Download Principle of Genetics - คณะแพทยศาสตร์ มหาวิทยาลัยนเรศวร

9/7/2012
Topics
Principle of Genetics
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Introduction
Genetic disorders
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Single gene disorders
Chromosomal disorders
Multifactorial diseases
Somatic cell genetic disorders
นายแพทย ดร. ณตพล ศุภณัฐเศรษฐกุล
ภาควิชาพยาธิวิทยา คณะแพทยศาสตร
มหาวิทยาลัยนเรศวร
Email : [email protected]
12 กันยายน พ.ศ. 2555
http://www.uga.edu/srel/kidsdoscience/images/genetics-puppets.gif
http://www.uwo.ca/biology/images/undergraduate/chromosome.jpg
Topics
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Clinical genetics and Molecular Diagnosis
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Genetic testing for carrier detection
Prenatal diagnosis
Newborn screening
Molecular diagnosis
Genetic counseling
Gregor Mendel
ค.ศ.1822-1884
http://history.nih.gov/exhibits/nirenberg/images/photos/01_mendel_pu.jpg
http://www.scq.ubc.ca/wp-content/mendel.jpg
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1990
–
2003
James D. Watson
1928 -
Structure of DNA
1953
Nobel prize in 1962
Francis H.C. Crick
1916 - 2004
http://tesla.desy.de/~rasmus/media/Coherence/PDFs%20and%20high%20res
olution/watson%20and%20crick.jpg
http://www.sanger.ac.uk/Info/Press/gfx/030414_hgp_300.jpg
Structure of DNA
“Central Dogma”
Transcription
DNA
Translation
RNA
Protein
Replication
http://academic.brooklyn.cuny.edu/biology/bio4fv/page/molecular%20biology/16-05-doublehelix.jpg
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Human Genome (chromosomes)
In Nucleus
In Mitochondria
3.1 x 109 bp
16,569 bp
10%
90%
Gene
Non-gene (Extragenetic)
<10%
Coding
Sequences
(Exon)
Cell cycle
>90%
Non coding
Sequences
(Intron)
50%
50%
Repetitive DNA
Non repetitive DNA
http://ghs.gresham.k12.or.us/science/ps/sci/soph/cells/cycle/cycle.gif
Tandem repeats
(satellite, minisatellite, microsatellite)
Interspersed repeats
(SINES, LINES)
http://www.cbp.pitt.edu/faculty/yong_wan/images/main_cell_cycle.jpg
Mutation
หมายถึงกระบวนการที่กอใหเกิดการเปลี่ยนแปลง
ทุกรูปแบบ ที่เกิดขึ้นกับโมเลกุลของ DNA
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“Wild type” and “mutant allele”
Normal variation, polymorphism, inherited disease
Types of mutation
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http://homepage.mac.com/enognog/cell%20cycle.jpg
http://tainano.com/Molecular%20Biology%20Glossary.files/image040.gif
Base substitution => silent mutation, missense, nonsense
Insertion => frameshift mutation
Deletion => frameshift mutation
Chromosomal abnormality
http://www.layevangelism.com/bastxbk/images/mutation.jpg
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http://www.robbinspathology.com/content/figure.cfm?ImageSeqNo=112100&screenWidth=1280&screenHeight=800
Genetic disorders
Terminology
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Single gene disorders
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Mendelian inheritance
Non-Mendelian inheritance
Chromosomal disorders
Polygenic or multifactorial disorders
Somatic cell genetic disorders (Neoplasm)
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Genotype = genetic constitution of an individual
Phenotype = observed characteristic
Homozygote = identical alleles at a given locus
Heterozygote = two different alleles at a given locus
Autosomes = any chromosomes other than sex
chromosomes
Autosomal inheritance = involve any chromosomes
other than sex chromosomes
Pedigree charts = to illustrate the inheritance
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Terminology
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Genotype = genetic constitution of an individual
Phenotype = observed characteristic
Homozygote = identical alleles at a given locus
Heterozygote = two different alleles at a given locus
Autosomes = any chromosomes other than sex
chromosomes
Autosomal inheritance = involve any chromosomes
other than sex chromosomes
Pedigree charts = to illustrate the inheritance
http://naturalsciences.sdsu.edu/ta/classes/lab2.4/trait.jpg
Terminology
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Locus = position of DNA sequences, or gene on a
chromosome
Allele = possible alternative form of a given gene
DNA polymorphism = the occurrence in a
population of two or more alternative genotypes
Gene pool = the study of frequency of total alleles
on a given locus
Population genetics = the study of the genetic
composition of populations
Cystic Fibrosis Transmembrane Regulator, CTFR
http://ghr.nlm.nih.gov/handbook/illustrations/chromosomallocation.jpg
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Gene loci
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/Chromo7.gif
http://www.geneticsandhealth.com/wp-content/allele.jpg
Terminology
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Genotype = genetic constitution of an individual
Phenotype = observed characteristic
Homozygote = identical alleles at a given locus
Heterozygote = two different alleles at a given locus
Autosomes = any chromosomes other than sex
chromosomes
Autosomal inheritance = involve any chromosomes
other than sex chromosomes
Pedigree charts = to illustrate the inheritance
http://www.genome.gov/Pages/Hyperion/DIR/VIP/Glossary/Illustration/Images/autosome.gif
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Terminology
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Genotype = genetic constitution of an individual
Phenotype = observed characteristic
Homozygote = identical alleles at a given locus
Heterozygote = two different alleles at a given locus
Autosomes = any chromosomes other than sex
chromosomes
Autosomal inheritance = involve any chromosomes
other than sex chromosomes
Pedigree charts = to illustrate the inheritance
http://www.geneticsandhealth.com/wp-content/pedigree%20image_1.gif
http://www.geneticsandhealth.com/wp-content/pedigree%20image_2.gif
http://www.migeneticsconnection.org/genomics/Family%20History/pedigreeSymbols.jpg
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Introduction
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Single gene disorders are caused by individual
mutant genes
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There are approximately 11,000 single gene
disorders, affecting 1% of the populations
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Follow Mendelian patterns of inheritance
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Autosomal dominant inheritance (AD)
Autosomal recessive inheritance (AR)
X-linked recessive inheritance (X-linked)
X-linked dominant inheritance
Y-linked (Holandic) inheritance
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A “dominant phenotype” is one that is
expressed in heterozygotes, whereas a
“recessive trait” is expressed only in
homozygotes
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If the expression of each allele can be
detected in the presence of the other, the two
alleles are termed “co-dominant”
Autosomal Dominant
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Phenotypically expressed in homozygotes and
heterozygotes for that gene
There is vertical inheritance (affected child usually
has an affected parent)
Unaffected family members usually have unaffected
partners, and they produce normal children
Affected family members, usually have unaffected
partners, and they produce a 1:1 ratio of normal and
affected children
Usually both sexes are equally affected, and they
are equally likely to pass on the disease
http://www.uic.edu/classes/bms/bms655/gfx/pedigree1.gif
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Achondroplasia
Marfan syndrome
http://www.sciencemuseum.org.uk/on-line/genes/images/1-3-5-1-4-2-1-1-1-3-0.jpg
http://www.nhlbi.nih.gov/health/dci/images/Marfan_lowres.gif
http://www.moondragon.org/obgyn/graphics/achondroplasiacomparison.jpg
http://www.commonwealthadoption.org/images/johnston.jpg
http://www.homoeopathiker.de/homoeopathik/syphilis/bilder/marfan3.jpg
Examples
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Skeletal: Marfan syndrome, Achondroplasia,
Osteogenesis imperfecta
Nervous system: Huntington disease,
Neurofibromatosis
Urinary: Polycystic kidney disease (Adult)
Gastrointestinal: Familial polyposis coli
Hematopoietic: Von Willebrand disease
Metabolic: Familial hypercholesterolemia,
Acute intermittent porphyria
http://www.uic.edu/classes/bms/bms655/lesson5.html
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Autosomal Recessive
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Expressed only in homozygotes, otherwise
can be trait
There is horizontal inheritance (normal parents
often have more than one affected child)
Affected individuals have phenotypically
normal parents
Affected individuals usually have unaffected
partners and all their children will be carriers
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If a carrier has an unaffected partner, there is a 50%
chance of the children being carriers
Only mating between heterozygotes (carrier) will
produce affected individuals, with an expected
frequency of 1 in 4
There is an association with consanguinity due to
sharing of genes in families (rare recessive genetic
disorders are more likely to arise through
consanguinity)
Both sexes are equally affected and equally likely to
pass the mutation to the next generation
http://healthnet.md.chula.ac.th/text/forum1/thalassemia2/picture/thalassemia.jpg
http://upload.wikimedia.org/wikipedia/commons/thumb/3/3e/Autorecessive.svg/300px-Autorecessive.svg.png
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http://www.microscopyu.com/galleries/pathology/images/sicklecell/sicklecellanemia40x02small.jpg
http://home.kku.ac.th/acamed/kanchana/p7.jpg
http://www.irondisorders.org/News/SickleCell.jpg
Example
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Metabolic: Cystic fibrosis, Phenylketonuria,
Hemochromatosis, Glycogen storage
diseases, Galactosemia, Homocystinuria,
Lysosomal storage diseases
Hematopoietic: Thalassemia, Sickle cell
disease
Endocrine: Congenital adrenal hyperplasia
Nervous: Friedreich ataxia
http://www.uic.edu/classes/bms/bms655/lesson7.html#RECESSIVE
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X-linked Recessive
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Many more males than females show the recessive
phenotype
The disease is transmitted by a carrier female, who
is usually asymptomatic
If a mother is a carrier, her son have a 50% chance
of being affected and her daughters a 50% chance
of being carriers
An affected male will usually have no affected
offspring, but all his daughters will be carriers and,
in turn, 50% of their sons will be affected
No sons of the affected male will inherit the gene
(there is no male-to-male transmission)
http://www.uic.edu/classes/bms/bms655/lesson7.html#RECESSIVE
Gower’s sign
Example
Duchenne muscular dystrophy
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http://www.neurologyarticles.com/sitebuilder/images/Scan10106-176x315.jpg
Musculoskeletal: Duchenne muscular
dystrophy, Becker muscular dystrophy
Blood: Glucose-6-phosphate dehydrogenase
(G6PD) deficiency, Hemophilia A and B
Metabolic: Diabetes insipidus, Lesch-Nyhan
syndrome
Nervous: Fragile-X syndrome (Atypical)
Immune: Agammaglobulinemia
http://medicalimages.allrefer.com/large/x-linked-recessive-genetic-defects.jpg
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II. Chromosomal Abnormalities
Terminology
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Terminology
Introduction
Numerical Chromosome abn.
Structural chromosome abn.
Chromosome instability synd.
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Karyotype = the chromosome constitution of an individual,
normal human karyotype is 46,XY (male) and 46,XX (female)
Polyploidy = the number of hapoloid chromosome sets is
greater than two (2n), triploidy, tetraploidy
Aneuploidy = chromosome number is not an exact multiple of
haploid number, monosomies, trisomies
Trisomy = three representatives of a given chromosome, trisomy
21 in Down dyndrome
Monosomy = one member of a chromosome pair is missing,
Turner syndrome (45,X)
Translocation = the transfer of one segment of a chromosome
to another
http://images.wikio.com/images/p/51ca/the-world-s-worst-genetic-mutation-in-a-dog.jpg
Terminology
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Karyotype = the chromosome constitution of an individual,
normal human karyotype is 46,XY (male) and 46,XX (female)
Polyploidy = the number of hapoloid chromosome sets is
greater than two (2n), triploidy, tetraploidy
Aneuploidy = chromosome number is not an exact multiple of
haploid number, monosomies, trisomies
Trisomy = three representatives of a given chromosome, trisomy
21 in Down dyndrome
Monosomy = one member of a chromosome pair is missing,
Turner syndrome (45,X)
Translocation = the transfer of one segment of a chromosome
to another
http://www.asklenore.info/miscarriage/bick/images/fig3.jpg
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Terminology
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Karyotype = the chromosome constitution of an individual,
normal human karyotype is 46,XY (male) and 46,XX (female)
Polyploidy = the number of hapoloid chromosome sets is
greater than two (2n), triploidy, tetraploidy
Aneuploidy = chromosome number is not an exact multiple of
haploid number, monosomies, trisomies
Trisomy = three representatives of a given chromosome, trisomy
21 in Down dyndrome
Monosomy = one member of a chromosome pair is missing,
Turner syndrome (45,X)
Translocation = the transfer of one segment of a chromosome
to another
http://www.ucl.ac.uk/~ucbhjow/bmsi/lec7_images/47_xx_21.gif
Terminology
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Karyotype = the chromosome constitution of an individual,
normal human karyotype is 46,XY (male) and 46,XX (female)
Polyploidy = the number of hapoloid chromosome sets is
greater than two (2n), triploidy, tetraploidy
Aneuploidy = chromosome number is not an exact multiple of
haploid number, monosomies, trisomies
Trisomy = three representatives of a given chromosome, trisomy
21 in Down dyndrome
Monosomy = one member of a chromosome pair is missing,
Turner syndrome (45,X)
Translocation = the transfer of one segment of a chromosome
to another
http://www.myoops.org/cocw/tufts/courses/20/content/D293242/C293223.jpg
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Spectral Karyotyping (SKY) Analysis
Introduction
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Maybe numerical or structural
Nomenclature
Numerical disorders :
[47, XY,+21],
[45,X]
Structural disorders :
[46,XY,t(14;21)(q11,p10)],
[46,XY,dup(5) (q20-q30)],
[46,XY,del(15)(q11-q13)],
(break point, margin, or region)
http://www.nature.com/onc/journal/v24/n33/images/1208711f1.jpg
Numerical Chromosome
Abnormalities
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Concern :
Extra single chromosome,
Missing single chromosome,
Extra haploid sets
Polyploidy
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Fertilization by two sperm
A diploid sperm (2n) due to failure in meiosis
A diploid ovum (2n) due to failure in meiosis
Mechanisms
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Polyploidy
Trisomies
Monosomies
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Trisomies
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Failure of separation (nondisjunction) of
homologous chromosomes at meiosis I
Failure of separation of chromatids in
meiosis II
Advancing maternal age is associated with
increased incidence of trisomy
http://www.anselm.edu/homepage/jpitocch/genbio/nondisjunction.JPG
Examples
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Autosomal disorders :
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Sex chromosome disorders :
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Trisomy 21 (Down syndrome)
Trisomy 18 (Edwards syndrome)
Trisomy 13 (Patau syndrome)
Klinefelter syndrome (47,XXY)
Turner syndrome (45,X)
XXX = female with an extra X chromosome
XYY = male with an extra Y chromosome
XX male = Y sequences are transferred to the X
chromosome, look like male with Klinefelter
syndrome
http://www.robbinspathology.com/content/figure.cfm?ImageSeqNo=108200&screenWidth=1280&screenHeight=800
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Down’s syndrome
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CVS : Endocardial cushion defect
(Atrioventricular septal defect) most common
GI : increase risk of Hirschprung’s diseases
(intestinal stenosis)
Down’s syndrome facies
Simian crease
Gap between 1st and 2nd toes
http://www.suriyothai.ac.th/en/node/1005
http://upload.wikimedia.org/wikipedia/commons/c/c3/Trisomy21_graph.jpg
http://cas.bellarmine.edu/tietjen/HumanBioogy/bills_developmental_abnormalities.htm
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http://www.robbinspathology.com/content/figure.cfm?ImageSeqNo=109400&screenWidth=1280&screenHeight=800
http://cas.bellarmine.edu/tietjen/HumanBioogy/bills_developmental_abnormalities.htm
Structural Chromosome
Abnormalities
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Result from breakage and limitations of
DNA repair systems
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Mechanisms
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Translocation
Inversion
Duplication
Deletion and ring chromosome
Isochromosome
http://www.robbinspathology.com/content/figure.cfm?ImageSeqNo=107050&screenWidth=1280&screenHeight=800
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III. Multifactorial Disorders
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Terminology
Multifactorial disorders
Threshold model of multifactorial disorders
Examples of multifactorial disorders
Cri du chat syndrome (cat-like cry)
: Deletion of the region on 5p15.2 or
the whole short arm of chromosome 5
mental retardation, low birth weight, low set ears, cat-like cry
http://cas.bellarmine.edu/tietjen/HumanBioogy/Finished%20Images/gen30.gif
Multifactorial Inheritance
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Normal human characteristics : Blood
pressure, height, finger ridges, and intelligence
Heritability and Environmental
factors
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Heritability : percentage denoting that the
genetic contribution of a given disease
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Congenital malformations : neural tube
defects, cleft lip and palate, and congenital
heart disease
Common disorders of adult life : DM,
Hypertension, peptic ulcer, and schizophrenia
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If heritability is high, there is a high correlation in
relatives
Environmental factors : can be manipulated
to reduce an individual’s susceptibility below
than the threshold
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Threshold model for
Multifactorial disorders
Example
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(Tendency)
Diabetes mellitus, type I (Insulin-dependent)
Essential hypertension (62% heritability)
Atherosclerosis (65% heritability)
Peptic ulcer (37% heritability)
Schizophrenia (85% heritability)
Asthma (80% heritability)
Alzheimer disease
http://www.uic.edu/classes/bms/bms655/gfx/figure18.gif
Clinical genetics
and Molecular Diagnosis
The age of expression of the major types of genetic disease
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Genetic testing for carrier detection
Prenatal diagnosis
Newborn screening
Molecular diagnosis
Genetic counseling
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Genetic Testing for Carrier Detection
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To identify asymptomatic heterozygotes for
AR traits, or AD disorders that have limited
penetrance or late onset
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Confined to small ethnic populations in which
there is an anomalously high incidence of a
particular disease
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Examples : Thalassemia, Cystic fibrosis,
ADPKD, Cascade screening
Prenatal diagnosis
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To assure of having unaffected children when the risk of
having an affected child is unacceptably high
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NOT equivalent to the assurance of having normal
children, It does not address all possible birth defects
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Noninvasive techniques : ultrasonography, maternal
serum screening
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Invasive technique : amniocentesis, chorionic villus
sampling, cordocentesis
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DNA analysis (PCR, Southern blot), Cytogenetic analysis
Cordocentesis
http://www.nlm.nih.gov/medlineplus/ency/images/ency/fullsize/1062.jpg
http://www.pennhealth.com/health_info/pregnancy/graphics/images/en/19177.jpg
http://www.pennhealth.com/health_info/pregnancy/graphics/images/en/19175.jpg
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Chorionic villi sampling
http://www.nlm.nih.gov/medlineplus/ency/images/ency/fullsize/19163.jpg
http://www.pennhealth.com/health_info/pregnancy/graphics/images/en/19166.jpg
Newborn screening
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To identify treatable genetic disorders such as
phenylketonuria, galactosemia, maple syrup urine
disease, and congenital adrenal hyperplasia in
newborn infants
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Dietary management is usually an early intervention
to eliminate clinical symptoms that would otherwise
lead to severe disability, mental impairment, or dealth
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Prevalence, severity of a condition, availability,
effectiveness of a treatment, and cost will determine
which disorder will be screened
http://www.health.state.mn.us/divs/fh/mcshn/ncfu/images/pkupath.gif
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Molecular techniques
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DNA , RNA Extraction
Polymerase Chain Reaction (PCR)
Gel Electrophoresis
Direct Hybridization Method
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Inborn error of metabolism
- PKU, galactosemia
Hormonal abnormality
- congenital hypothyroidism
- congenital adrenal hyperplasia
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Southern blot analysis
Northern blot analysis
Fluorescence In situ Hybridization (FISH)
DNA Microarrays
Cytogenetics
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Karyotyping
Spectral karyotyping (SKY analysis)
http://www.qctimes.com/content/articles/2005/07/22/features/health/doc42e079564f5f3070410001_thumb.jpg
Polymerase Chain
Reaction (PCR)
DNA
Extraction
Taq DNA
Polymerase
http://www.favorgen.us/sitebuilder/images/Blood_Genomic_DNA_Mini_chart-437x463.jpg
http://www.bio.miami.edu/~cmallery/150/gene/c7.20.7.pcr.jpg
http://www.obstbau-kompetenzzentrum.de/arbeitsbereiche/Folder.2006-11-07.1358/Thermocycler_.jpg
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DNA Gel Electrophoresis
http://users.ugent.be/~avierstr/principles/pcrcopies.gif
http://oceanexplorer.noaa.gov/explorations/03bio/background/molecular/media/gel_plate_600.jpg
http://universe-review.ca/I11-50-gelectrophoresis.jpg
Southern Blot Analysis
http://images.google.co.th/imgres?imgurl=http://users.ugent.be/~avierstr/principles/pcrcopies.gif&imgrefurl=http://users.ugent.b
e/~avierstr/principles/pcr.html&usg=__kCFieOdf4YXbyVmdNjY2uR9bquI=&h=306&w=598&sz=14&hl=th&start=9&um=1&tbnid
=3Kupvmv7CJ2gM:&tbnh=69&tbnw=135&prev=/images%3Fq%3Dpcr%26ndsp%3D18%26hl%3Dth%26sa%3DN%26um%3D1
http://www.mmi.mcgill.ca/mmimediasampler2002/images/5no15/5no15overview.gif
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Blot Detection Method
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Southern blot = DNA detection (DNA probe)
Edwin Southern, Professor of Biochemistry, 1975
Northern blot = RNA detection (RNA probe)
Western blot = Protein detection (Antibody)
Southwestern blot = DNA binding protein (DNA
probe)
Eastern blot = Protein post translation modification
(probe detect CHO, lipid, etc.)
Dot blot (Slot blot) = Nucleotide or Protein
Fluorescent In situ
Hybridization
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Localized specific DNA sequences on
chromosomes using fluorescent probes
Fluorescence microscopy
Localized specific mRNA = gene expression
http://micro.magnet.fsu.edu/primer/techniques/fluorescence/anatomy/images/fluoromicrofigure1.jpg
http://en.wikipedia.org/wiki/File:FISH_(Fluorescent_In_Situ_Hybridization).jpg
http://www.nature.com/modpathol/journal/v18/n12/images/3800465f1.jpg
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DNA Microarrays
http://img.medscape.com/fullsize/migrated/430/330/cc430330.fig2.gif
http://en.wikipedia.org/wiki/File:NA_hybrid.svg
http://www.fao.org/DOCREP/003/X6884E/x6884e00.jpg
http://en.wikipedia.org/wiki/File:Affymetrix-microarray.jpg
http://neurophilosophy.files.wordpress.com/2006/08/cdna-array.jpg
http://farm3.static.flickr.com/2077/2034113679_ac5a5c688d_m.jpg
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Cytogenetics : Karyotyping
Spectral Karyotyping (SKY) Analysis
http://www.cityofhope.org/PublishingImages/Research/Shared%
20Resources%20%20Equipment/Cytogenetics%20Core%20Laboratory/HumanSK
Y_Large.jpg
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Genetic Counseling
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Indications for genetic counseling
Information conveyed in genetic counseling
Indications for
Genetic Counseling
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Known or suspected hereditary disease
in a patient or family
Birth defects
Mental retardation
Advanced maternal age
Family history of early onset cancer
Recurrent pregnancy loss
Teratogen exposure
Consanguinity
http://www.gen.vcu.edu/images/counseling.jpg
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Information Conveyed in
Genetic Counseling
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References
The magnitude of the risk of occurrence
or recurrence
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The impact of the disease on the patient
and the family
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The possibility of modification of either
the impact or the risk
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Anticipated future development
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คัมภิรานนท, อมรา., “พันธุศาสตรมนุษย (Human Genetics), พิมพครัง้ ที่ 2.” เท็กซ แอนด
เจอรนลั พับลิเคชัน่ , กรุงเทพมหานคร, 2546.
บุญแสง, วิชยั ., และคณะ., “ลายพิมพดเี อ็นเอ..จากสารพันธุกรรมสูเ ทคโนโลยีพสิ จู นบคุ คล,
พิมพครัง้ ที่ 2.” สํานักงานพัฒนาวิทยาศาสตร และเทคโนโลยีแหงชาติ, ปทุมธานี, 2545.
Gelehrter, T.D., Collins, F.S., Ginsburg, D., “Principles of Medical Genetics, 2nd edition.”
Williams & Wilkins, Maryland, 1998.
Lamb, N.E., “Crash course : Cell Biology and Genetics.” Mosby-Elsevier, Inc.,
Philadelphia, 2007.
Kumar, V., et al., “Robbins and Cotran Pathologic Basis of Disease, 7th edition.” Elsevier
Inc., Philadelphia, 2005.
Rimoin, D. L., editors, et al., “Emery and Rimoin’s Principles and Practice of Medical
Genetics, 4th edition.” Churchill Livingstone, London, 2002, volume 1.
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