Download - Home Uterine Activity Monitor
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Tools for teaching genetics in an OBGYN Residency Program
Charles J. Macri, MD Gabriel M. Cohn, MD
APGO Meeting - March 2001
Uniformed Services Universityof the Health Sciences
Baystate Medical CenterTufts University School of Medicine
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Introduction
Genetics is the study of biologic variation
Medical genetics is the application of this study of biologic variability to human health and disease
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Learning Objectives
Recognize that Medical Genetics is an important part of the practice of Obstetrics and Gynecology
List the major topics in genetics that should be covered in the 4-year OBGYN residency curriculum
Identify Institutional resources that provide standards for genetics education and services
Identify Web based resources in Medical Genetics
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Where can Genetics be incorporated into the OBGYN training program?
Basics of Genetics– Chromosome– Molecular
Pre-conception CareObstetrics
– Genetic counselingGynecologyWomen’s Health Care
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Chromosome structure and function
Histones, chromatin, nucleosomes, centromere, telomeres, satellites
Euchromatin, heterochromatin, constitutive heterochromatin, facultative heterochromatin
Mitosis Meiosis Recombination
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Chromosomal basis of inheritance Numerical abnormalities
– aneuploidies - trisomy 13, 18, 21– sex chromosomal abnormalities
Structural abnormalities – insertions, deletions, inversions (paracentric,
pericentric), – translocations - Robertsonian, recipricol, balanced,
unbalanced Contiguous gene syndromes
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Chromosomal basis of inheritance
What chromosome abnormalities are most commonly seen in first trimester loss?
What patients are at increased risk for chromosome abnormalities?
What ultrasound clues identify the fetus with chromosome abnormalities?
What screening and diagnostic tests are available for chromosomal abnormalities during pregnancy?
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Molecular Genetics
DNA structure and function – replication, transcription, translation
Classes of DNA– Organization of genes
mRNA, tRNA protein structure mitochondrial DNA polymorphisms, dinucleotide repeats, SINEs, LINEs mutations, loss of function, gain of function,
dominant negative
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Control of gene expression
the operon genomic imprintingDNA methylationX inactivationIsodisomy
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Mendelian Inheritance
Autosomal Recessive Inheritance and Disorders– pedigree analysis and example cases
Autosomal Dominant Inheritance and Disorders– pedigree analysis and example cases
Sex Linked Recessive and Dominant Inheritance and Disorders
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Non-Mendelian Inheritance
Mitochondrial Inheritance and Disorders Multifactorial Inheritance and Disorders Mosaicism Uniparental Disomy Trinucleotide repeats and genetic instablity Imprinting
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Non-Mendelian Inheritance
Penetrance Expressivity Anticipation Sex Influence Sex Limitation Pleitropy Phenotypic and Genetic Heterogeneity
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Mendelian Inheritance
What are some of the common inherited conditions that will be seen in Pregnancy?– Cystic Fibrosis (Current recommendations for
Cystic Fibrosis Testing ACOG, ACMG, ASHG)– Sickle cell disease, thalassemias, hemophilias– Triplet Repeat Disorders - Fragile X as a cause of
Mental Retardation, Huntington’s Disease, other Neurological disorders
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Molecular Genetics: Clinical Applications
Karyotype: chromosome analysis and banding FISH, painting, cloning, PCR Southern blots, northern blots, western blots,
immunohistochemistry SSCP, direct sequence analysis ASO, dot blot RFLP analysis, linkage UPD, deletion analysis
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Methods of studying genetic changes in populations
Linkage Analysis Gene Mapping and the Human Genome Project Pharmacogenetics Human Major Histocompatibility Complex and
Disease Susceptibility Gametogenesis Twinning (dizygotic, monozygotic) and timing
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Genetic Counseling
Definition of counseling Mendelian Inheritance and Genetic
Counseling Testing for family history of mental
retardation Non-directive counseling Risk Assessment
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Goals of Genetic Counseling Education about the medical facts (diagnosis,
prognosis, management options) Education about mode of inheritance , recurrence
risks, penetrance, expressivity, and availability of genetic testing
Education about pregnancy and reproductive options Supporting the family as they choose a course of
action Helping family to adjust to the condition
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Genetic Counseling - Indications
advanced maternal age, advanced paternal age exposure to teratogens patient, partner or family member with a history of
genetic disorder, birth defect or mental retardation fetal anomaly recurrent pregnancy loss high risk populations: African, Acadian, Eastern
European Jewish, Mediterranean or SE Asian ancestry
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Genetic counseling process
How to draw a three-generation pedigree Genetic Assessment and Pedigree Analysis (three
generation pedigree, medical history, medical record review, physical examination)
Risk assessment (Bayesean analysis) Genetic education (non-directive counseling) Psychosocial issues (psychological burdens,
shame, guilt, cultural and socioeconomic differences, counselor biases)
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Genetic counseling process
Problems in genetic counseling may include genetic heterogeneity, phenotypic heterogeneity nonpaternity, sporadic cases, incomplete penetrance, variable expressivity
what questionaire tools are helpful in preparing the family history?
What computer-assisted tools are available for pedigree construction?– Progeny– Cyrillic
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Ethical Issues in Genetics
autonomy/confidentiality versus beneficence
autonomy/confidentiality versus nonmalificence
autonomy versus paternalism gene therapy genetic screening
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Obstetrics - What should we learn?
Genetic screening– maternal serum screening
Preconception counseling Human malformations Reproductive options Medico-legal issues
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Genetic screening
Definition and goal, screening criteria, test characteristics, sensitivity, specificity, positive and negative predictive values, cost effectiveness
2x2 tables test sensitivity and test specificity positive predictive value and negative predictive
value test limitations
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Genetic screening
Environmental (radiation, alcohol, drugs)
Advanced Maternal AgeAdvanced Paternal AgeFamily History (Three generation
pedigree)Population Based screen
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Maternal Serum Screening
Maternal Serum Screening First trimester biochemical and/or Nuchal
Translucency Second trimester biochemical screening “Genetic Ultrasound” ACOG Technical Bulletin – Maternal
Serum Screening – www.acog.org
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Preconception counseling
Genetic risks and prior pregnancy risks Nutritional aspects - folic acid,
avoidance of alcohol and tobaccooccupational risks and exposures infectious risks – e.g. toxoplasmosis
precautions
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Prenatal Counseling
Advanced maternal or paternal age Abnormal maternal serum screen Fetal anomalies Recurrent pregnancy loss High risk populations Family history genetic disorders, birth defects,
mental retardation, teratogen exposure
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Teratology - Viral infections, medications, drug exposures
What are the known human teratogens?– Medications (include Vitamin A)
– Virus (CMV, Toxo, Parvovirus, Rubella) What is the timing of exposure? Why is this timing important? REPROTOX website – www.reprotox.org
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Population Screens Some populations at higher risk than others
– Cystic Fibrosis – Sickle Cell anemia– Tay - Sachs– Canavan’s disease– Neimann Pick– Gaucher– Thalassemias
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Recurrent Pregnancy Loss - etiology and evaluation
What is the definition of RPL? What tests should be offered? What treatments are available? What are the most common causes of RPL? What women are at increased risk for this
complication of pregnancy? What tests should be offered to couples with
this history?
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Mental Retardation
What are the most common causes of Mental Retardation
What causes are identifiable?
– Fragile X syndrome and its variants
– Down syndrome
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Human Malformations
normal embryologic and fetal milestones and development
homeobox genes developmental fields abnormal development differentiation cell death developmental timing
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Human Malformations
malformation malformation sequence deformation disruption aplasia, hypoplasia, dysplasia major and minor anomalies associations syndromes
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Multifactorial Inheritance
Open Neural Tube Defect (ONTD)Cleft Lip and/or Palate (CL/P)Congenital Heart Disease (CHD)Club feetCongenital Hip Dysplasia
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Risk Calculations
AR, AD, XLR, XLD, mitochondrial disorders
Multifactorial disordersBayessian Analysis
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Prenatal Testing
Pre-implantation genetic diagnosisAmniocentesis, Chorionic Villus
SamplingPUBS, placental biopsyFISH
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Reproductive options
adoption Pre-implantation genetic diagnosis Termination of pregnancy special needs adoption altered Obstetric and/or Pediatric management fetal therapy Medico-legal and ethical considerations
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Gynecologic, Surgical, and Primary Care Genetics
Cancer Cardiovascular Disease and Pulmonary Thrombophilias and bleeding diathesis Connective Tissue Disorders Hematologic Disorders Renal and metabolic disorders Genetic Disorders of the Endocrine System Neurological disorders Anesthetic considerations
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Cancer
Molecular Basis of Cancer Cell cycle, Viral oncogenes, retroviruses Tumor biology, clonal nature of cancer Proto-oncogenes, Oncogenes, Tumor suppressor
genes Acquired cancers, genetic alterations, cancer
cytogenetics (translocations and oncogenesis) Heritable cancers, Knudson two hit hypothesis Acquired Tumors and Cancers
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Heritable Cancer Syndromes
clinical characteristics (BRCA1&2, HNPCC, LFS) risk identification (high risk screening) genetics (genes, loci, inheritance, penetrance,
expressivity and polymorphisms) Symptomatic versus Pre-symptomatic testing Genetic Counseling issues Ethical and legal issues Management
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Cardiovascular Disease
Molecular basis for cadiovascular disease
Normal and abnormal lipid metabolismNormal and abnormal coagulation and
hemostasisNormal and abnormal connective
tissue composition and physiology
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Cardiovascular Disease
Familial Hypercholesterolemia, combined familial hyperlipidemia
ApoE, ApoA1, Homocysteinemia, ApoB, MTHFR
Hyperlipoproteinemia types I, IIFamilial hypertryglyceridemia factor II (prothrombin)
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Cardiovascular Disease clinical characteristics risk identification (high risk screening) genetics (genes, loci, inheritance, penetrance,
expressivity, and polymorphisms) molecular biology and physiology Symptomatic vs. Presymptomatic testing Genetic Counseling issues Ethical and legal issues
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Thrombophilias Leiden factor V antithrombin III protein C protein S prothrombin (factor II) MTHFR homocysteinemia antiphospholipid symdrome
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Thrombophilias clinical characteristics risk identification (high risk screening) genetics (genes, loci, inheritance, penetrance,
expressivity and polymorphisms) molecular biology and physiology Symptomatic vs. Presymptomatic testing Genetic Counseling issues Ethical and legal issues Management
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Bleeding diathesis
VWDHemophiliaFactor V, X deficiencyFactor VII deficiencyGlanzman’s thrombastheniaWiskott Aldrich
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Bleeding diathesis clinical characteristics risk identification (high risk screening) genetics (genes, loci, inheritance, penetrance,
expressivity and polymorphisms) molecular biology and physiology Symptomatic versus Presymptomatic testing Genetic Counseling issues Ethical and legal issues Management
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Connective Tissue Disorders Marfans syndrome and Ehlers - Danlos
syndrome molecular biology and physiology clinical
characteristics risk identification (high risk screening) genetics (genes, loci, inheritance, penetrance,
expressivity polymorphisms) Symptomatic vs. Presymptomatic testing
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Hematologic Disorders
The Hemoglobinopathies and Thalassemias molecular biology and physiology clinical
characteristics risk identification (high risk screening) genetics (genes, loci, inheritance, penetrance,
expressivity and polymorphisms) Symptomatic versus Presymptomatic testing
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Renal Disorders
Renal Cystic Disorders, Congenital Disorders of the Urinary Tract, Wilms Tumor
molecular biology and physiology, and clinical characteristics
risk identification (high risk screening) genetics (genes, loci, inheritance, penetrance,
expressivity and polymorphisms) Symptomatic versus Presymptomatic testing
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Endocrine System Disorders Type II DM Thyroid disorders
– Autosomal Dominant Hyperthyroidism– Familial Graves Disease and Hashimoto Thyroiditis
Multiple Endocrine Deficiency Medullary Thyroid Carcinoma molecular biology and physiology clinical
characteristics risk identification (high risk screening) Symptomatic vs. Presymptomatic testing
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Pulmonary Disorders alpha 1 - antitrypsin deficiency cystic fibrosis, asthma molecular biology and physiology clinical
characteristicsrisk identification (high risk screening)
genetics (genes, loci, inheritance, penetrance, expressivity and polymorphisms)
Symptomatic vs. Presymptomatic testing
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Metabolic Disorders Hemochromatosis Wilson’s disease molecular biology and physiology, clinical
characteristics risk identification (high risk screening) genetics (genes, loci, inheritance,
penetrance, expressivity, polymorphisms) Symptomatic vs. Presymptomatic testing
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Neurologic Disorders Fragile X Myotonic Dystrophy Huntington Disease Alzheimer Disease molecular biology and physiology, and clinical
characteristics risk identification (high risk screening) genetics (genes, loci, inheritance, penetrance,
expressivity and polymorphisms) Symptomatic vs. Presymptomatic testing
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Anesthesia Issues
Malignant Hyperthermia Acetylcholinesterase Deficiency clinical characteristics risk identification (high risk screening) genetics (genes, loci, inheritance, penetrance,
expressivity, polymorphisms) molecular biology and physiology Symptomatic vs. Presymptomatic testing
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Medical Organizations on the Web: ACGME – www.acgme.org CREOG – www.creog.org ASHG -www.faseb.org/genetics/ashg/ashgmenu.htm ACOG – www.acog.org ABOG – www.abog.org AMA – www.ama-assn.org NIH Consensus Panels – www.nih.org
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Genetic Information Sites OMIM – www.ncbi.nlm.nih.gov/omim GeneClinics – www.geneclinics.org Ethics -www.nhgri.nih.gov/ELSI March of Dimes -
www.modimes.org/HealthLibrary2/portal.htm Contact a family charity – www.cafamily.org.uk USU - www.usuhs.mil/genetics
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REFERENCES Clinical Genetics Handbook
Author: ROBINSON, A; ISBN: 0865421943; Publisher: Blackwell Science; Published: 1993
Fetology: Diagnosis and Management of the Fetal PatientBianchi, D; ISBN: 0838525709; Publisher: McGraw-Hill Incorp
Smith’s Recognizable Patterns of Human MalformationsAuthor: Jones, K; ISBN: 0721661157; Publisher: Saunders, W. B.; Published: 1996
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REFERENCES REFERENCESBirth Defects EncyclopediaAuthor: BUYSE, M; ISBN: 0865422281; Publisher: Blackwell Science; Published: 1992; Edition: 02
Emery and Rimoin: Principles and Practice of Medical Genetics in two volumesAuthor: RIMOIN, D; ISBN: 0443048517; Publisher: Churchill Livingst; Published: 1996; Edition: 03
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REFERENCES Principles of Medical GeneticsAuthor: GELEHRTER, T; ISBN: 0683034456; Publisher: Williams & Wilkins; Published: 1998
Genetics in Medicine: Thompson and ThompsonAuthor: WILLARD; ISBN: 0721669026; Publisher: Saunders, W. B.; Published: N/A
Maternal Serum Screening for Fetal Genetic DisordersAuthor: ELIAS, S; ISBN: 0443088675; Publisher: Churchill; Published: 1992
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REFERENCES Genetics in Obstetrics and GynecologyAuthor: SIMPSON, J; ISBN: 0721641644; Publisher: Saunders, W. B.; Published: N/A;
Prenatal Diagnosis of Congenital AnomaliesAuthor: ROMERO, R; ISBN: 0838579213; Publisher: Appleton-Lange; Published: 1987;
Practical Genetic CounselingAuthor: HARPER, PETER; ISBN: 0750633689; Publisher: Butterworth-Heinem; Published: 1998; Edition: 05