Chromosome Disease
Medical Genetics
Painter TS,Studies in mammalian spermatogenesis,II.
The spermatogenesis of man,J Exp Zool,1923; 37,291-
336
Dark Ages
Hsu TC,Mammalian chromosomes in vitro,I,The
karyotype of man,J Hered,1952; 43,167-172
Tjio JH,Levan A,The chromosome number of man.
Am J Obstet Gynecol,1956; 130,723-724
Hypotonic Period
Dark Ages
Trisomy Period
Lejeune J,et al,Etude des chromosomes somatiques de
neuf enfants mongoliens,G,R,Acad,Sciences,1959;
248,1721-1722
Ford CE,et al,A sex chromosomal anomaly in a case of
gonadal dysgenesis (Turner's syndrome),Lancet,1959;
1,711-713
JACOB PA,et al,A case of human intersexuality
having a possible XXY sex determining mechanism.
Nature,1959; 183,302-303.
Hypotonic Period
Dark Ages
Banding Era
Caspersson T,et al,Differential banding of alkylating
fluorochromes in human chromosomes,Exp Cell Res.
1970; 60,315-319
Hypotonic Period
Dark Ages
Trisomy Period
Molecular Era
Pardue ML,et al,Molecular hybridization of radioactive
DNA to the DNA of cytological preparations,Proc,Natl.
Acad.Sci,USA,1969; 64,600 - 604
Pinkel D,et al,Cytogenetic analysis using quantitative,
high-sensitivity,fluorescence hybridization,Proc,Natl.
Acad.Sci,USA,1986; 83,2934-2938.
Hypotonic Period
Dark Ages
Banding Era
Trisomy Period
Karyotype analysis,arranging the chromosomes
of a cell into a karyotype,then analysis and
compare with Denver system.
Denver System
The karyotype is a photograph of all of the
chromosomes of an individual cell; the term
covers the number,relative sizes and structure
of the chromosomes.
Chromosome can be distinguished by the
relative sizes and the position of the centromere.
Metacentric
(1,3,16,19,20)
Submetacentric
(2,4-12,17,18,X)
Acrocentric
(13,14,15,21,22,Y)
Denver System
Denver System
Banding Pattern
Band,treated with chemical dyes,the chromosome
will appear as a series of alternate dark and
light striations.
Banding pattern,treated with chemical dyes,24 types
of chromosomes appear its unique
striations individually.
Q-banding,QM
G-banding,pancreatin＋ Giemsa
Banding Pattern
Band,treated with chemical dyes,the chromosome
will appear as a series of alternate dark and
light striations.
R-banding,treated specimen＋ Giemsa or Acridine Orange
Banding Pattern
Q-banding,QM
G-banding,pancreatin＋ Giemsa
Band,treated with chemical dyes,the chromosome
will appear as a series of alternate dark and
light striations.
C-banding,Y chromosome,centromere,secondary constriction
Banding Pattern
R-banding,treated specimen＋ Giemsa or Acridine Orange
Q-banding,QM
G-banding,pancreatin＋ Giemsa
Band,treated with chemical dyes,the chromosome
will appear as a series of alternate dark and
light striations.
T-banding,ending of chromosome
Banding Pattern
C-banding,Y chromosome,centromere,secondary constriction
R-banding,treated specimen＋ Giemsa or Acridine Orange
Q-banding,QM
G-banding,pancreatin＋ Giemsa
Band,treated with chemical dyes,the chromosome
will appear as a series of alternate dark and
light striations.
N-banding,AgNO3＋ Giemsa,NOR
T-banding,ending of chromosome
Banding Pattern
C-banding,Y chromosome,centromere,secondary constriction
R-banding,treated specimen＋ Giemsa or Acridine Orange
Q-banding,QM
G-banding,pancreatin＋ Giemsa
Band,treated with chemical dyes,the chromosome
will appear as a series of alternate dark and
light striations.
Landmark
Xp
Xq
Region
Band
1
1
2
2
12
34
5
67
8
Xq28
Banding Pattern
Development
1,High resolution banding chromosome (HRBC)
FISH (fluorescence in situ hybridization)
DNA fiber-FISH
Chromosome Painting
CGH (comparative genomic hybridization)
3,Molecular cytogenetics
Development
2,Microcytogenetics
1,High resolution banding chromosome (HRBC)
Heteromorphism
Banding pattern polymorphism
Chromosome heteromorphisms are
normal variations in the appearance of
chromosomes.
Be inherited in a Mendelian fashion
Constitutive heterochromatin
Not chromosomal abnormality in clinical
Heteromorphism
Banding pattern polymorphism
Chromosomal length
Satellite
Secondary constriction
Polymorphism of Q,G,C banding
Chromosomal Aberration
Numerical Abnormality
Structural Aberration
Numerical Abnormality
Haploid,22+X,22+Y
Diploid,44+XX,44+XY
Numerical Abnormality
Variation in chromosome number can
take 2 forms:
Euploid,that which involves whole sets (genomes) of
chromosomes
Aneuploid,the chromosome number is not an exact
multiple of the haploid number
Euploid
Triploid,the cell which has 3 sets (genomes)
of chromosomes —— 3n ＝ 69
Numerical Abnormality
Numerical Abnormality
Euploid
Triploid,the cell which has 3 sets (genomes)
of chromosomes —— 3n ＝ 69
Tripolar spindle
Diandry,fertilization of 1 oocyte by 2
spermatozoa
Digyny,non-expulsion of the 2nd polar
body
Numerical Abnormality
Euploid
Triploid,the cell which has 3 sets (genomes)
of chromosomes —— 3n ＝ 69
Euploid —— polyploid
Tetraploid,the cell which has 4 sets (genomes)
of chromosomes —— 4n ＝ 92
Endoreduplication
Numerical Abnormality
Endoreduplication
Diplochromosome
Diplochromosome
Euploid —— polyploid
Tetraploid,the cell which has 4 sets (genomes)
of chromosomes —— 4n ＝ 92
Endoreduplication
Numerical Abnormality
Endomitosis
Be found more commonly than Euploid.
Hypodiploid,less than the normal 2n number of
chromosomes
Numerical Abnormality
Aneuploid
Hyperdiploid,more than the normal 2n number
of chromosomes
Monosomy,is the presence of only one
copy of any chromosome
Loss of autosomes is not tolerated
Turner syndrome,45,X
Numerical Abnormality
Aneuploid
Hypodiploid
Be found more commonly than Monosomy
Trisomy of sex chromosome is more commonly
Numerical Abnormality
Aneuploid
Hyperdiploid
Trisomy,is the presence of only three
copy of any chromosome
Meiotic non-disjunction
Mitotic non-disjunction
Chromosome non-disjunction
Chromosome loss
Numerical Abnormality
Mechanism of Aneuploid
The Breakage and the Rejoin after
breakage are the basis of chromosomal
structural aberration.
Chromosomal rearrangement
Rearrangement chromosome
Structural Aberration
Short system
Detailed system
Terminal Deletion
Structural Aberration
4q27
Interstitial Deletion
Structural Aberration
4q13
4q25
Paracentric Inversion
Structural Aberration
4q13
4q24
Pericentric Inversion
Structural Aberration
4p14
4q21
Structural Aberration
Pericentric Inversion
Structural Aberration
Pericentric Inversion
Inversion loop
Structural Aberration
Pericentric Inversion
Structural Aberration
Pericentric Inversion
Inversion loop
Structural Aberration
Pericentric Inversion
Ring Chromosome
Structural Aberration
2q31
2p21
Ring Chromosome
Structural Aberration
2q31
2p21
p21
q31
Ring Chromosome
Structural Aberration
Ring Chromosome
Structural Aberration
Reciprocal Translocation
Structural Aberration
4q25
20q12
Structural Aberration
Reciprocal Translocation
Structural Aberration
Reciprocal Translocation
A
B
C
D Four-way junction
Structural Aberration
Reciprocal Translocation
Robertsonian Translocation
Structural Aberration
Structural Aberration
Robertsonian Translocation
Whole Arm Translocation
Structural Aberration
Complex Translocation
Structural Aberration
Isochromosome
Structural Aberration
Isochromosome
Structural Aberration
Dicentric Chromosome
Structural Aberration
6q22
11p15
Direct Insertion
Structural Aberration
Inverse Insertion
Structural Aberration
Chromosome Disease in Clinical
Clinical feature
The general features in autosome abnormalities
are a triad of growth retardation,mental
retardation,and specific somatic abnormalities.
Change of sex chromosome also have the
abnormalities and malformations of internal or
external genital organs.
Down Syndrome (trisomy 21 syndrome)
Chromosome Disease in Clinical
Characteristics
o Growth retardation
o Varying degrees of mental
retardation
o Flattened face
o Upward slanting of the eyes
with epicanthal folds
1 in 600 ~ 800 newborns
Chromosome Disease in Clinical
Down Syndrome (trisomy 21 syndrome)
1,Trisomy —— 95%,47,XX(XY),＋ 21
Caused by non-disjunction of chromosome
21,correlated with age of mother.
Chromosome Disease in Clinical
Down Syndrome (trisomy 21 syndrome)
Karyotype of affected：
46,XX(XY),－ 14,＋ t(14q21q)
2,Mosaic —— 2% ~ 4%,46/47
3,Unbalance translocation
Karyotype of balance carrier：
45,XX(XY),－ 14,－ 21,＋ t (14q21q)
Chromosome Disease in Clinical
1,Trisomy —— 95%,47,XX(XY),＋ 21
Down Syndrome (trisomy 21 syndrome)
1 in 4000 ~ 5000 newborns
Edwards Syndrome (trisomy 18 syndrome)
Characteristics
o Growth retardation
o Mental retardation
o Congenital heart disease
o Rocker-bottom feet
o fixed flexion deformity of the
fingers
Chromosome Disease in Clinical
Chromosome Disease in Clinical
1 in 4000 ~ 5000 newborns
Edwards Syndrome (trisomy 18 syndrome)
1 in 5000 ~ 7000 newborns
Patau Syndrome (trisomy 13 syndrome)
Characteristics
o Varying degrees of mental
retardation
o Cleft lip & Cleft palate
o Polydactyly (postaxial)
o Equinovarus
Chromosome Disease in Clinical
1 in 50000 newborns
5p－ Syndrome (Cat Cry syndrome)
Characteristics
o Round,moon-shaped face
o,Cry of the cat”
o Varying degrees of mental
retardation
o Low set ears
Chromosome Disease in Clinical
Turner Syndrome (45,X)
1 in 2500 liveborn females
Characteristics
o Short stature & Webbed neck
o Ovarian dysgenesis,primary
amenorrhea,infertility
o Absence of secondary sex
characteristics
o Underdeveloped breasts;
wide nipples
Chromosome Disease in Clinical
Trisomy X syndrome (47,XXX)
1 in 1000 liveborn females
1 in 250 psychopath of females
Two of the three X chromosomes are inactivated.
Chromosome Disease in Clinical
1 in 800 males
o Tall with disproportionately long
arms/legs
Klinefelter syndrome (47,XXY)
1 in 100 mentally retarded males
1 in 10 infertile males
o Poorly developed secondary sex
characteristics
o Testicular dysgenesis
Chromosome Disease in Clinical
1 in 750 ~ 1500 males
o Tall stature
XYY syndrome (47,XXY)
1 in 30 male prison populations
o Predisposition to violent,criminal
behavior
＞ 180 cm,1/200
＞ 190 cm,1/30
＞ 200 cm,1/10
Chromosome Disease in Clinical
1 in 1250 males
Fragile X chromosome syndrome (Fra X)
Characteristics
o Show mild to severe mental
retardation
o Large,protruding ears
o Enlarged testes
o Narrow face with a prominent chin
o Behavioral problems
Chromosome Disease in Clinical
FISH
FISH
FISH
X染色体 Y染色体 13号染色体 18号染色体 21号染色体
Back
FISH
DNA fiber-FISH
3 cosmid from MHC locus
35～ 40 Kb/cosmid
Back
Chromosome Painting
Chromosome Painting
Back
Chromosome Painting
CGH
CGH
CGH
Advantages
Whole genome in 1 experiment
No need to culture tumor cells
Sensitive detection of gene amplification
Disadvantages
Limited resolution (~10 Mb del/dup)
Laborious
Only gains and losses/no balanced rearrangements
No information on the nature of the aberrations
Retrospective analysis
Back
CGH
Meiotic Non-Disjunction
Meiotic non-disjunction arises
from failure of paired homologous
chromosomes or sister chromatid to
disjoin at meiotic anaphase.
2N
N
N＋ 1 N－ 1
2N＋ 1 2N＋ 1 2N－ 1 2N－ 1
N＋ 1N＋ 1 N－ 1N－ 1
Meiotic Non-Disjunction
2N 2N 2N＋ 1 2N－ 1
2N
N N
NN N－ 1N＋ 1
Primary non-disjunction
Primary non-disjunction is the failure of
chromosomes or sister chromatid to separate in
meiosis,The gamete thus has two copies of a
chromosome,Fertilization adds another copy to
give a total of 3 copies.
Secondary non-disjunction
Trisomy offspring arise from segregation at
meiosis of an already-trisomy parent.
Meiotic Non-Disjunction
Back
Meiotic Non-Disjunction
2N+1
N
2N 2N 2N＋ 1 2N＋ 1
N N＋ 1
NN N＋ 1N＋ 1
Mitotic Non-Disjunction
Mitotic non-disjunction arises from
failure of sister chromatids to disjoin
at mitotic anaphase.
2N
2N
2N
2N
2N
2N－ 1
2N＋ 1
2N
2N－ 1
2N＋ 1
47/45 Mosaic 46/47/45 Mosaic Back
The causality where a chromosome is
missing from the new cell created via cell
division.
Anaphase lag may be due to delayed
movement of a chromosome at anaphase.
Chromosome Loss
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