cytogentics i and ii

7/30/2019 Cytogentics I and II

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Cytogentics I and II

Cytogenetics

Chromosome Analysis Abnormal chromosomal number or structure

Normal Chromosomes

Metacentric Submetacentric Acrocentric

o P arm: stalk and satelliteo 5 acrocentric chromosomes: 13, 14, 15, 21, 22

Chromosome banding

Chromosomes arms are divided into regions Each region has several bands which may contain sub-bands

o These stain dark or light. G: dark, R: reverse Regions and bands are numbered from the centromere outward

Aneuploidy

An increase or decrease in the number of chromosomeso Some chromosomes: mosaicism

Mechanisms of Aneuploidy

Non-Disjunction

Meiosis I --- 2 Nullsomic gametes, 2 Disomic gametes (most common) Meiosis II --- 1 Nullsomic gamete, 1 DIsomic gamete, 2 Normal gametes

Mechanisms of Mosaicism

Anaphase Lag Post-zygotic (mitotic) non

disjuntion


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Autosomal Aneuploidies

DOWN SYNDROME Trisomy 21

Most common form of aneuploidy is:

Down Syndrome: Trisomy 21

47,XX,+21 or 47,XY,+21

Mosaics: 46,XX/47,XX,+21 or 46,XY/47,XY,+21

Critical Region: 21q22 Factors:

Increasing maternal age Disomic or nullisomic gametes Normal gametes can produce trisomic or monosomic zygotes

Symptoms

Head: Low nasal root Upslanting palpebral fissures

o Palpebral fissure is the anatomic name for the separation between theupper and lower eyelids

Small overfolded ears Flattened malar region Short neck Flat occiput

Other: Broad, short hands and feet Simian crease Sandal gap Hypotonia Respiratory infections Atresia (Atresia is a condition in which a body orifice or passage in the body is

abnormally closed or absent):

o Duodenalo Oesophagaelo Anal

Moderate to severe mental retardation Congenital heart defects Leukemia Sterility in males

Mechanisms:

o Non-Disjunction (80%) Failure to migrate to opposite poles in Anaphase I will cause disomic gametes

(Usually maternal)

o Robertsonian translocations on chromosome 21 Long arms of 2 acrocentric chromosomes are fused and the short arms are lost


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Occurs typically on chromosome 13,14,15,21,22 If it occurs on other chromosomes the fetus is not viable

5% of caseso Mosaicism:

Only some chromosomes are affected 1-3% of cases 46,XX/47,XX,+21 or 46,XY/47,XY,+21

EDWARDS SYNDROME

Trisomy 18

47,XX,+18 or 47, XY,+18

Mosaics: 46,XX/47,XX,+18 or 46,XY/47,XY,+18

Increases with increasing maternal age Second most common autosomal trisomy in live births

o 50% die in the first weeks of lifeo 5% are alive at age 1

Clinical Features

Intrauterineo Growth deficit

Postnatalo Mental deficiencyo Prominent occiputo Small malformed earso Small moutho Hypertonia (increased muscle tone)o Cleanched fists with overlapping fingerso Short sternumo Short first toeso Congenital heart defects

PATAU SYNDROME Trisomy 13

47,XX,+13 or 47,XY,+13

Mosaics: 46, XX/47,XX,+13 or 46,XY/47,46,XY,+13

Incidence

1 in 10,000 births Risk increases with increasing maternal age 95% ofconceptuses lost spontaneously during pregnancy 95% of live births die within first yr of life

Clinical Features

Cleft Palate/Lip Polydactyly in hands and feet Sloping forehead Abnormal ears Holoprosencephaly

o Cyclopia failure of the embryonic prosencephalon to divide the orbits into 2 cavitieso The forebrain (prosencephalon) fails to develop into 2 hemispheres


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Sex Chromosome Aneuplodies

TURNER SYNDROME Monosomy X

45, X

Incidence

1 in 2,000 to 1 in 3,000 Presence of only one X (or Xp - paternal X) chromosome Monosomy X (50%) Mosaic monosomy (30%) Structural abnormalities of X (20%)

Causes

Caused by non-disjunction in paternal meiosis producing a nullsomic gameteClinical Features

Short stature Triangle-shaped face Posteriorly rotated ears Broad, webbed neck Broad chest Intelligence is usually normal Bicuspid aortic valve Contraction of aorta Streak gonads Neonatal lymphoedema of hands and feet

TRISOMY X

47, XXX

1 in 1000 females Nondisjunction in maternal meiosis I Risk increases with increasing maternal age Variable phenotype Usually, no physical abnormalities May have mild mental deficiency Most have normal fertility

KLINEFELTER SYNDROME

47, XXY

Mechanism

Meiotic Disjunction (usually maternal, but some paternal -28%) Postzygotic errors

Clinical Features

Taller than average Disproportionately long arms and legs Small testis Gynecomastia Sparse body hair


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Decreased muscle mass Infertility (fertility may be present in pt with mosaicism)

47, XYY SYNDROME

Mechanism

Paternal disjunction (meiosis II)Clinical Features

Taller than average Usually no toher physical problems IQ lower than in siblings

Polyploidy

Increase in number of complete sets of chrmosomesEg. Each cell has 3 or more times the haploid chromosome

Triploidy

Mechanisms Phenotypes

Dispermy

- Normal ovum + two spermPartial Hyatidiform Mole

- large placenta + foetus with orwithout microcephaly

(circumference of the head is

more than two standard

deviations smaller than average

for the person's age and sex.)

Diandry

- Normal Ovum + Diploid sperm(failure of meiosis)

Digyny

- Diploid egg + Normal sperm(failure of meiosis or retention of

2nd polar body)

Foetus with severe intrauterine growth retardation and

relative macrocephaly + Small, non cystic placenta


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Non-Aneuploidic Disorders of Sex Chromosomes

COMPLETE SEX REVERSAL

1. 46, XY FemalesXY Pure Gonadal Dysgenesis (Swyer Syndrome)

MECHANISMS

1. De novo mutation in SRY (10-15%)2. Deletion of SRY (due to aberrant XY recombination in paternal meiosis)

3. Intact SRY. Mutation in another gene in the testis-determining pathwayCLINICAL FEATURES


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Dysgenetic (streak) gonad Lack of female sex hormones: amenorrhea & failed pubertal development Tumors may develop in the streak gonads

Complete Androgen Sensitivity (aka Testicular feminization syndrome)

MECHANISMS Mutation in androgen receptor gene (Xq11 Xq12) X-linked recessive inheritance

CLINICAL FEATURES

Functional Testis Present Genital tract resistant to testicular hormones Short vagina Rudimentary uterus & fallopian tubes Amenorrhea, absent pubic hair

1. 46, XX MalesMECHANISMS

SRY present on one X chromosome due to aberrant XY recombination (paternal meiosis)SRY+

SRY absent. Activating mutations of genes normally activated only by SRY. SRY-CLINICAL FEATURES (SRY positive)

More common than SRY negative Normal height Unimpaired intelligence Normal male external genitalia Testicular atrophy with azoospermia

CLINICAL FEATURES (SRY positive)

Variable phenotype

TRUE HERMAPHRODITISM

46,XX(SRYNegative, some may have cryptic gonadal mosaicism)

46, XX/46, XY (Post zygotic loss of X and Y in separate cells of an initially 47, XXY)

CLINICAL FEATURES

Rare Ambiguous external genitalia Both ovarian and testicular tissue present

One Ovary and one testis


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One ovary (or testis) and one ovotestis Two ovotestis

Abnormalities of Chromosome Structure

1. Deletions

Large Deletions Microdeletions

Visible by microscopy May cause clinical syndromes

Eg. Cru-du-chat syndrome

Not visible by microscopy Requires special techniques for detection May cause clinical syndromes

Eg. Prader Willi

Angelman Syndrome

Williams Syndrome

22q11 deletion syndrome

DiGeorge Anomaly

Velo-Cardio-Facial (VCF)

Isolated Conotruncal defects


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Cri-du-Chat Syndrome

46, XY, del (5p)

46, XX, del (5p)

CLINICAL FEATURES Mental Retardation Microcephaly (small head) Not likely to survive till adulthood

Prader-Willi Syndrome

15q11-13, paternal copy

CLINICAL FEATURES

Mental Retardation Short stature Obesity Narrow head Small hands and feet (males) small penis, undescended testes (females) hypoplastic labia minora and clitoris

Angelman Syndrome

15q11-13, maternal copy

CLINICAL FEATURES

Severe mental retardation Episodes of inappropriate laughter Absent speech Brachycephaly (flat head syndrome Large mouth Puppet gait

DiGeorge Anomaly

CLINICAL FEATURES

Absent Thymus Congenital Heart Disease Growth Retardation Mental retardation Hypothyroidism Hypocalcemia


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SeizuresVelo-Cardio-Facial Syndrome

CLINICAL FEATURES

Learning Disabilities Short stature

Cleft palate Prominent Nose Microcephaly Slender Limbs Cardiac Effects

2. Duplications Doubling of genetic material within a chromosome

MECHANISMS

Unequal crossover in meiosis Meiosis in individuals with reciprocal translocations or inversions

CLINICAL FEATURES

Beckwith-Wiedemann Syndrome

3. Inversions


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4. TranslocationsInterchange of genetic material between non-homologous chromosomes

Pericentric

Inversion

One break on each arm

Centrome involved

Arm ratio change

Paracentric

Inversion

Both breaks in same arm

Centromere not involved

No change in arm ratio

Inversion 3

No genetic material islost

Chromosomecomplement is balanced

Abnormal offspring

Inversion 1

Two chromosomalbreaks

Missing fragment re-inserted in the invertedorder


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Reciprocal Translocation 1

Breaks in two non-homologous chromosomes Material distal to the breaks exchanged

Reciprocal Translocation 2 No genetic material is lost Translocation is balanced Carrier is usually normal Abnormal offspring (meiosis problems)

Translocations

Reciprocal

Translocations

Type 1

Type 2

Robertsonian

Translocations

Type 1

Type 2

Derivative chromosomoes (der) named

based on centromere present


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Robertsonian Translocation 1

Acrocentric chromosomes: 13, 14, 15, 21, 22 Loss of short arms

Fusion of long arms

Robertsonian Translocation 2

Loss of short arms has no clinical significance Carriers phenotypically normal Abnormal offspring

5. IsochromosomesChromosome divides transversely resulting in

isochromosomes

Each has 2 copies of one arm and none of theother

Only one isochromosome has a functional centromere Other is lost from Karyotype

Most autosomal isochromosomes are incompatible with life

Individuals with isochromosome Xq have Turner syndrome due to monosomy of Xp


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6. Ring ChromosomesChromosomes break near ends and telomeres lost, sticky ends

formed join and become a ring

Result: Monosomies (Turner syndrome due to ring chromosome

X)

Molecular Cytogenetics

Fluorescence in situ hybridization (FISH)

Used to detect and localize the presence or absence of specific DNA sequences on chromosomes.
http://en.wikipedia.org/wiki/DNAhttp://en.wikipedia.org/wiki/DNA_sequencehttp://en.wikipedia.org/wiki/Chromosomehttp://en.wikipedia.org/wiki/Chromosomehttp://en.wikipedia.org/wiki/DNA_sequencehttp://en.wikipedia.org/wiki/DNA


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FISH usesfluorescent probes that bind to only those parts of the chromosome with which they show a

high degree of sequence complementarity.

Probes can be made for

Centromes

Telomeres

Specific Regions of interest

Entire chromosome (whole chromosome probes/whole chromosome paint)

Fluorescence microscopycan be used to find out where the fluorescent probe bound to the chromosomes.

Applications of FISH

FISH is often used for finding specific features in DNA for use in genetic counselling, medicine, and species

identification.

FISH can also be used to detect and localize specific mRNAs within tissue samples. In this context, it can

help define the spatial-temporal patterns ofgene expression within cells and tissues.
http://en.wikipedia.org/wiki/Hybridization_probehttp://en.wikipedia.org/wiki/Hybridization_probehttp://en.wikipedia.org/wiki/Fluorescence_microscopyhttp://en.wikipedia.org/wiki/Fluorescence_microscopyhttp://en.wikipedia.org/wiki/MRNAhttp://en.wikipedia.org/wiki/Gene_expressionhttp://en.wikipedia.org/wiki/Gene_expressionhttp://en.wikipedia.org/wiki/MRNAhttp://en.wikipedia.org/wiki/Fluorescence_microscopyhttp://en.wikipedia.org/wiki/Hybridization_probe

cytogentics i and ii

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