Transcript
By:By:Majid MojarradMajid Mojarrad
Why do we study humanWhy do we study humanchromosomes?chromosomes?
Chromosome disorders Chromosome disorders -- major category of major category of genetic diseasegenetic disease Responsible for >Responsible for >100100 identifiable syndromesidentifiable syndromes
More common than all mendelian single gene More common than all mendelian single gene disorders!disorders!
11% % livebirthslivebirths
22% % pregnanciespregnancies
HistoryHistory 18901890--19201920: : techniques of plant and insect cell staining techniques of plant and insect cell staining
applied to human cellsapplied to human cells 19231923: : XX/XY was postulated to be the sexXX/XY was postulated to be the sex--determining determining
mechanismmechanism 19561956: : 4646 chromosomes in human cellschromosomes in human cells
First karyotypeFirst karyotype 19591959: : Lejeune:Lejeune: Down Syndrome (extra small chr.), Down Syndrome (extra small chr.),
Turner Syndrome, Kleinfelter Syndrome other trisomies Turner Syndrome, Kleinfelter Syndrome other trisomies visualizedvisualized
19601960: : phytohemoglutanin (PHA)phytohemoglutanin (PHA)——stimulates blood cells stimulates blood cells to divideto divide When they divide, they condense to we can see them When they divide, they condense to we can see them
betterbetter
HistoryHistory
19701970: : chromosome bandingchromosome banding
19771977: : high resolution bandinghigh resolution banding
19861986: : fluorescence in situ hybridization fluorescence in situ hybridization (FISH)(FISH)
Clinical Indications forClinical Indications forChromosome AnalysisChromosome Analysis
Problems of early growth and developmentProblems of early growth and development
Stillbirth/neonatal deathStillbirth/neonatal death
Fertility problemsFertility problems
Family history of chromosome Family history of chromosome rearrangementrearrangement
Pregnancy indications Pregnancy indications –– LMA, U/S abn etcLMA, U/S abn etc
NeoplasiaNeoplasia
CytogeneticsCytogenetics
About About 400400 metaphase bands (haploid)metaphase bands (haploid) About About 66 million bp per bandmillion bp per band About About 8080--100100 genes per bandgenes per band Can see only gross changes (about Can see only gross changes (about 1010 genes or genes or
more), not a single gene deletionmore), not a single gene deletion GG--banding: dark bands are AT rich, light bands banding: dark bands are AT rich, light bands
are GC richare GC rich Centromeres are AT rich (stain darkly)Centromeres are AT rich (stain darkly) Light regions are generally more rich with coding Light regions are generally more rich with coding
sequences (promoters are GC rich)sequences (promoters are GC rich)
Chromosome nomenclatureChromosome nomenclature
Two armsTwo arms p (petite)p (petite) and q (follows p in alphabet)and q (follows p in alphabet)
11--2222 = = autosome numbersautosome numbers
X, Y = sex chromosomesX, Y = sex chromosomes
Karyotype Karyotype -- the chromosome constitution of an the chromosome constitution of an individualindividual
When chromosomes are preparing to divide the DNA When chromosomes are preparing to divide the DNA replicates itself into two strands called chromatidsreplicates itself into two strands called chromatids
Replicating chromosome The same chromosome under normal conditions
Centromere
Telomere
Telomere
The two chromatids
4646,,XX = femaleXX = female 4646,,XY = maleXY = male
Giemsa banding (G-banding)
Three classes of chromosomeThree classes of chromosome
Metacentric Metacentric -- centromere centromere in middlein middle
Submetacentric Submetacentric --centromere distant from centromere distant from middlemiddle
Acrocentric Acrocentric -- centromere centromere at endat end
Structural abnormalities ofStructural abnormalities ofchromosomeschromosomes
Six main typesSix main types
DeletionDeletion Ring chromosomeRing chromosome DuplicationDuplication IsochromosomeIsochromosome InversionInversion
paracentric ¶centric & pericentricpericentric
TranslocationTranslocation Robertsonian &Robertsonian & reciprocalreciprocal
Involves loss of part of a Involves loss of part of a chromosomechromosome
Results in Results in monosomymonosomy of that of that chromosomal segmentchromosomal segment
Clinical effects due toClinical effects due to Insufficient gene productsInsufficient gene products
Unmasking of mutant alleles Unmasking of mutant alleles on normal chromosomeon normal chromosome
DeletionDeletion
Beforedeletion
Afterdeletion
Two types of deletionTwo types of deletion
InterstitialTerminal
WolfWolf--Hirschhorn syndromeHirschhorn syndrome
• deletion of distal arm of chromosome 4p
• growth and mental retardation
• seizures
Ring chromosomeRing chromosomeBreaks occur in both arms of a chromosome. Breaks occur in both arms of a chromosome.
The two broken ends anneal; the two acentric fragments are The two broken ends anneal; the two acentric fragments are lost. lost.
Results in double deletion (in p and in q).Results in double deletion (in p and in q).
Epilepsy, mental retardation and craniofacial abnormalities
DuplicationDuplication
Direct Inverted
Trisomy of duplicated segment
IsochromosomeIsochromosomeMirror image chromosome
Loss of one arm with duplication of other
Loss of p-arm Duplication of q-arm
InversionInversionTwo breaks in one chromosomeTwo breaks in one chromosome
The fragment generated rotates The fragment generated rotates 180180oo and reinserts into and reinserts into the chromosomethe chromosome
Pericentric Pericentric -- involves p and q arminvolves p and q arm Paracentric Paracentric -- involves only one arminvolves only one arm
Chromosome structure
balanced rearrangements
inversions – 2 breaks, piece reattached in inverted order
paracentric – centromere not included
crossing over
Chromosome structure
balanced rearrangements
inversions – 2 breaks, piece reattached in inverted order
pericentric – centromere included
crossing over
TranslocationTranslocation -- exchange of exchange of chromosomal material between two or chromosomal material between two or
more chromosomesmore chromosomes ReciprocalReciprocal
RobertsonianRobertsonian
If no essential chromosome material lost or If no essential chromosome material lost or genes damaged then the individual is clinically genes damaged then the individual is clinically normalnormal
However, there is an increased chance of However, there is an increased chance of chromosomally unbalanced offspring chromosomally unbalanced offspring
Reciprocal TranslocationReciprocal Translocation
Involves two Involves two chromosomes chromosomes
One break in each One break in each chromosomechromosome
The two chromosomes The two chromosomes exchangeexchange broken segmentsbroken segments
Meiotic segregation in a reciprocal translocation
Chr. 3 Chr. 21
Reciprocal translocation
SEGREGATION
normal balanced
Alternate Adjacent 1 Adjacent 2
Pairing at meiosis
2
1
--unbalanced-- --unbalanced--
GAMETES
OFFSPRING normal balancedtranslocation
trisomy 3qmonosomy 21q
monosomy 3qtrisomy 21q
trisomy 3monosomy 21
monosomy 3trisomy 21
Robertsonian translocationRobertsonian translocation Named after W. R. B. Robertson who first identified Named after W. R. B. Robertson who first identified
them in grasshoppers in them in grasshoppers in 19161916 Most common structural chromosome abnormality in Most common structural chromosome abnormality in
humanshumans Frequency =Frequency = 11//10001000 livebirthslivebirths
Involves two acrocentric chromosomesInvolves two acrocentric chromosomes Two typesTwo types
Homologous acrocentrics involvedHomologous acrocentrics involved NonNon--Homologous acrocentrics involvedHomologous acrocentrics involved
Homologous acrocentric, i.e. chromosome 14
+ =
lost
Non-homologous acrocentric, i.e. chromosomes 14 & 21
+ =
lost
14 21
Robertsonian translocation
SEGREGATION
Meiotic segregation in a Robertsonian translocation
Alternate Adjacent
GAMETES
OFFSPRING
Pairing at meiosis
AB
A
C
B C
normal balanced ----------------unbalanced ----------------
----------A---------- ----------B---------- ----------C----------normal balanced
translocationunbalanced translocation
Down syndrome
monosomy 21 trisomy 14 monosomy 14
A balanced chromosome A balanced chromosome 1414 & & 2121Robertsonian translocationRobertsonian translocation
An unbalanced chromosome An unbalanced chromosome 1414 & & 2121Robertsonian translocation Robertsonian translocation --trisomy trisomy 2121,, Down syndromeDown syndrome
Numerical nomenclature & abnormalitiesNumerical nomenclature & abnormalities
Haploid Haploid -- the number of chromosomes in a gamete, N the number of chromosomes in a gamete, N (i.e. (i.e. 2323 chromosomes)chromosomes)
Diploid Diploid -- the number of chromosomes in a somatic the number of chromosomes in a somatic cell, cell, 22N (i.e. N (i.e. 4646 chromosomes)chromosomes)
Euploid Euploid -- any exact multiple of Nany exact multiple of N i.e. triploidy (i.e. triploidy (33N, N, 6969 chromosomes) chromosomes) -- spontaneous spontaneous
abortionsabortions
Aneuploid Aneuploid -- extra copy or absence of a chromosomeextra copy or absence of a chromosome i.e. trisomy i.e. trisomy 2121, Down syndrome, Down syndrome
Aneuploidy results from the failureAneuploidy results from the failureof chromosomes to separateof chromosomes to separatenormally during cell divisionnormally during cell division
NondisjunctionNondisjunction
NORMAL SEPARATION
NORMAL ZYGOTE
First meiotic division
Second meiotic division
Gametes
Fertilization
Zygotes
4N
2N
N
2N
NONDISJUNCTION
TRISOMIC ZYGOTE MONOSOMIC ZYGOTE
First meiotic division
Second meiotic division
Gametes
Fertilization
Zygotes
Distribution of nonDistribution of non--disjunctiondisjunction
Meiosis I Meiosis II
Mitosis
Maternal 21, 15, 16 18 15, 18, 21, 8
Paternal - 18, 21 18, 21
Parental origin ofParental origin ofaneuploidyaneuploidy
Paternal %Paternal % Maternal %Maternal %
Trisomy Trisomy 1313 1515 8585
Trisomy Trisomy 1818 1010 9090
Trisomy Trisomy 2121 55 9595
4545,,XX 8080 2020
4747,,XXXXXX 55 9595
4747,,XXYXXY 4545 5555
4747,,XYYXYY 100100 00
Clinically Important Autosomal Clinically Important Autosomal Chromosomal AbnormalitiesChromosomal Abnormalities
TrisomyTrisomy: : 2121,, 1818, , 1313, , 88, , 2222, , 99, mosaicism for trisomic and , mosaicism for trisomic and normal cellsnormal cells
Partial Trisomy (duplication)Partial Trisomy (duplication): : 11q,q, 1313q, q, 99p, p, 44p, p, 1010q, q, 1111q, q, 77q, q, 1414q, q, 11q, q, 33p, p, 44q, q, 88q, q, 1010p, p, 1111p, p, 1515q, q, 2020pp
MonosomyMonosomy: : 2121,,2222 Partial Monosomy (deletion of part)Partial Monosomy (deletion of part): : 55p,p, 1313q, q, 44p, p, 1818p, p,
1818q, q, 1111q, q, 77p, p, 99p, p, 1212pp DuplicationDuplication--deficiencydeficiency: : 33,,44,,22 TriploidyTriploidy Chromosome breakageChromosome breakage: : Fanconi anemia, Fanconi anemia,
Bloom syndrome, ataxia telangiectasia, Bloom syndrome, ataxia telangiectasia, glutathione reductase deficiencyglutathione reductase deficiency
Down Syndrome (Trisomy 21)Clinical Features (Clinical Features (11 in in 800800 births)births)•• Mental retardationMental retardation
•• Flat facial profileFlat facial profile
•• Oblique palpabral fissureOblique palpabral fissure
•• Muscle hypotoniaMuscle hypotonia
•• HyperflexibilityHyperflexibility
•• Lack of Moro reflexLack of Moro reflex
•• Abundant neck skinAbundant neck skin
•• Broad and short trunkBroad and short trunk
•• Dysplastic earsDysplastic ears
•• Horizontal palmar creaseHorizontal palmar crease
•• Dysplastic pelvisDysplastic pelvis
•• Dysplastic middle pharynxDysplastic middle pharynx
•• Epicanthic foldsEpicanthic folds
•• Acute leukemiasAcute leukemias
Down syndrome with downslanting palpebral fissures and a slightly protruding tongue.
Epicanthal fold Light smudgy opaque pupil
Simian crease
karyotypeExamples of Incidence MaternalExamples of Incidence MaternalKaryotypeKaryotype age age
Trisomy Trisomy 2121 typetype 4747,,XX,+XX,+2121 >>9090%% IncreasedIncreased Translocation typeTranslocation type
4646,,XX,der(XX,der(1414;;2121)(q)(q1010;q;q1010),+),+2121 33--44% % NormalNormal4646,XX,+,XX,+2121,der(,der(2121;;2222)(q)(q1010;q;q1010))
Mosaic typeMosaic type 4646,,XX/XX/4747,XX,+,XX,+2121 22--33%% NormalNormal Partial trisomyPartial trisomy
47,XY,+21
47,XX,+21
4646,,XX,+XX,+2121,der(,der(2121;;2121)(q)(q1010;q;q1010))
Edwards Syndrome (Trisomy 18)
KaryotypeKaryotype IncidenceIncidence
Trisomy Trisomy 1818 typetype 4747,,XX,+XX,+1818 9090%%
Translocation typeTranslocation type 4646,,XX,der(Dq;XX,der(Dq;1818q),+q),+1818 rarerare
Mosaic typeMosaic type 4646,,XX/XX/4747,XX,+,XX,+1818 1010%%
Clinical feature (Clinical feature (11 in in 75007500 births)births)Mental retardation, Failure to thrive, Prominent occiput, Mental retardation, Failure to thrive, Prominent occiput, Micrognathia and lowMicrognathia and low--set ears, Hypertonicity, Flection of fingersset ears, Hypertonicity, Flection of fingers
Cardiac,Cardiac, renal and intestinal defects, Short sternum and small renal and intestinal defects, Short sternum and small pelvis, Abduction deformity of hippelvis, Abduction deformity of hip
Mental retardation, Failure to thrive, Prominent occiput, Micrognathia and low-set ears, Hypertonicity, Overlapping fingers
(clenched fist)
Cardiac, renal and intestinal defects, Short sternum and Small pelvis, Abduction deformity of hipRocker bottom feet
A child with multiple congenital anomalies withSmall face, micrognathia Small chest & Low-set ear
9595% % of embyoes have been lostof embyoes have been lost
8080% % of livebirths are femaleof livebirths are female
Karyotype Karyotype
8080% % are trisomy are trisomy 1818
2020% % resultes from translocationresultes from translocation
Patau Syndrome (Trisomy 13)
KaryotypeKaryotype IncidenceIncidence
Trisomy Trisomy 1313 typetype 4747,,XX,+XX,+1313 >>8080%% Translocation Translocation 4646,,XX,der(Dq;XX,der(Dq;1313q),+q),+13 1013 10%% Mosaic typeMosaic type 4646,,XX/XX/4747,XX,+,XX,+1313 55%%
Clinical Features (Clinical Features (11 in in 2000020000--2500025000 births)births)Microcephaly and mental retardation, Scalp defect, Microcephaly and mental retardation, Scalp defect, Microphthalmia, Cleft palate, Polydactyly, RockerMicrophthalmia, Cleft palate, Polydactyly, Rocker--bottom bottom feet, Abnormal ears, Apneic spells and myotonic seizures, feet, Abnormal ears, Apneic spells and myotonic seizures, Extensive visceral defectsExtensive visceral defects
cleft palate, atrial septal defect, inguinal hernia, and postaxial polydactyly of the left hand.
Polydactyly, particularly of all extremities, strongly suggests trisomy 13.
Autosome deletion syndromesAutosome deletion syndromes
CRI DU CHAT syndromeCRI DU CHAT syndrome
Small deletion syndromesSmall deletion syndromes
Cri du Chat (Cat-cry) Syndrome
Karyotype : Karyotype : 4646,XX,,XX,55pp-- 4646,XY,,XY,55pp--1515 Incidence :Incidence : 11 in in 5050,,000000 birthsbirths Maternal age : NormalMaternal age : Normal
Clinical featuresClinical featuresMental retardationMental retardationMicrocephaly and round faciesMicrocephaly and round faciesMewing cryMewing cryEpicanthic foldsEpicanthic folds
Wolf-Hirschhorn Syndrome
Karyotype : Karyotype : 4646,XX,,XX,44pp--4646,XY,,XY,44pp--
Incidence :Incidence : 11 in in 5050,,000000 birthsbirths Maternal age : NormalMaternal age : Normal
Clinical featuresClinical featuresMental retardationMental retardationMicrocephaly and Microcephaly and abnormal facies. Cardiac, renal, and genital abnormalities. Most are stillborn or die in infancy
wide-spaced eyes and repaired cleft lip
46,XY,del(4)(p16)
DiGeorge Syndrome (DGS)22q11 Deletion Syndrome Velocardiofacial Syndrome (VCFS)
Disease characteristics: • Congenital heart disease (74%)• Palatal abnormalities (69%) • Characteristic facial features • Learning difficulties (70 - 90%)
Diagnosis: 22q11 submicroscopic deletion
Genetic counseling. 94% of probands have a de novo deletion of 22q11
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