NF1 P081 Lot C1-0114. As compared to the previous B2 version (lot 0813 and 0912), 11 target probes are replaced or added, and 10 new reference probes are included. P082
More informationGenetic Testing for Neurologic Disorders
Genetic Testing for Neurologic Disorders MP9497 Covered Service: Prior Authorization Required: Additional Information: Yes when meets criteria below Yes as shown below Pre- and post-test genetic counseling
More informationMEDICAL GENOMICS LABORATORY. Peripheral Nerve Sheath Tumor Panel by Next-Gen Sequencing (PNT-NG)
Peripheral Nerve Sheath Tumor Panel by Next-Gen Sequencing (PNT-NG) Ordering Information Acceptable specimen types: Blood (3-6ml EDTA; no time limitations associated with receipt) Saliva (OGR-575 DNA Genotek;
More informationGenerating Spontaneous Copy Number Variants (CNVs) Jennifer Freeman Assistant Professor of Toxicology School of Health Sciences Purdue University
Role of Chemical lexposure in Generating Spontaneous Copy Number Variants (CNVs) Jennifer Freeman Assistant Professor of Toxicology School of Health Sciences Purdue University CNV Discovery Reference Genetic
More informationAMERICAN BOARD OF MEDICAL GENETICS AND GENOMICS
AMERICAN BOARD OF MEDICAL GENETICS AND GENOMICS Logbook Guidelines for Certification in Clinical Genetics and Genomics for the 2017 Examination as of 10/5/2015 Purpose: The purpose of the logbook is to
More informationLecture 20. Disease Genetics
Lecture 20. Disease Genetics Michael Schatz April 12 2018 JHU 600.749: Applied Comparative Genomics Part 1: Pre-genome Era Sickle Cell Anaemia Sickle-cell anaemia (SCA) is an abnormality in the oxygen-carrying
More informationAbstract. Introduction
Brazilian Journal of Medical and Biological Research (2003) 36: 1403-1407 Thr(118)Met in Charcot-Marie-Tooth disease ISSN 0100-879X 1403 Thr(118)Met amino acid substitution in the peripheral myelin protein
More information