Genetic Testing, Prenatal Genetic Diagnosis and Pre-implantation Genetic Diagnosis
Clinical-Laboratory Perspectives and Ethical Issues Involved
Teguh Haryo Sasongko, MD, PhD
Human Genome Center, School of Medical Sciences Universiti Sains Malaysia
Lecture for Undergraduate Study in Medicine Bioethics and Health Law 4 Faculty of Medicine and Health Sciences Universitas Jenderal
Soedirman Purwokerto, 12 January 2012
KOTA BHARU KOTA BHARU
Tujuan Pembelajaran
Genetic Testing (GT), Prenatal Genetic Diagnosis (PND), Pre-implantation Genetic Diagnosis (PGD)
Mahasiswa mampu menjelaskan definisi dan perbedaan antara GT, PND dan PGD Mahasiswa mampu menjelaskan indikasi klinis dan metode-metode laboratorium dalam melakukan GT, PND dan PGD Mahasiswa mampu menjelaskan implikasi etik, hukum dan sosial atas informasi genetika pada manusia
Mahasiswa mampu mengidentifikasi dan menganalisa permasalahan etik yang berkaitan dengan privasi dan kerahasiaan informasi genetika manusia Mahasiswa mampu mengidentifikasi dan menganalisa permasalahan etik yang berkaitan dengan pengambilan keputusan klinis atas hasil GT, PND dan PGD
Beware! Science does mislead
During the development of an individual, genes influence not only bodily features at microscopic and macroscopic levels and the metabolic and physiologic condictions underlying medical health, but also the etheral aspects of human nature, including emotions, psychologies, personalities, and even ethical and religious predilections
Mathematics 1+1=2
Bioethics 1+1= 1+1
1+1
D>D
1+1
Chromosome; Gene; DNA
Gene is a segment of DNA
Gene 1
that is involved in producing a polypeptide chain;
It can include regions preceding and following the coding DNA as well as
Gene 2
introns between the exons; It is considered a unit of heredity
Allele : one of two or more
different versions of a gene
www.genome.gov; www.wordnetweb.princeton.edu
C h r o m osom al Disor ders
(Down Syndrome, Patau Syndrome, Klinefelter Syndrome, Fragile X Syndrome, Cri du Chatetc)
Single-gene Disorders
(Thalassemias, Cystic Fibrosis, Spinal Muscular Atrophy, Duchenne Muscular Dystrophy, Tuberous Sclerosis Complex, Arginase Deficiencyetc)
Multifactorial Disorders/Conditions
(Hypertension, Diabetes Mellitus, Other Cardiovascular Diseases, Schizophrenia;
Skin Color, Hair color, Heightetc)
www.genome.gov
www.genome.gov
www.genome.gov
Genetic Testing
Test to identify genetic cause or risk factor for a disease
Done based on clinical diagnosis
Methodologies :
1. Chromosomal aberrations (number and structure) : Karyotyping and Fluorescence In-situ Hybridyzation (FISH) 2. Gene aberrations (point mutations, deletions, insertions) : PCR, PCR-RFLP, DHPLC, HRMA, MLPA DNA Sequencing
Genetic Testing
Purpose :
1. To confirm clinical diagnosis prognosis and treatment 2. To identify inheritance risk 2. To predict risk of having multifactorial disorder
Genetic Testing in Human Genome Center-USM
Cyto-Molecular (Chromosome) Analyses :
Down, Edward, Patau, Klinefelter, Fragile X, Turner, Prader-Willi, DiGeorge, Recurrent Miscarriages
Molecular (Gene) Analyses :
Ambiguous Genitalia (Sex-Determining Region Y SRY) Spinal Muscular Atrophy (SMA SMN1) Duchenne/ Becker Muscular Dystrophy (DMD/BMD
-Dystrophin) Gilbert Syndrome (UGT1A1) Beta-Thalassemia (Beta-Globin)
Karyotyping for Down Syndrome (Trisomy 21)
FISH for DiGeorge Syndrome
Ambiguous Genitalia
A birth defect where the outer genitals do not have the typical appearance of either a boy or a girl
http://www.nlm.nih.gov/medlineplus/ency/arti www.dshs.state.tx.us/newborn/ cle/003269.htm
SRY Gene
1 2 3 4 5 1 DNA ladder
2 Control with SRY absent 3 Control with SRY
present 4 Patient 5 Water PCR
Y
Duchenne/Becker Muscular Dystrophy
Inherited Muscular Dystrophy Most Severe form of MD Progressive Muscle Weakness X-linked recessive 1:3500 males Caused mostly by exonic
deletions of Dystrophin gene Dystrophin 79 exons; the largest gene in human
MLPA for DMD/BMD
xqcon
73 14 54 34 74 15 55 35
Exons Control
Patient
Prenatal Genetic Diagnosis
Test to identify genetic cause of a particular human genetic disorder before birth
Done based on existence of risk or screening of common disorders; high-risk pregnancy
Methodologies : Same as Genetic Testing
Specimen Sampling : Aminiocentesis, Chorionic Villus Sampling
to obtain DNA or chromosomes
Prenatal Genetic Diagnosis in Human Genome Center USM
Prenatal Genetic Diagnosis; Benefits
Prenatal Diagnosis for Prognosis Prediction
Sasongko et al., 2010
Pre-implantation Genetic Diagnosis
Test to identify genetic defects in embryos created through in-vitro fertilization (IVF) before implantation
Done based on existence of risk or chromosomal screening for aneuploidy
Methodologies : Same as genetic testing
Specimen Sampling : Embryo Biopsy post-fertilization; few cells biopsied to obtain DNA or chromosomes
Pre-implantation Genetic Diagnosis
Purposes :
1. To avoid selecting embryos with genetic defects; successful pregnancy 2. To match HLA type potential organ/tissue donor 3. To avoid embryos with high cancer predisposition 4. Sex Selection 5. 6. 7. 8.
ELSI Ethical, Legal and Social Implications
Genetic Information Eugenics Establishing Diagnosis
ELSI Ethical, Legal and Social Implications
Why would YOU bother ?
Genetic Information
What is genetic information ? Genotype Others (epigenetic, transcriptomic, proteomic) Environmental Factors; Lifestyle; Diet PHENOTYPES
Central Dogma of Molecular Biology
Categories of Genetic Information
Non-sensitive information Observable information Private information Sensitive information
Issues with Privacy
Who owns your genetic information ? Who have access to your genetic information ? Misuse and Discrimination
Health Insurance
Employment Use other than those stated in informed consent
Issues with Privacy
Eubios Ethics Institute, A Cross Cultural Introduction to Bioethics, 2005
Eugenics
Any effort to interfere with individuals procreative choices in order to attain a societal goal
Prenatal Genetic
Diagnosis Pre-implantation Genetic Diagnosis
Ensuring Good Breeding ? Eliminating Genetic Disorders ?
Eugenics
Eubios Ethics Institute, A Cross Cultural Introduction to Bioethics, 2005
21 10 6 21 10 6 Would you consider PND for the next pregnancy ?
YES NO Unsure
Sasongko and Zabidi-Hussin, 2011 (unpublished)
If the test turned up positive; What then ?
20
1
Abort Not Abort
Sasongko and Zabidi-Hussin, 2011 (unpublished)
Issues when establishing diagnosis
Chromosomal Aberration Straightforward
Variable Severity Issues with PND
Single-gene defect Straightforward
Multifactorial Disorder Is genetic testing alone enough ?
Complications with Incidental Finding of Non-paternity
Case 1 B-Thalassemia Case 2 B-Thalassemia -Both parents identified to
have -First son identified of having compound heterozygous mutation of codon 41/42 heterozygous of IVS2-654 and codon 17 -Fetus identified to have compound mutation heterozygous of codon 41/42 mutation -Mother identified of having heterozygous and codon 17 mutation IVS2-654
-Father does not have any mutation
Li and Liao, 2008
Disease Labeling
Legal Instruments
UNESCOs Universal Declaration on the Human Genome and Human Rights, 1997 Malaysia: DNA Identification Act No. 699, 2009 The Philippines Rule on DNA Evidence
US: Genetic Information Non-discrimination Act (GINA), 2008
Matur Nuwun Thank You, Terima kasih [email protected] [email protected] +6012-9874175 Matur Nuwun Thank You, Terima kasih [email protected] [email protected] +6012-9874175
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