1 ChromosomesII Dr Pupak Derakhshandeh, PhD Ass Prof Medical Science of Tehran University Email: [email protected]@tums.ac.ir Website:

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ChromosomChromosomesesIIIIDr Pupak Derakhshandeh, PhD

Ass Prof Medical Science of Tehran University

Email: [email protected]: http://medicine.tums.ac.ir/en/Professor_cv.aspx?lt=8&uid=5984

(English)http://medicine.tums.ac.ir/fa/Professor_cv.aspx?lt=8&uid=889 (Persian)

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Trisomy 18, 47 Ch.Trisomy 18, 47 Ch.

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Trisomy 18, 47 Ch.Trisomy 18, 47 Ch. incidence of about 1 in 3,000 incidence of about 1 in 3,000 There is a 3:1 preponderance of females There is a 3:1 preponderance of females

to malesto males Thirty percent of affected newborns die Thirty percent of affected newborns die

within the first monthwithin the first month 50% by two months50% by two months and 90% by one year.and 90% by one year. severe mental retardationsevere mental retardation microcephalymicrocephaly overlapping fingers, and rocker bottom overlapping fingers, and rocker bottom

feetfeet Neurologically they are hypertonic Neurologically they are hypertonic Other common malformations include Other common malformations include

congenital heart, kidney, .... congenital heart, kidney, .... abnormalities.abnormalities.

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Trisomy 18, 47 Ch.Trisomy 18, 47 Ch.

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Trisomy 13Trisomy 13 (XX/XY, 47 Ch)(XX/XY, 47 Ch) has an incidence of 1 in 5,000has an incidence of 1 in 5,000 Forty-four percent of affected newborns Forty-four percent of affected newborns

succumb in the first month of life succumb in the first month of life and 69% by six monthsand 69% by six months Only 18% of the babies born with trisomy Only 18% of the babies born with trisomy

13 survive the first year13 survive the first year microcephalymicrocephaly microophthalmia (small eyes)microophthalmia (small eyes) cleft lip or cleft palatecleft lip or cleft palate polydactyly (extra fingers)polydactyly (extra fingers) congenital heart defectscongenital heart defects urogenital defectsurogenital defects brain malformationsbrain malformations severe mental retardation.severe mental retardation.

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Turner SyndromeTurner Syndrome ( ( 45 45, , X)X)

4545, X, X

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Turner Turner SyndromeSyndrome ( (4545, , X)X)

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Turner syndromeTurner syndrome• OOnly femalesnly females• OOne X chromosome ne X chromosome • OOr has two X chromosomes but r has two X chromosomes but one is one is damageddamaged• SShort staturehort stature• DDelayed growth of the skeletonelayed growth of the skeleton• SSometimes heart abnormalitiesometimes heart abnormalities• UUsually infertile due to ovarian sually infertile due to ovarian failurefailure• Diagnosis is by blood test Diagnosis is by blood test (karyotype)(karyotype)• 1 out of every 2,500 female live 1 out of every 2,500 female live births births worldwideworldwide• SShort neck with a webbed hort neck with a webbed appearanceappearance

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KleinefelterKleinefelter/47/47XXYXXY

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Klinefelter syndrome Klinefelter syndrome (47, XXY) (47, XXY) IIn boys and men n boys and men 47 chromosomes with XXY sex 47 chromosomes with XXY sex

chromosomeschromosomes XXY is one of the most common XXY is one of the most common

chromosomal abnormalitieschromosomal abnormalities 1 in 500 male births1 in 500 male births the most common genetic cause of the most common genetic cause of

male infertilitymale infertility OOften ften : : undiagnosed undiagnosed :: variation in variation in

clinical presentation clinical presentation SSmall testes , insufficient production mall testes , insufficient production

of testosterone , and infertility of testosterone , and infertility

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Klinefelter syndrome Klinefelter syndrome (47, XXY) (47, XXY)

BBreast enlargement, lack of facial reast enlargement, lack of facial and body hair, a rounded body type and body hair, a rounded body type , to be overweight , and be taller , to be overweight , and be taller than their fathers and brothersthan their fathers and brothers

LLearning and/or behavioral earning and/or behavioral problemsproblems

Testosterone replacement corrects Testosterone replacement corrects the symptoms of androgen the symptoms of androgen deficiency deficiency

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KleinefelterKleinefelterXXYXXY

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Fragile X SyndromeFragile X Syndrome 1 in 3,600 males and 1 in 4,000 to 1 in 3,600 males and 1 in 4,000 to

6,000 females with the full mutation 6,000 females with the full mutation worldwideworldwide

It is estimated that 1 in 250 females It is estimated that 1 in 250 females and 1 in 700 males are carriers of and 1 in 700 males are carriers of the premutation. the premutation.

It is second only to Down Syndrome It is second only to Down Syndrome as a cause of mental retardation as a cause of mental retardation

Fragile X syndrome appears in Fragile X syndrome appears in children of all ethnic, racial and children of all ethnic, racial and socio-economic backgrounds socio-economic backgrounds

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Fragile X SyndromeFragile X Syndrome most common most common inheritedinherited form of familial mental form of familial mental

retardationretardation (CGG)n trinucleotide expansion in the FMR1 (CGG)n trinucleotide expansion in the FMR1

gene leading to the typical Martin-Bell gene leading to the typical Martin-Bell phenotypephenotype

Clinical features vary depending on age and Clinical features vary depending on age and seseXX

Expansion of a (CCG)n repeat in the FMR2 gene Expansion of a (CCG)n repeat in the FMR2 gene corresponds to the FRAXE fragile site which corresponds to the FRAXE fragile site which lies distal to FRAXA and is also associated with lies distal to FRAXA and is also associated with mental retardation, but it is less frequent and mental retardation, but it is less frequent and lacks a consistent phenotype lacks a consistent phenotype

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Fragile X Fragile X SyndromeSyndrome

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Fragile X Fragile X SyndromeSyndrome

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Chromosome Chromosome abnormalitiesabnormalities

AAbnormality of bnormality of chromosome number or chromosome number or structure:structure:

Numerical AbnormalitiesNumerical Abnormalities Structural AbnormalitiesStructural Abnormalities

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Structural AbnormalitiesStructural Abnormalities

DeletionsDeletions: : A portion of the A portion of the chromosome is missing or chromosome is missing or deleted (>5 Mb)deleted (>5 Mb)..

Paraderwilli Syndrome (Ch 15)Paraderwilli Syndrome (Ch 15) Angleman Syndrome (Ch 15)Angleman Syndrome (Ch 15)

Imprinting effectImprinting effect

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DELETIONSDELETIONS

Deletion refers to the loss of a Deletion refers to the loss of a segment of a chromosomesegment of a chromosome

This can be terminal (close to This can be terminal (close to the end of the chromosome on the end of the chromosome on the long arm or the short arm)the long arm or the short arm)

or it can be interstitial (withinor it can be interstitial (within))eg.DGS IIeg.DGS II

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DELETIONSDELETIONS

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Structural AbnormalitiesStructural Abnormalities

• DuplicationsDuplications: A portion of the : A portion of the chromosome is duplicated, chromosome is duplicated, resulting in extra genetic resulting in extra genetic material.material.

• Oncogenes (c-onc, c-fos, c-myc)Oncogenes (c-onc, c-fos, c-myc)

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DUPLICATIONSDUPLICATIONS refers to an extra chromosomal refers to an extra chromosomal

segment within the same homologous segment within the same homologous chromosome or an extra chromosomal chromosome or an extra chromosomal segment on another nonhomologous segment on another nonhomologous chromosome.chromosome.

Again, the clinical findings are highly Again, the clinical findings are highly variable depending upon the variable depending upon the chromosomal segments involved. chromosomal segments involved. Gene expantion:Gene expantion:

in Huntington Disease/ Fragile X, ….in Huntington Disease/ Fragile X, ….

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Structural AbnormalitiesStructural Abnormalities

TranslocationsTranslocations: : When a portion When a portion of one chromosome is of one chromosome is transferred to another transferred to another chromosomechromosome. .

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There are two main types of There are two main types of translocations. translocations. In a In a reciprocal translocationreciprocal translocation, ,

segments from two different segments from two different chromosomes have been chromosomes have been exchanged. In a exchanged. In a Robertsonian translocationRobertsonian translocation, an , an entire chromosome has attached entire chromosome has attached to another at the centromere.to another at the centromere.

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RReciprocaleciprocal TRANSLOCATIONSTRANSLOCATIONS

Translocation involves two Translocation involves two nonhomologous chromosomes nonhomologous chromosomes ((ee..gg.., chromosome 2 and , chromosome 2 and chromosome 6chromosome 6))

Following a break in each of Following a break in each of the chromosomes, and the chromosomes, and subsequent reunionsubsequent reunion

a segment of chromosome 2 a segment of chromosome 2 becomes attached to becomes attached to chromosome 6chromosome 6

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TRANSLOCATIONSTRANSLOCATIONS

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Balanced reciprocal translocation Balanced reciprocal translocation

Balanced reciprocal Balanced reciprocal translocationtranslocation

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Structural AbnormalitiesStructural Abnormalities

InversionsInversions: : A portion of the A portion of the chromosome has broken chromosome has broken off, turned upside down off, turned upside down and reattached, therefore and reattached, therefore the genetic material is the genetic material is invertedinverted..eg Ch9 inv in Iraneg Ch9 inv in Iran

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involve only one chromosomeinvolve only one chromosome the intervening segment is rejoined in an the intervening segment is rejoined in an

inverted or opposite manner.inverted or opposite manner. Since there is no loss nor gain of Since there is no loss nor gain of

chromosomal material, inversion carriers chromosomal material, inversion carriers are normalare normal

ParacentricParacentric: : does not include the does not include the centromerecentromere

pericentric:inverted segment contains the pericentric:inverted segment contains the centromerecentromere

In meiosis, the normal chromosome and In meiosis, the normal chromosome and the inverted chromosome will form a loop the inverted chromosome will form a loop to allow pairing of specific DNA sequencesto allow pairing of specific DNA sequences

that occur within the inversion loop result that occur within the inversion loop result in gametes with both deletions and in gametes with both deletions and duplications duplications

inversion carriers have a relatively low risk inversion carriers have a relatively low risk of having abnormal offspring.of having abnormal offspring.

Inversions

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Inversions

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Meiosis in an individual heterozygous for a pericentric Meiosis in an individual heterozygous for a pericentric inversioninversion

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RingsRings: : A portion of a chromosome A portion of a chromosome has broken off and formed a has broken off and formed a circle or ringcircle or ring. . This can happen This can happen with or without loss of genetic with or without loss of genetic materialmaterial. .

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Ring

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OncologyOncology Chronic Myelogenous Leukemia

(CML) a clonal expansion of transformed

hematopoietic progenitor cells: Myeloid Monocytic Erythroid Megakaryocytic lymphoid lineages

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Molecular level

CML: characterized by the bcr-abl fusion gene

reciprocal translocation t(9;22)(q34;q11)

creating the Philadelphia (Ph) chromosome

survival time of patients : to 5 to 7 years

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HematologyHematology Bone Bone marrowmarrow

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Chronic myelogenous Chronic myelogenous leukemia leukemia ((CMLCML))

15% to 20% of leukemias in adults incidence of 1 to 2 cases per 100,000 population

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Chronic myelogenous Chronic myelogenous leukemialeukemia occurs more frequently in males than in

females (ratio of 1.3 to 1) Incidence: increases with age the median age at presentation is

between 45 and 55 years

which is an important consideration for the selection of therapeutic strategies stem-cell transplantation treatment with interferon-alfa (Intron A,

Roferon-A)

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The Philadelphia The Philadelphia ChromosomeChromosome

a reciprocal translocation between the long arms of chromosome 9 and chromosome 22

the large segment of the c-abl gene from chromosome 9q34

to the part of the bcr gene on chromosome 22q11 in a head-to-tail fashion

creating a hybrid bcr-abl gene that is transcribed into a chimeric bcr-abl mRNA

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Detection of Detection of bcrbcr--ablabl Cytogenetic analysis Ph chromosome in 90% of patients

with CML Such analysis is tedious and time-

consuming allows the examination of only 20

to 25 metaphases per bone marrow sample

misses the 5% of patients who are Ph-negative but bcr-abl-positive

Despite these shortcomings, cytogenetic analysis is the gold standard in the diagnosis of CML.

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FISHFISH

Fluorescence in situ hybridization allows for the analysis of

metaphase

Results of FISH studies are easily quantifiable

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fluorescence in situ hybridization fluorescence in situ hybridization ((FISHFISH))

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fluorescence in situ fluorescence in situ hybridization hybridization ((FISHFISH) )

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FISHFISH

Abl-Bcr

Abl

Bcr

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Abl-Bcr