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

Tujuan Pembelajaran
Genetic Testing (GT), Prenatal Genetic Diagnosis (PND), Preimplantation 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 1

Gene 2

Gene is a segment of DNA that is involved in producing a polypeptide chain; It can include regions preceding and following the coding DNA as well as 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

Chromosomal Disorders
(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 treatment 2. To identify inheritance risk 2. To predict risk of having multifactorial disorder

prognosis and

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 cle/003269.htm

www.dshs.state.tx.us/newborn/

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

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

Exons Control
73 14 54 34 74
xqcon

15

55 35

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

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

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

Would you consider PND for the next pregnancy ?

21

10 6

YES

NO

Unsure

Sasongko and Zabidi-Hussin, 2011 (unpublished)

If the test turned up positive; What then ?

20

Abort

Not Abort
Sasongko and Zabidi-Hussin, 2011 (unpublished)

Issues when establishing diagnosis

Chromosomal Aberration Single-gene defect Straightforward Variable Severity with PND Issues

Straightforward

Multifactorial Disorder

Is genetic testing alone enough ?

Complications with Incidental Finding of Non-paternity Case 1 B-Thalassemia -Both parents identified to have heterozygous mutation of codon 41/42 - Fetus identified to have compound heterozygous of codon 41/42 mutation and codon 17 mutation Case 2 B-Thalassemia -First son identified of having compound heterozygous of IVS2-654 and codon 17 mutation -Mother identified of having heterozygous 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

tghsasongko@gmail.com teguhhs@kk.usm.my +6012-9874175