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 tghsasongko@gmail.com teguhhs@kk.usm.my +6012-9874175 Matur Nuwun Thank You, Terima kasih tghsasongko@gmail.com teguhhs@kk.usm.my +6012-9874175