Principle of Genetics

นายแพทย ดร. ณตพล ศุภณัฐเศรษฐกุล

ภาควิชาพยาธิวิทยา และนิติเวชศาสตร

คณะแพทยศาสตร มหาวิทยาลยันเรศวร

Email : nsupanat@yahoo.com

http://www.uga.edu/srel/kidsdoscience/images/genetics-puppets.gifhttp://www.uwo.ca/biology/images/undergraduate/chromosome.jpg8 กรกฎาคม พ.ศ. 2554

Topics

The Role of Genetics in MedicineGenes and ChromosomesGenetic disorders

Single gene disordersMendelian inheritanceNon-mendelian inheritance

Chromosomal disordersPolygenic or multifactorial diseasesSomatic cell genetic disorders

Clinical geneticsGenetic screening testPrenatal diagnosis, newborn screeningGenetic counseling / ethicsGene therapy

Topics The Role of Genetics in Medicine

First report in human genetics : Jewish report on hemophilia and gender transmissionIn 1865, Mendel published his workIn 1956, the correct chromosome number was reportedIn January 1959, the chromosomal abnormality associated with clinical disorders was ever reportedMapping of genes to chromosomes and specific chromosome region, abnormal gene functions

http://history.nih.gov/exhibits/nirenberg/images/photos/01_mendel_pu.jpg

http://www.scq.ubc.ca/wp-content/mendel.jpg

http://images.google.co.th/imgres?imgurl=http://www.virtualsciencefair.org/2004/mcgo4s0/public_html/t2/dwn_chromo.gif&imgrefurl=http://www.virtualsciencefair.org/2004/mcgo4s0/public_html/t2/dna.html&h=318&w=430&sz=29&hl=th&start=32&um=1&tbnid=4sRt4QRwm30RKM:&tbnh=93&tbnw=126&prev=/images%3Fq%3DDown%2Bsyndrome%26start%3D18%26ndsp%3D18%26um%3D1%26hl%3Dth%26sa%3DN

http://www.virtualsciencefair.org/2004/mcgo4s0/public_html/t2/dwn_chromo.gif http://ghr.nlm.nih.gov/handbook/illustrations/chromosomallocation.jpgCystic Fibrosis Transmembrane Regulator, CTFR

The DNA sequence provided by the Human Genome Project (1988 – 2003)

3,095,784,273 base pairs with 32,020 genes

Approximately 3% of all pregnancies result in the birth of a child with a significant genetic disease or birth defect

Four major types of genetic disease:Single gene disorders Chromosomal disordersPolygenic or multifactorial diseasesSomatic cell genetic disorders

The Role of Genetics in Medicine Genes and Chromosomes

Structure of DNACentral dogmaChromosomesGeneCell cycle and cell divisions :

mitosis meiosis

Mutation

Structure of DNA

http://academic.brooklyn.cuny.edu/biology/bio4fv/page/molecular%20biology/16-05-doublehelix.jpg

“Central Dogma”

DNA RNA Protein

TranslationTranscription

Replication

http://www.dnareplication.info/images/dnareplication.jpg

http://images2.clinicaltools.com/images/gene/mrnatext_highlight.jpg

Chromosomes

http://infohost.nmt.edu/~klathrop/DNA%20Coiling.jpg

Human Genome (chromosomes)

In Nucleus3.1 x 109 bp

In Mitochondria16,569 bp

Gene

Coding Sequences

(Exon)

Non coding Sequences

(Intron)

Non-gene (Extragenetic)

Repetitive DNA

Tandem repeats (satellite, minisatellite, microsatellite)

Interspersed repeats (SINES, LINES)

Non repetitive DNA

10% 90%

<10% >90% 50%50%

Cell cycle

http://www.cbp.pitt.edu/faculty/yong_wan/images/main_cell_cycle.jpg

http://ghs.gresham.k12.or.us/science/ps/sci/soph/cells/cycle/cycle.gif

http://tainano.com/Molecular%20Biology%20Glossary.files/image040.gifhttp://homepage.mac.com/enognog/cell%20cycle.jpg

Cell division

MitosisMeiosis and gametogenesisCrossing over

http://www.uhh.hawaii.edu/~ronald/392/Mitosis.JPG http://www.mun.ca/biology/desmid/brian/BIOL2060/BIOL2060-20/2010.jpg

Mutationหมายถึงกระบวนการที่กอใหเกิดการเปลี่ยนแปลง

ทุกรูปแบบ ที่เกิดขึ้นกับโมเลกุลของ DNA

“Wild type” and “mutant allele”Normal variation, polymorphism, inherited diseaseTypes of mutation

Base substitution => silent mutation, missense, nonsenseInsertion => frameshift mutationDeletion => frameshift mutationChromosomal abnormality

http://www.layevangelism.com/bastxbk/images/mutation.jpg

http://www.robbinspathology.com/content/figure.cfm?ImageSeqNo=112100&screenWidth=1280&screenHeight=800

Genetic disorders

Single gene disordersMendelian inheritanceNon-Mendelian inheritance

Chromosomal disordersPolygenic or multifactorial disordersSomatic cell genetic disorders

I. Single gene disorders

TerminologyMechanism of mutationFunctional effects of mutation on proteinMendelian inheritance of single gene disorders

TerminologyGenotype = genetic constitution of an individualPhenotype = observed characteristicHomozygote = identical alleles at a given locusHeterozygote = two different alleles at a given locusAutosomes = any chromosomes other than sex

chromosomesAutosomal inheritance = involve any chromosomes

other than sex chromosomesPedigree charts = to illustrate the inheritance

http://naturalsciences.sdsu.edu/ta/classes/lab2.4/trait.jpg

TerminologyLocus = position of DNA sequences, or gene on a chromosomeAllele = possible alternative form of a given geneDNA polymorphism = the occurrence in a population of two or more alternative genotypesGene pool = the study of frequency of total alleles on a given locusPopulation genetics = the study of the genetic composition of populations

http://www.geneticsandhealth.com/wp-content/allele.jpg http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/Chromo7.gif

Gene loci

http://www.genome.gov/Pages/Hyperion/DIR/VIP/Glossary/Illustration/Images/autosome.gif 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

Introduction

Single gene disorders are caused by individual mutant genes

There are approximately 11,000 single gene disorders, affecting 1% of the populations

Follow Mendelian patterns of inheritanceAutosomal dominant inheritance (AD)Autosomal recessive inheritance (AR)X-linked recessive inheritanceX-linked dominant inheritanceY-linked (Holandic) inheritance

Mandelian Inheritance

Autosomal dominant inheritanceAutosomal recessive inheritanceX-linked recessive inheritanceX-linked dominant inheritanceY-linked (Holandic) inheritance

A “dominant phenotype” is one that is expressed in heterozygotes, whereas a “recessive trait” is expressed only in homozygotes

If the expression of each allele can be detected in the presence of the other, the two alleles are termed “co-dominant”

http://www.uic.edu/classes/bms/bms655/gfx/pedigree1.gif

Autosomal Dominant

Phenotypically expressed in homozygotes and heterozygotes for that geneThere is vertical inheritance (affected child usually has an affected parent)Unaffected family members usually have unaffected partners, and they produce normal childrenAffected family members, usually have unaffected partners, and they produce a 1:1 ratio of normal and affected childrenUsually both sexes are equally affected, and they are equally likely to pass on the disease

http://www.sciencemuseum.org.uk/on-line/genes/images/1-3-5-1-4-2-1-1-1-3-0.jpg

http://www.moondragon.org/obgyn/graphics/achondroplasiacomparison.jpg

http://www.commonwealthadoption.org/images/johnston.jpg

Achondroplasia

http://www.nhlbi.nih.gov/health/dci/images/Marfan_lowres.gif

http://www.homoeopathiker.de/homoeopathik/syphilis/bilder/marfan3.jpg

Marfan syndrome

Examples

Skeletal: Marfan syndrome, Achondroplasia, Osteogenesis imperfectaNervous system: Huntington disease, NeurofibromatosisUrinary: Polycystic kidney diseaseGastrointestinal: Familial polyposis coliHematopoietic: Von Willebrand diseaseMetabolic: Familial hypercholesterolemia, Acute intermittent porphyria

http://www.uic.edu/classes/bms/bms655/lesson5.html

Autosomal Recessive

Expressed only in homozygotes, otherwise can be traitThere is horizontal inheritance (normal parents often have more than one affected child)Affected individuals have phenotypically normal parentsAffected individuals usually have unaffected partners and all their children will be carriers

If a carrier has an unaffected partner, there is a 50% chance of the children being carriersOnly mating between heterozygotes (carrier) will produce affected individuals, with an expected frequency of 1 in 4There 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://upload.wikimedia.org/wikipedia/commons/thumb/3/3e/Autorecessive.svg/300px-Autorecessive.svg.png

http://healthnet.md.chula.ac.th/text/forum1/thalassemia2/picture/thalassemia.jpg

http://home.kku.ac.th/acamed/kanchana/p7.jpg

http://www.microscopyu.com/galleries/pathology/images/sicklecell/sicklecellanemia40x02small.jpg

http://www.irondisorders.org/News/SickleCell.jpg

Example

Metabolic: Cystic fibrosis, Phenylketonuria, Hemochromatosis, Glycogen storage disease, Galactosemia, HomocystinuriaHematopoietic: Thalassemia, Sickle cell diseaseEndocrine: Congenital adrenal hyperplasiaNervous: Friedreich ataxia

X-linked Dominant

Rare, and difficult to distinguish from AD except that affected males have normal sons, but all daughters are affected

Example : X-linked hypophosphatemic rickets, Rett syndrome

http://www.uic.edu/classes/bms/bms655/gfx/pedigree5.gif

http://www.uic.edu/classes/bms/bms655/lesson7.html#RECESSIVE

X-linked Recessive

Many more males than females show the recessive phenotypeThe disease is transmitted by a carrier female, who is usually asymptomaticIf a mother is a carrier, her son have a 50% chance of being affected and her daughters a 50% chance of being carriersAn affected male will usually have no affected offspring, but all his daughters will be carriers and, in turn, 50% of their sons will be affectedNo sons of the affected male will inherit the gene (there is no male-to-male transmission)

Females do not tend to show X-linked recessive disease. However, woman can be affected in the following condition :

If she is the daughter of an affected male (XdY) and a carrier female (XdX)If there is X chromosome-autosome translocationIf 45,X (Turner syndrome) is presentIf greater proportion of normal X chromosomes are inactivated

http://www.neurologyarticles.com/sitebuilder/images/Scan10106-176x315.jpg

Gower’s sign

http://medicalimages.allrefer.com/large/x-linked-recessive-genetic-defects.jpg

Duchenne muscular dystrophy

Example

Musculoskeletal: Duchenne muscular dystrophy, Becker muscular dystrophyBlood: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, Hemophilia A and BMetabolic: Diabetes insipidus, Lesch-Nyhan syndromeNervous: Fragile-X syndromeImmune: Agammaglobulinemia

Y-linked (Holandic)

http://cas.bellarmine.edu/tietjen/HumanBioogy/Finished%20Images/gen17.gifhttp://cas.bellarmine.edu/tietjen/HumanBioogy/bills_developmental_abnormalities.htm

II. Chromosomal Abnormalities

TerminologyIntroductionNumerical Chromosome abn.Structural chromosome abn.Chromosome instability synd.

http://images.wikio.com/images/p/51ca/the-world-s-worst-genetic-mutation-in-a-dog.jpg

TerminologyKaryotype = 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, tetraploidyAneuploidy = chromosome number is not an exact multiple of haploid number, monosomies, trisomiesTrisomy = three representatives of a given chromosome, trisomy 21 in Down dyndromeMonosomy = 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 http://www.ucl.ac.uk/~ucbhjow/bmsi/lec7_images/47_xx_21.gif

http://www.myoops.org/cocw/tufts/courses/20/content/D293242/C293223.jpg http://www.nature.com/onc/journal/v24/n33/images/1208711f1.jpg

Spectral Karyotyping (SKY) Analysis

IntroductionMaybe numerical or structuralNomenclatureNumerical 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)

Numerical Chromosome Abnormalities

Concern : Extra single chromosome, Missing single chromosome, Extra haploid sets

MechanismsPolyploidyTrisomiesMonosomies

Polyploidy

Fertilization by two spermA diploid sperm due to failure in meiosisA diploid ovum due to failure in meiosis

TrisomiesFailure of separation (nondisjunction) of homologous chromosomes at meiosis I Failure of separation of chromatids in meiosis IIAdvancing maternal age is associated with increased incidence of trisomy

Monosomies

Result from nondisjunctionFrom “anaphase lag” = delay in movement of one chromosome to reach the pole of the cell before the nuclear membrane reforms during anaphase

http://www.anselm.edu/homepage/jpitocch/genbio/nondisjunction.JPG

ExamplesAutosomal disorders :

Trisomy 21 (Down syndrome)Trisomy 18 (Edwards syndrome)Trisomy 13 (Patau syndrome)

Sex chromosome disorders : Klinefelter syndrome (47,XXY)Turner syndrome (45,X)

XXX = female with an extra X chromosomeXYY = male with an extra Y chromosomeXX 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

Down’s syndrome

CVS : Endocardial cushion defect (Atrioventricular septal defect) most commonGI : increase risk of Hirschprung’s diseases(intestinal stenosis)Down’s syndrome faciesSimian creaseGap between 1st and 2nd toes

http://upload.wikimedia.org/wikipedia/commons/c/c3/Trisomy21_graph.jpg

http://cas.bellarmine.edu/tietjen/HumanBioogy/Finished%20Images/gen30.gif

Trisomy-13Patau syndromeTrisomy DPolydactyly, CL/CP

http://cas.bellarmine.edu/tietjen/HumanBioogy/bills_developmental_abnormalities.htm

Trisomy -18Edwards syndromeTrisomy E

http://cas.bellarmine.edu/tietjen/HumanBioogy/bills_developmental_abnormalities.htm http://www.robbinspathology.com/content/figure.cfm?ImageSeqNo=109400&screenWidth=1280&screenHeight=800

http://cas.bellarmine.edu/tietjen/HumanBioogy/bills_developmental_abnormalities.htm http://www.biology.iupui.edu/biocourses/n100/images/XYYMale.gif

http://modculture.typepad.com/photos/uncategorized/2007/03/14/xyy.jpg

The XYY Man is Spider Scott (Stephen Yardley), a burglar with an extra "Y" chromosome - which makes him predisposed towards crime. So when he's tapped up fresh out of prison by British intelligence to do a big job for a big price, he goes for it - which leads to a chain of events that threaten his life - and indeed other people's lives.It's one of those 70s plots that involves various secret agents from several different countries - South Africa, Rhodesia (it still existed) and China in particular.

Structural Chromosome Abnormalities

Result from breakage and limitations of DNA repair systems

MechanismsTranslocationInversionDuplicationDeletion and ring chromosomeIsochromosome

http://www.robbinspathology.com/content/figure.cfm?ImageSeqNo=107050&screenWidth=1280&screenHeight=800

http://www.nature.com/ejhg/journal/v11/n10/images/5201047f1.jpg

ExamplesPrader-Willi syndrome and Angelman syndrome : deletion on 15q11-13

Prader-Willi : inheritance of the deletion from the fatherAngelman : inheritance of the deletion from the mother

Cri du chat syndrome (cat-like cry) : Deletion of the region on 5p15.2 or the whole short arm of chromosome 5

http://www.robbinspathology.com/content/figure.cfm?ImageSeqNo=112800&screenWidth=1280&screenHeight=800 http://atlasgeneticsoncology.org/Deep/Images/GenomImprintFig6.jpghttp://www.blackwellpublishing.com/korfgenetics/jpg/300_96dpi/Fig6-30.jpg

ExamplesPrader-Willi syndrome and Angelman syndrome : deletion on 15q11-13

Prader-Willi : inheritance of the deletion from the fatherAngelman : inheritance of the deletion from the mother

Cri du chat syndrome (cat-like cry) : Deletion of the region on 5p15.2 or the whole short arm of chromosome 5

http://cas.bellarmine.edu/tietjen/HumanBioogy/Finished%20Images/gen30.gif

mental retardation, low birth weight, low set ears, cat-like cry

III. Multifactorial Disorders

TerminologyMultifactorial disordersThreshold model of multifactorial disordersExamples of multifactorial disorders

Terminology

Polygenic inheritance : the inheritance of traits that are influenced by many genes at different loci

Multifactorial disorder : disorder in which both environmental and genetic factors are important

Multifactorial Inheritance

Normal human characteristics : Blood pressure, height, finger ridges, and intelligence

Congenital malformations : neural tube defects, cleft lip and palate, and congenital heart disease

Common disorders of adult life : DM, Hypertension, peptic ulcer, and schizophrenia

Heritability and Environmental factors

Heritability : percentage denoting that the genetic contribution of a given disease

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

Threshold model for Multifactorial disorders

http://www.uic.edu/classes/bms/bms655/gfx/figure18.gif(Tendency)

Example

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

The age of expression of the major types of genetic disease Clinical genetics

Genetic testingPrenatal diagnosis, newborn screeningGenetic counseling / ethicsGene therapy

Genetic Testing for Carrier Detection

To identify asymptomatic heterozygotes for AR traits, or AD disorders that have limited penetrance or late onset

Confined to small ethnic populations in which there is an anomalously high incidence of a particular disease

Examples : Thalassemia, Cystic fibrosis, ADPKD, Cascade screening

Prenatal diagnosis

To assure of having unaffected children when the risk of having an affected child is unacceptably high

NOT equivalent to the assurance of having normal children, It does not address all possible birth defects

Noninvasive techniques : ultrasonography, maternal serum screening

Invasive technique : amniocentesis, chorionic villus sampling, cordocentesis

DNA analysis (PCR, Southern blot), Cytogenetic analysis

http://www.nlm.nih.gov/medlineplus/ency/images/ency/fullsize/1062.jpghttp://www.pennhealth.com/health_info/pregnancy/graphics/images/en/19177.jpghttp://www.pennhealth.com/health_info/pregnancy/graphics/images/en/19175.jpg

Cordocentesis

http://www.nlm.nih.gov/medlineplus/ency/images/ency/fullsize/19163.jpghttp://www.pennhealth.com/health_info/pregnancy/graphics/images/en/19166.jpg

Chorionic villi sampling

Newborn screening

To identify treatable genetic disorders such as phenylketonuria, galactosemia, maple syrup urine disease, and congenital adrenal hyperplasia in newborn infants

Dietary management is usually an early intervention to eliminate clinical symptoms that would otherwise lead to severe disability, mental impairment, or dealth

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

http://www.qctimes.com/content/articles/2005/07/22/features/health/doc42e079564f5f3070410001_thumb.jpg

Inborn error of metabolism- PKU, galactosemia

Hormonal abnormality- congenital hypothyroidism- congenital adrenal hyperplasia

Genetic Counseling / Ethics

Indications for genetic counselingInformation conveyed in genetic counselingThe process of genetic counseling

http://www.gen.vcu.edu/images/counseling.jpg

Indications for Genetic Counseling

Known or suspected hereditary disease in a patient or familyBirth defectsMental retardationAdvanced maternal ageFamily history of early onset cancerRecurrent pregnancy lossTeratogen exposureConsanguinity

Information Conveyed in Genetic Counseling

The magnitude of the risk of occurrence or recurrence

The impact of the disease on the patient and the family

The possibility of modification of either the impact or the risk

Anticipated future development

The process of genetic counseling

Establishing the diagnosis (most important)

Presenting the risk in context

Discussing options, communication, and support

Other considerations

Ethical Considerations in Genetic Counseling

Consanguinity and incestDisputed paternityConfidentiality and conflicts of interestRespect for AutonomyBeneficence and Nonmaleficence (do no harm)Privacy and confidentialityJustice and Equity

Examples of ethical issues

The mating of the first-degree relativesTesting for identification of biologic fatherPrenatal diagnosis for determination of fetal sex, or congenital birth defectsHigh risk experimental therapy in a gravely ill infantLoss of health insurance, or job because of a genetic predisposition

Gene therapyThe treatment of a disease by addition, insertion, or replacement of a normal gene or genes

Two possible strategies :Germ-line gene therapySomatic cell therapy

Requirements :The gene involved should be cloned and characterizedThe specific tissue to be targeted should be accessible and identifiedA safe and efficient vector system for the gene should be definedThe scientific rationale for the gene therapy approach should besound and the perceived risks commensurate with the potential benefits

Germ-line Gene Therapy

Genetic changes would be introduced into every cell type, including the germ line

Can be passed from generation to generation

Considered unethical

Somatic Cell Gene Therapy

The genetic modifications are targeted specifically to the diseased tissue

Germ cells would continue to carry the mutant forms of the disease gene

http://fig.cox.miami.edu/Faculty/Dana/germinalsomatic.jpg

Gene therapyThe treatment of a disease by addition, insertion, or replacement of a normal gene or genes

Two possible strategies :Germ-line gene therapySomatic cell therapy

Requirements :The gene involved should be cloned and characterizedThe specific tissue to be targeted should be accessible and identifiedA safe and efficient vector system for the gene should be definedThe scientific rationale for the gene therapy approach should besound and the perceived risks commensurate with the potential benefits

http://openlearn.open.ac.uk/file.php/2430/SK195_5_001i.jpg

Vector system

The vector system is the means by which DNA is delivered to the target cells

Two main types of vector systemPhysical (nonviral) vector systems : LiposomesViral vectors

Integrate into the genome : retroviral, lentiviral, adeno-associated virus (AAV)Maintained as an episome : adenovirus

http://www.acceleratingfuture.com/michael/blog/images/Gene_therapy.jpg http://openlearn.open.ac.uk/file.php/2430/SK195_5_002i.jpg

Therapeutic strategies

Selecting which genes to transfer and into what types of target cells

Two general approaches to deliver gene therapy vector to the patient

Ex vivo gene therapyIn vivo gene therapy

The most obvious and direct strategy is the treatment of a recessive genetic deficiency with the replacement of the missing DNA sequence

http://www.biochem.arizona.edu/classes/bioc471/pages/Lecture25/Lecture25.html

http://www.biochem.arizona.edu/classes/bioc471/pages/Lecture25/Lecture25.html

Diseases which can potentially be treated by gene therapy

Disorder Defect

Hypercholesterolemia LDL receptor abnormalities

Hemophilia Factor VIII (A), Factor IX (B) deficiency

Emphysema Alpha-1 antitrypsin deficiency

Cystic fibrosis CTFR mutations

Phenylketonuria Phenylalanine hydroxylase deficiency

Muscular dystrophy Dystrophin mutations

Thalassemia Alpha- and beta- globin gene mutations

Cancer Protooncogene and tumor suppressor gene mutations

Referencesคัมภิรานนท, อมรา., “พันธศุาสตรมนุษย (Human Genetics), พิมพคร้ังที่ 2.” เท็กซ แอนด เจอรนัล พับลิเคชั่น, กรุงเทพมหานคร, 2546.บุญแสง, วิชัย., และคณะ., “ลายพิมพดีเอ็นเอ..จากสารพันธุกรรมสูเทคโนโลยีพิสูจนบุคคล, พิมพคร้ังที่ 2.” สํานักงานพัฒนาวิทยาศาสตร และเทคโนโลยีแหงชาต,ิ ปทุมธาน,ี 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.