Lecture Notes
染色体病
张咸宁（细胞生物学与医学遗传学系）
2013/09
I. Overview – 临床细胞遗传学
Clinical cytogenetics is the discipline in medical genetics that is concerned with
disorders of chromosomes. Chromosome disorders are a major category of disease,
representing a large proportion of reproductive wastage, congenital malformations
and mental retardation, as well as a significant role in the pathogenesis of malignancy.
Specific chromosomal abnormalities（染色体畸变） are responsible for more
than 100 identifiable syndromes, and are said to be more common collectively than all
of the Mendelian single gene disorders together.
Cytogenetic disorders represent:
- Nearly 1% of live births
- Approximately 2% of prenatal diagnoses in women >35 yrs old
- 50% of all first trimester spontaneous abortions
哪些病需要做染色体检查？
- Growth and developmental abnormalities
- Family history of chromosome abnormalities
- Infertility
- Pregnancy with “advanced maternal age” (AMA), usually defined as 35 yo or
older
- Stillbirth or neonatal death
- Neoplasia
A karyotype may be prepared from many kinds of tissue samples, including blood,
skin, amniocentesis and chorionic villus samples (CVS). The cells are grown in
culture, cell division is blocked in metaphase, cells are spread on a slide and stained,
and chromosome number, morphology and banding pattern are evaluated.
II. 正常染色体的结构
Evaluation of chromosomal anatomy involves examination of the karyotype for:
- Centromere placement
- p arm (short arm)
- q arm (long arm)
- Size
- Banding pattern (Giemsa) for heterochromatin (inactive, condensed, dark) and
euchromatin (active, decondensed, light)
Greater resolution can be achieved using FISH (Fluorescence in situ
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hybridization), aCGH (array comparative genome hybridization) or flow karyotyping,
when available.
III. 染色体数目和结构的异常
A. Abnormalities of chromosome number
Abnormalities of chromosome number can be categorized:

Heteroploid – any chromosome number other than 46

Euploid – an exact multiple of haploid chromosome number (n)
 Aneuploid – Any chromosome number that is not an exact multiple of the
haploid number (n)
Human euploidies include:

Haploid
n=23

Diploid
n=46

Triploid
n=69
 Tetraploid
n=92
Triploidy is most often due to fertilization by two sperm (dispermy) or
occasionally a diploid sperm or egg. Triploidy, with an extra paternal chromosome set,
results in a partial hydatidiform mole (from Latin mola for false conception), which
represents remnants of fetal tissue including placenta with or without a small atrophic
fetus, i.e., extraembryonic with or without embryonic tissues. A partial mole is
contrasted with a complete mole, in which there is no fetus or normal placenta. A
complete mole is diploid, but with all chromosomes paternal, and approximately 50%
of choriocarcinomas, which are malignancies of fetal origin, develop from complete
moles. Triploidy with an extra maternal set results in early spontaneous abortions.
Tetraploidy is always 92,XXXX or 92,XXYY. Therefore tetraploidy is thought to
be due to an early defect in embryogenesis, with failure of completion of an early
cleavage division of the zygote.
Aneuploidies are due to nondisjunction, or failure of a pair of chromosomes to
separate (to disjoin) normally in meiosis I or meiosis II. A trisomy refers to three
copies of a chromosome, instead of the normal two copies; e.g., trisomy 21 or Down
syndrome in a male would be designated 47,XY,+21. A monosomy refers to only one
copy of a chromosome; e.g., monosomy X or Turner syndrome would be designated
45,X.
To consider the different consequences of nondisjunction for meiosis I or II, we
will examine trisomy 21. If nondisjunction occurred at meiosis I, then both parental
21s would be present. If nondisjunction occurred at meiosis II, then only one parental
21 would be present.
B. Abnormalities of chromosome structure
Structural abnormalities may be balanced (nothing gained or lost) or unbalanced
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(material gained or lost).
Among patients with Down syndrome, 4% have unbalanced translocations with
karyotypes of 46,XX or 46,XY. One chromosome is a Robertsonian translocation
involving 21q + q of another acrocentric chromosome, usually 14 or 22:
46,XX,rob(14;21)+21 or 46,XY,rob(14;21)+21.
Since the Robertsonian
translocation involves two acrocentric chromosomes the net change is the third q arm
of 21 with no net increase in chromosome number.
Unbalanced structural changes can involve deletions or duplications. Examples of
deletions include marker chromosomes, which represent a small extra chromosome,
like a ring or dicentric (two centromere) chromosome. A complex rearrangement
representing an unbalanced change involving both a monosomy and a trisomy is due
to an isochromosome. Isochromosomes can be thought of as a chromosomal division
that occurs horizontally between the centromere, resulting in products representing
two long arms fused at the centromere and two short arms fused at the centromere.
For a cell that had an isochromosome for the long arm along with the normal
chromosome, it would be trisomic for the long arm and monosomic for the short arm.
Since individuals with balanced translocations are normal, they may not be
detected until they become the parent of a child with an unbalanced rearrangement or
they undergo an infertility evaluation.
C. FISH and chromosomal painting to assess abnormalities of chromosome
number and structure
FISH uses a fluorescently labeled specific DNA sequence as a probe to detect a
specific position on a chromosome. FISH can be used to detect numeric problems or
rearrangements. Chromosomal painting involves labeling an entire chromosome with
a dye specific to that chromosome and is particularly useful to detect complex
rearrangements.
D. Submicroscopic polymorphic chromosome region copy number variants
are increasingly being detected by high-resolution techniques such as aCGH.
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