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Human Genetic Human Genetic Disorders Disorders

Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

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Page 1: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Human Genetic Human Genetic DisordersDisorders

Page 2: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Types of mutationsTypes of mutations

Genetic disorders occur due to mutations. Genetic disorders occur due to mutations. Mutations are defined as permanent damage of Mutations are defined as permanent damage of DNA. DNA. Mutations that affect the germ cells are Mutations that affect the germ cells are transmitted to the progeny and may give rise to transmitted to the progeny and may give rise to inherited diseases. inherited diseases. Mutations affecting somatic cells do not cause Mutations affecting somatic cells do not cause hereditary disease, but are important factors in hereditary disease, but are important factors in the development of cancer and some congenital the development of cancer and some congenital malformations. malformations.

Page 3: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Mutations are classified into three Mutations are classified into three categoriescategories

1.1. Genome mutations:Genome mutations: these involve loss these involve loss or gain of a whole chromosome. Thus or gain of a whole chromosome. Thus genome mutations affect the number of genome mutations affect the number of chromosomeschromosomes

2.2. Chromosomes mutations:Chromosomes mutations: structural structural changes within a chromosome due to re-changes within a chromosome due to re-arrangement of genetic materialarrangement of genetic material

3.3. Gene mutations:Gene mutations: affecting individual affecting individual genes within a chromosomegenes within a chromosome

Page 4: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

MENDELIAN DISORDERSMENDELIAN DISORDERS

They are caused by mutations affecting single They are caused by mutations affecting single genes. genes.

More than 4500 disorder were listed. More than 4500 disorder were listed.

These disorders are inherited either as These disorders are inherited either as autosomal dominant, autosomal recessive or X-autosomal dominant, autosomal recessive or X-linked inheritance. linked inheritance.

It has to be remembered that each gene is It has to be remembered that each gene is represented as a pair (alleles) on a specific gene represented as a pair (alleles) on a specific gene locus on the corresponding chromosomes.locus on the corresponding chromosomes.

Page 5: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

MENDIALIAN DISORDERSMENDIALIAN DISORDERS

AUTOSOMAL DOMINANTAUTOSOMAL DOMINANT

AUTOSOMAL RECESSIVEAUTOSOMAL RECESSIVE

X-LINKED DISORDERSX-LINKED DISORDERS

Page 6: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

AUTOSOMAL DOMINANT AUTOSOMAL DOMINANT DISORDERSDISORDERS

Definition:Definition:– These are disorders manifested in the These are disorders manifested in the

heterozygous state i.e. resulting from heterozygous state i.e. resulting from mutations affecting one of a paired allele and mutations affecting one of a paired allele and the other is not necessarily affected. the other is not necessarily affected.

Page 7: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Examples of autosomal dominant diseases:Examples of autosomal dominant diseases:

Nervous disorders such as neurofibromatosisNervous disorders such as neurofibromatosisRenal disorders such as adult type polycystic Renal disorders such as adult type polycystic kidneykidneyGastrointestinal disorders as familial polyposisGastrointestinal disorders as familial polyposisSkeletal disorders such as Marfan syndromeSkeletal disorders such as Marfan syndromeHaemopeotic disorders such as hereditary Haemopeotic disorders such as hereditary spherocytosisspherocytosisMetabolic disorders such as familial Metabolic disorders such as familial hypercholesterolemiahypercholesterolemiaBone disorder such as multiple exostosisBone disorder such as multiple exostosis

Page 8: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

NEUROFIBROMATOSIS NEUROFIBROMATOSIS

Page 9: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Polycystic Kidney DiseasePolycystic Kidney Disease

Page 10: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Dominant DisorderDominant Disorder 1/20,000 people1/20,000 people

Connective Tissue Connective Tissue defectsdefects

Dislocation of lens in Dislocation of lens in eyeeye

Rupture of aorta (weak Rupture of aorta (weak vessel walls)vessel walls)

““Spider fingers”Spider fingers” Elongated body, faceElongated body, face Caved-in chestCaved-in chest

Page 11: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Abraham Lincoln?Abraham Lincoln? Lincoln could have Lincoln could have

had a mild form of had a mild form of Marfan’sMarfan’s

Page 12: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

AUTOSOMAL RECESSIVE AUTOSOMAL RECESSIVE DISORDERSDISORDERS

Definition:Definition:– These are disorders manifested in the These are disorders manifested in the

homozygous state i.e. resulting from mutation homozygous state i.e. resulting from mutation affecting both of a paired allele. affecting both of a paired allele.

– Abnormality of one allele without its Abnormality of one allele without its corresponding allele results in a heterozygous corresponding allele results in a heterozygous carrier state without clinical manifestationscarrier state without clinical manifestations

Page 13: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Examples of autosomal recessive diseases:Examples of autosomal recessive diseases:

1.1. Nervous disorders such as spinal muscular Nervous disorders such as spinal muscular atrophyatrophy

2.2. Renal disorder such as infantile type of Renal disorder such as infantile type of polycystic kidneypolycystic kidney

3.3. Haematopoeitic disorders such as sickle cell Haematopoeitic disorders such as sickle cell anemia and thalassaemiasanemia and thalassaemias

4.4. Metabolic disorders such as cystic fibrosis, Metabolic disorders such as cystic fibrosis, phenylketonuria, galactosaemia, alpha one phenylketonuria, galactosaemia, alpha one anti-trypsin deficiency and haemochromatosis.anti-trypsin deficiency and haemochromatosis.

Page 14: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Recessive Recessive Defective Defective

Haemoglobin yn Haemoglobin yn RBCsRBCs

Anemia (loss of Anemia (loss of blood cells)blood cells)

Damage to brain, Damage to brain, heart, lungsheart, lungs

Primarily in African Primarily in African Americans; 1/10 in Americans; 1/10 in US is a carrierUS is a carrier

Page 15: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

X-LINKED DISORDERSX-LINKED DISORDERS

Definition:Definition:– Disorders resulting from a mutant gene Disorders resulting from a mutant gene

existing in the X chromosomeexisting in the X chromosome

Types:Types:– May be recessive or rarely dominant:May be recessive or rarely dominant:

Page 16: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

X-linked recessive disorders:X-linked recessive disorders:

The abnormal (mutant) gene is of a The abnormal (mutant) gene is of a recessive nature. recessive nature.

Thus females are carriers and do not Thus females are carriers and do not suffer from a clinical disease since the suffer from a clinical disease since the other allele is normal, while males suffer other allele is normal, while males suffer from a disease since the abnormal gene from a disease since the abnormal gene has no corresponding allele on the Y has no corresponding allele on the Y chromosomechromosome

Page 17: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Examples of X-linked recessive disorders:Examples of X-linked recessive disorders:

1.1. Skeletal disorders as Duchenne muscular Skeletal disorders as Duchenne muscular dystrophydystrophy

2.2. Haempoeitic disorders as hemophilia A&BHaempoeitic disorders as hemophilia A&B

3.3. Ocular disorders as color blindnessOcular disorders as color blindness

4.4. Immune disorders as agammaglobuniemiaImmune disorders as agammaglobuniemia

5.5. Metabolic disorders as diabetes insipidusMetabolic disorders as diabetes insipidus

Page 18: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

X-linked recessiveX-linked recessive Most Common in malesMost Common in males

1/35001/3500 Muscle EnlargementMuscle Enlargement DystrophinDystrophin

Protein that provides Protein that provides support for the cell; support for the cell; without it the cell without it the cell enlarges and explodesenlarges and explodes

Page 19: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

X-linked recessiveX-linked recessive Most Common in malesMost Common in males ““Bleeder’s Disease”Bleeder’s Disease” Missing clotting factorMissing clotting factor Bleeding spontaneously Bleeding spontaneously

and in jointsand in joints Queen Victoria: Queen Victoria:

descendents affected descendents affected with hemophilia with hemophilia

Page 20: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

X-linked dominant disorders X-linked dominant disorders (rare)(rare)

The mutant gene is of a dominant nature, The mutant gene is of a dominant nature, i.e. only one abnormal gene of the allele i.e. only one abnormal gene of the allele pair is sufficient to cause disease; pair is sufficient to cause disease; therefore the disease affects both males therefore the disease affects both males and femalesand females

Example:Example:– Vitamin D resistant ricketsVitamin D resistant rickets

Page 21: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

CYTOGENETIC CYTOGENETIC (CHROMOSOMAL) DISORDERS(CHROMOSOMAL) DISORDERSThe normal human karyotype of somatic cells is The normal human karyotype of somatic cells is 46 chromosomes including 44 (22 pairs) of 46 chromosomes including 44 (22 pairs) of autosomes and two sex chromosomes either XY autosomes and two sex chromosomes either XY (male) or XX (female)(male) or XX (female)

The normal human karyotype (44 XY or 44XX) is The normal human karyotype (44 XY or 44XX) is symbolized as 2n- diploid.symbolized as 2n- diploid.

The normal gamete (sperm or ovum) karyotype The normal gamete (sperm or ovum) karyotype is symbolized as in 1n-haploid (22X or 22Y)is symbolized as in 1n-haploid (22X or 22Y)

Page 22: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

NORMAL KARYOTYPINGNORMAL KARYOTYPING

Page 23: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Chromosomal abnormalities include:Chromosomal abnormalities include:

Structural abnormalitiesStructural abnormalities

Numerical (number) abnormalitiesNumerical (number) abnormalities

Page 24: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Numerical (number) Numerical (number) abnormalities of chromosomesabnormalities of chromosomes

Page 25: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Numerical (number) abnormalities:Numerical (number) abnormalities:

Euploidy:Euploidy: – Euploidy refers to the normal number of chromosomes Euploidy refers to the normal number of chromosomes

within the cell; for example the euploid number of within the cell; for example the euploid number of chromosomes in a human cell is 46.chromosomes in a human cell is 46.

Aneuploidy: Aneuploidy: – Aneuploidy is defined as an abnormal number of Aneuploidy is defined as an abnormal number of

chromosomes. Syndromes caused by an extra or chromosomes. Syndromes caused by an extra or missing chromosome are among the most widely missing chromosome are among the most widely recognized genetic disorders in humans.recognized genetic disorders in humans.

Page 26: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Examples of syndromes with Examples of syndromes with chromosome number abnormalities:chromosome number abnormalities:

Abnormal number of sex chromosomes:Abnormal number of sex chromosomes:

Klinefelter's syndrome:Klinefelter's syndrome:– Male with karyotype 47XXY, characterized by atrophic Male with karyotype 47XXY, characterized by atrophic

testis, infertility and gynaecomastiatestis, infertility and gynaecomastia

Turner's syndrome:Turner's syndrome:– Female with karyotype 45X, characterized by atrophic Female with karyotype 45X, characterized by atrophic

ovaries, infantile external genitalia, underdeveloped ovaries, infantile external genitalia, underdeveloped breast, amaenorrhea, infertility, normal or subnormal breast, amaenorrhea, infertility, normal or subnormal mentality and may be congenital heart diseasesmentality and may be congenital heart diseases

Page 27: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Klinefelter SyndromeKlinefelter Syndrome1 in 1,100 births

47 chromosomesXXY only

#23 Trisomy Nondisjunction

Scarce beard

Longer fingers and arms

Sterile

Delicate skin

Low mental ability

Normal lifespan

Page 28: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

George Washington?George Washington? No Children – Sterile?No Children – Sterile? Dental ProblemsDental Problems Height – Very tall for Height – Very tall for

generationgeneration Still InconclusiveStill Inconclusive

Page 29: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Turners SyndromeTurners Syndrome1 in 5,000 births

45 chromosomes X only

96-98% do not survive to birthNo menstruationNo breast developmentNarrow hipsBroad shoulders and neck

Page 30: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Monosomy of Sex Monosomy of Sex Chromosomes; Chromosomes; XO femaleXO female

InfertileInfertile DwarfismDwarfism Some mental Some mental

retardationretardation Webbed NeckWebbed Neck

Page 31: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Abnormal number of autosomes:Abnormal number of autosomes:

Trisomy 21 ( Down syndrome):Trisomy 21 ( Down syndrome):– Karyotype: 47 XX or XY +21Karyotype: 47 XX or XY +21– Most common type of chromosomal Most common type of chromosomal

disordersdisorders– Incidence: 1:700 birthsIncidence: 1:700 births– Risk usually increases with maternal ageRisk usually increases with maternal age

Page 32: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Down SyndromeDown SyndromeShort, broad hands Stubby fingersRough skinImpotency in malesMentally retardedSmall round faceProtruding tongueShort lifespan

Page 33: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Trisomy 21Trisomy 21 Mild to severe mental Mild to severe mental

retardationretardation Distinct Facial FeaturesDistinct Facial Features Heart DefectsHeart Defects Fingerprints – SworlFingerprints – Sworl Most Common Birth Most Common Birth

Defect – 1/700 birthsDefect – 1/700 births Mother’s Age over 40 – Mother’s Age over 40 –

1/801/80 Problems during Problems during

OogenesisOogenesis

Page 34: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Downs Syndrome - Trisomy-21Downs Syndrome - Trisomy-21

Simian Crease

Page 35: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Edwards syndrome:Edwards syndrome:– Karyotype: 47 XX or XY +18Karyotype: 47 XX or XY +18– Risk also increase with maternal ageRisk also increase with maternal age

Page 36: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Trisomy 18Trisomy 18 Elfin AppearanceElfin Appearance Low set earsLow set ears Malformation of many Malformation of many

organs – specifically organs – specifically heart/lungsheart/lungs ““Blue Babies” due to Blue Babies” due to

lack of oxygenlack of oxygen

90% die within first 6 90% die within first 6 monthsmonths

Page 37: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Patau syndrome:Patau syndrome:– Karyotype; 47XX or XY +13Karyotype; 47XX or XY +13– Risk increase with maternal ageRisk increase with maternal age

Page 38: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

Trisomy 13Trisomy 13 Cleft Lip and Cleft Lip and

PalatePalate Polydactyl – more Polydactyl – more

than ten than ten fingers/toesfingers/toes

1/6000 births1/6000 births Most die within Most die within

first yearfirst year

Page 39: Human Genetic Disorders. Types of mutations Genetic disorders occur due to mutations. Mutations are defined as permanent damage of DNA. Mutations that

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