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Genetic DisordersGenetic Disorders
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INTRODUCTION:INTRODUCTION:DEFINITION OF TERMSDEFINITION OF TERMS
CHROMOSOMES- cellular structures where genes are located
GENES- basic units of heredity carry information necessary to determine specific biologic structures & functions ex. ABO Ag in RBC membrane coded by
chromosome 9
LOCUS- position in the chr where particular gene is located; all gene loci occur in pairs except X & Y genes
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INTRODUCTION:INTRODUCTION:DEFINITION OF TERMSDEFINITION OF TERMS
ALLELES- alternative genes in a single locus ex. Kell blood group system
alleles K & k
KK- homozygous Kk- heterozygous
HOMOZYGOUS GENES- gene pair that are alike
HETEROZYGOUS GENES- gene pair that are not alike
GENOTYPE- actual gene composition that make the trait
PHENOTYPE- manifestation of the structure/ form produced by the genes
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INTRODUCTION:INTRODUCTION:DEFINITION OF TERMSDEFINITION OF TERMS
DOMINANT GENES- genes that are always expressed in the phenotype whether homozygous or heterozygous
RECESSIVE (AMORPH) GENES- genes that are masked if paired w/ a dominant gene, thereby only expressed when paired w/ another recessive gene
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INTRODUCTION:INTRODUCTION:DEFINITION OF TERMSDEFINITION OF TERMS
EUPLOIDY- multiples of the haploid # that is considered normal HAPLOID (N)= 23- OCCURS IN MEIOSIS
DIPLOID (2N)= 46- OCCURS IN MITOSIS
ANEUPLOID- not exact multiples of the haploid #; only 1 pair of chr involved, therefore, germ cells have 2 copies of the same chr or lack the affected chr entirely HYPODIPLOID 2N- 1, -2, ETC. (MONOSOMY)
HYPERDIPLOID 2N+ 1, +2, ETC. (TRISOMY)
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INTRODUCTION:INTRODUCTION:DEFINITION OF TERMSDEFINITION OF TERMS
POLYPLOID- multiples of haploid #; entire set of chrs fail to divide & all the chrs are segregated in a single daughter cell TRIPLOID (3N)= 69
TETRAPLOID (4N)= 92
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Congenital Disorders
Non Genetic: Developmental defects – Malformations
Genetic Disorders Chromosomal
Gene - Mendelian
Multifactorial
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Mutations:
Genome: whole set – Polyploidy 4n, 8n etc.
Chromosomal: change in chromosome Number: Trisomy, monosomy
Structure: Deletion, Translocation etc.
Gene: Submicroscopic Point mutation – single base sequence
Deletions
Insertions
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Cytogenetic Abnormalities:
Abnormal # of chrs: Non-disjunction - Down’s Syndrome
Anaphase lag - Turner’s xxx
Abnormal Structure: (normal #) Deletion - 5q- Cri - du - chat syndrome
Inversion -
Translocation - Ph Chromosome - t(9:22) CML,
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GENETIC PATHOLOGY:
DEFINITION: Abnormalities or disease states that may or may not be congenital, transmitted by genes or chromosomal aberrations, that may be heritable (familial) or mutational
If mutational, may give the following outcomes: Heritable
Disappear
Lethal
Sterility
Malignancy
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CATEGORIES:
CHROMOSOMAL ABNORMALITIES/ MUTATIONS
GENE ABNORMALITIES/ MUTATIONS
POLYGENIC/ MULTIFACTORIAL ABNORMALITIES
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I. CHROMOSOMAL ABNORMALITIES/ MUTATIONS
GENERAL CONCEPTS:
Children born to older women show more chromosomal aberrations than children born to younger women
Most major chromosomal abnormalities are incompatible w/ life
Detectable by karyotyping (chromosomal analysis) w/ or w/o banding techniques (use of stains)
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I. CHROMOSOMAL ABNORMALITIES/ MUTATIONS::: TYPES:
NONDISJUNCTION (Chromosomal numerical aberration)- failure of chrs to sort themselves in equal #s into daughter cells
SUBTYPES: POLYPLOIDY- see previous definition
ANEUPLOIDY- see previous definition
MOSSAICISM/ MYXOPLOIDY
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Non-disjunction:
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I. ANEUPLOIDY: TRISOMY
TRISOMY- presence of 3 homologous chromosome in a cell
AUTOSOMAL TRISOMY- viable throughout pregnancy, even live born but die soon after birth except Down's syndrome TRISOMY 21- DOWN'S SYNDROME
TRISOMY 18- EDWARD'S SYNDROME
TRISOMY 13- PATAU'S SYNDROME
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I. ANEUPLOIDY: TRISOMY
SEX CHR. TRISOMY- abnormal development but non lethal; # of X chr. is directly proportional to mental retardation while number of Y chr. is directly proportional to aggressive behavior
TRIPLE X
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I. ANEUPLOIDY: MONOSOMY
MONOSOMY- absence of one of a pair of homologous chr AUTOSOMAL MONOSOMY- IUFD is the usual
outcome
SEX CHR. MONOSOMY- compatible w/ life only if the conserved chr is an X, if not it will be less viable
• TURNER'S SYNDROME- 45, XO
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Hydrops Fetalis – Monosomy X:
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I. ANEUPLOIDY: MOSSAICISM/ MYXOPLOIDY
MOSSAICISM/ MYXOPLOIDY- nondisjunction at a later cell division resulting to population of normal & trisomic or monosomic cells coexisting in an individual AUTOSOMAL MOSSAICISM- rare & lethal
SEX CHR. MOSSAICISM- common
• GONADAL DYSGENESIS- TURNER'S SYNDROME 45, XO
• KLINEFELTER'S SYNDROME 47 XXY
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I. CHROMOSOMAL ABNORMALITIES/ MUTATIONS::: TYPES: I. MORPHOLOGIC/
STRUCTURAL SUBTYPES:DELETION- loss of chromosomal material
following a break in the chr arm or partial monosomy CRI DU CHAT- partial monosomy of p5
RETINOBLASTOMA- q13
WILM'S TUMOR ANIRIDIA SYNDROME- p11
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I. MORPHOLOGIC/ STRUCTURAL SUBTYPES:
TRANSLOCATION- transfer of segment of chromosomal material to another chromosome leading to imbalance of material in each daughter cell between non homologous chr RECIPROCAL- acentric segments of chr exchanged for
similar segment from a heterologous chr; use banding techniques for detection
ROBERTSONIAN (CENTRIC FUSION)- 2 acrocentric chr broken near centromere, exchange 2 arms and form new large metacentric chr and a small fragment, devoid of centromere & lost during subsequent division
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I. MORPHOLOGIC/ STRUCTURAL SUBTYPES:
TRANSLOCATION BALANCED- transfer w/ no loss of genetic
material; individuals are normal except for infertility & if fertile, have a high risk of having malformed offspring
UNBALANCED- transmitted in the haploid gamete & paired w/ a new set of genes from the other parent
• MALIGNANT LYMPHOMA- between 8 & 14
• LEUKEMIAS- between 22 & 9
• DOWN'S SYNDROME- chr 21
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I. MORPHOLOGIC/ STRUCTURAL SUBTYPES:
TRANSLOCATION ISOCHROMOSOMAL- faulty division of
centromere at the transverse plane of the long axis w/ formation of a pair of isochromosome (one short arm & one long arm)
• TURNER'S SYNDROME
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I. MORPHOLOGIC/ STRUCTURAL SUBTYPES:
INVERSION- break of a chr at 2 points, followed by inversion of the intermediate segments & reunion results in the formation of a chr w/ rearranged distribution of genes PERICENTRIC- rotation occurs around the
centromere
PARACENTRIC- rotation occurs only on the acentric portion of the arm
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I. MORPHOLOGIC/ STRUCTURAL SUBTYPES:
RING CHROMOSOME- break in the telomeric ends of the chr followed by deletion of the broken acentric segments & end to end fusion of the remaining portion
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II. GENE ABNORMALITIES/ MUTATIONS GENERAL CONCEPTS:
Single gene defect detectable in the phenotype
Modified by penetrance, expressivity & whether defect is dominant, intermediate, recessive or X linked
Dominant pattern of inheritance usually due to alteration of aa sequence in the gene
Recessive pattern of inheritance (inborn errors of metabolism) usually is due to manufacture of abnormal enzymes or enzyme deficiencies
Follows Mendelian patterns of inheritance
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PATTERNS OF INHERITANCE: AUTOSOMAL DOMINANT
Autosome- gene location
Gene expression- both homozygous & heterozygous state
Transmission of traits in every generation unless Low penetrance or modified by gene mutations
Unaffected family members do not transmit trait to offspring; affected family members usually heterozygous & transmit trait to only half of the offspring
M = F
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PATTERNS OF INHERITANCE: AUTOSOMAL DOMINANT
Pp x pp
Pp : Pp : pp : pp DIABETIS INSIPIDUS
MUSCULAR DYSTROPHY
POLYDACTYLISM
MARFAN'S SYNDROME
ACHONDROPLASTIC DWARFISM
HUNTINGTON'S CHOREA
GARDNER'S SYNDROME
GOUT
HEMOCHROMATOSIS
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PATTERNS OF INHERITANCE: AUTOSOMAL RECESSIVE
Autosome- gene location
Gene expression only in the homozygous state
Both parents usually heterozygous for the trait & clinically unaffected
Symptoms appear in 25% of offspring
50% of all siblings will be heterozygous for the trait thus assymptomatic
M = F
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PATTERNS OF INHERITANCE: AUTOSOMAL RECESSIVE
Nn x Nn
NN : Nn : Nn : nn
ANDROGENITAL SYNDROME
ALBINISM
ALKAPTONURIA
DEAF MUTISM
GALACTOSEMIA
PHENYLKETONURIA
FAMILIAL GOITROUS CRETINISM
CYSTIC FIBROSIS
GLYCOGEN STORAGE DISEASES
MUCOPOLYSACCHARIDOSIS
LIPID STORAGE DISEASE
WILSON'S DISEASE
TYROSINOSIS
BILIRUBIN METABOLIC ABNORMALITIES
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PATTERNS OF INHERITANCE: X LINKED RECESSIVE
X chromosome - Gene location
Expression of traits
100% heterozygous male
Rare homozygous female
Partial heterozygous female if X Chromosome inactivation occurs
Transmission via asymptomatic female
Each son of heterozygous female carrier has 1 in 2 chances of having the disease
Affected males do not transmit trait to their sons, only to their daughters; Unaffected males do not transmit the gene
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PATTERNS OF INHERITANCE: X LINKED RECESSIVE
FEMALE X MALE (HEMOPHILIAC)
XX x Xh Y
XXh : XY : XXh : XY
FEMALE (CARRIER) x MALE (NORMAL)
Xh X x XY
Xh X : Xh Y : XX : XY
HEMOPHILIC
COLOR BLINDNESS
G6 PD DEFICIENCY
MUSCULAR DYSTROPHY- DUCHENNE TYPE
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PATTERNS OF INHERITANCE: X LINKED DOMINANT
Rare
Affected heterozygous female transmit to 50% sons & 50% daughters
Affected males transmit to 100% daughters & none to their sons VIT. D RESISTANT RICKETS
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PATTERNS OF INHERITANCE: Y LINKED
Not clinically significant Hairy ears
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III. POLYGENIC/ MULTIFACTORIAL ABNORMALITIES
GENERAL CONCEPTS:
Environmentally influenced interactions of a number of different gene pairs HYPERTENSION
DIABETIS MELLITUS
PEPTIC ULCER
OTHER CONGENITAL HEART DISEASES
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CHROMOSOMAL DISEASES:SEX CHROMOSOMAL ABNORMALITIES
X DEFICIENCY TURNER'S SYNDROME 45, XO
• Short stature female w/ webbed neck, cubitus valgus, immature genitalia w/ small fibrotic (streak) ovaries, coarctation of aorta; mostly abort; no Barr Bodies; almost 50% are mossaics w/ less stigmata
ULLRICH NOONAN SYNDROME (46, XX or XY ::: 46, X(Xq)
• Turner like phenotype; often w/ pulmonary stenosis; giant Barr Bodies
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CHROMOSOMAL DISEASES:SEX CHROMOSOMAL ABNORMALITIES
KLINEFELTER'S SYNDROME 47, XXY Most common of X chromosomal abnormality
Tall eunuchoid male w/ gynecomastia, small testis w/o spermatogenesis (infertile)
Mossaics occur
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CHROMOSOMAL DISEASES:SEX CHROMOSOMAL ABNORMALITIES
MISCELLANEOUS SYNDROMES TRIPLE X (47 XXX)- mildly retarded; normal
female phenotype
47 XYY- tall, aggressive, mildly retarded male; increased incidence among criminal
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CHROMOSOMAL DISEASES:SEX CHROMOSOMAL ABNORMALITIES
INTERSEX STATES- HERMAPHRODITISM TRUE HERMAPHRODITE- XX or XY or both;
variable phenotype, both ovaries & testis are present
PSEUDOHERMAPHRODITES (NORMAL GENECITY)
• Male phenotypically female; testicular feminization
• Female phenotypically male; virilizing ovarian or adrenal tumors
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CHROMOSOMAL DISEASES: AUTOSOMAL ABNORMALITIES
More severe effects than X chr anomalies
Monosomies more severe than trisomies
The larger chromosome involved, the more serious the phenotypic disorder
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CHROMOSOMAL DISEASES: AUTOSOMAL ABNORMALITIES
DOWN'S SYNDROME- TRISOMY 21, MONGOLISM; 47 G21+
Most common of the trisomies; maternal risks increases w/ age; incidence equal in both sexes; usually due to maternal nondisjunction
Floppy infants w/ psychomotor retardation, mongoloid facies, epicanthic folds, flat nose, cardiovascular anomalies, simian palm creases, cryptorchidism, increased incidence of leukemia
Variant - Translocation type (heritable)- occurs at any maternal age; 46 XY -D; +tDqGq
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Downs Karyotype: Trisomy-21
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Downs Sy.
Trisomy-21
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Downs Syndrome - Trisomy-21
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Downs Syndrome - Trisomy-21
Simian Crease
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Downs Syndrome:
Mental retardation
Neck folds
Epicanthic folds
Flat facial profile
Simian crease
Hypotonia
Umbilical hernia
Leukemia
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CHROMOSOMAL DISEASES: AUTOSOMAL ABNORMALITIES
EDWARD'S SYNDROME (16 - 18 TRISOMY, E TRISOMY); 47, E18+ Female predilection; low set ears, epicanthic folds,
micrognathia, CVS anomalies, overlapping 2nd & 5th finger, rocker bottom feet, renal anomalies, early death
PATAU'S SYNDROME (13 - 15 TRISOMY, D TRISOMY); 47, D13+ Least common, both sexes equally affected; low set ears,
micropthalmia, brain anomalies, cleft lip & palate, overlapping 2nd & 5th finger, CVS anomalies, rocker bottom feet
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Cleft Lip - Trisomy 13:
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Polydactyly - Trisomy 13:
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CHROMOSOMAL DISEASES: AUTOSOMAL ABNORMALITIES
CRI DU CHAT SYNDROME, 5p- Rare, common in females, cat cry, moon faced,
retarded, micrognathia, antimongoloid slant, CVS anomalies
D13p-, D13q-, E18q-, TRIPLOIDY Severe anomalies, lethal
PHILADELPHIA CHROMOSOME, G22q- Associated w/ CML; good prognosis
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Syndactyly - Triploidy
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Philadelphia Chromosome (Ph)
Reciprocal translocation t(9;22)
Results in bcr/abl gene fusion c-abl (Abelson) chr 9
bcr (break point cluster region) chr 22
Protein w/ tyrosine kinase activity - plays critical role in pathogenesis
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CML - t(9;22) - (Ph chr)
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DISEASES DUE TO GENE ABNORMALITIES AND MUTATIONS:
AUTOSOMAL DOMINANT ABNORMALITIES ACHONDROPLASIA
Defective endocndral ossification
Most common type of dwarfism
High incidence of early death
80% sterility
HUNTINGTON'S CHOREA Progressive neurologic disorder w/ choreic movements,
seizures, dementia, death
Average onset is 35 years of age so offspring is born before parent is affected
Reproduction not impaired
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DISEASES DUE TO GENE ABNORMALITIES AND MUTATIONS:
AUTOSOMAL DOMINANT ABNORMALITIES: MARFAN SYNDROME
Complex defective formation of collagen & elastin
Tall, long extremities (arachnodactyly), subluxation of lens, cystic medial necrosis of aorta w/ dissecting aneurysm
Mechanism is single gene w/ multiple effects (pleiotropy), variable expression, forme fruste expression, may skip generations
GARDNER SYNDROME Complex cyst of the skin, osteomas, lower intestinal polyps
with development of colonic ca
Pleiotropy
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Cell Cycle
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Mitosis
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Meiosis
Reduction Division (4n-2n) Prophase-1(Synapsis, g.rec)
Metaphase-1
Anaphase-1
Telophase-1
Equatorial Division (2n-n) Prophase-2
Metaphase-2
Anaphase-2
Telophase-2