chromosomal disorders 张咸宁 [email protected] tel ： 13105819271; 88208367 office: a705,...

Chromosomal Disorders

张咸宁[email protected]

Tel ： 13105819271; 88208367

Office: A705, Research Building

2012/09

Chromosome Disorders Are A Major Chromosome Disorders Are A Major Category of Genetic DiseaseCategory of Genetic Disease

• Large proportion of: Large proportion of: – Reproductive wastage (miscarriages)Reproductive wastage (miscarriages)– Congenital malformationsCongenital malformations– Mental retardationMental retardation

• Significant role in pathogenesis of Significant role in pathogenesis of malignancymalignancy


• Specific chromosomal abnormalities are:Specific chromosomal abnormalities are:– Responsible for >100 identifiable syndromesResponsible for >100 identifiable syndromes– Collectively more common than all of the Collectively more common than all of the

Mendelian single gene disorders together!Mendelian single gene disorders together!


– ~ 1% of live births~ 1% of live births– ~ 2% of prenatal diagnoses in women >35 ~ 2% of prenatal diagnoses in women >35

yrs oldyrs old– 50% of all first trimester spontaneous 50% of all first trimester spontaneous

abortionsabortions

What are the indications for ordering What are the indications for ordering a chromosome analysis?a chromosome analysis?

• Growth and Growth and developmental developmental abnormalitiesabnormalities

• Family history of Family history of chromosome chromosome abnormalitiesabnormalities

• InfertilityInfertility

• Pregnancy with Pregnancy with ““advanced maternal advanced maternal ageage”” (AMA) (AMA)

• Stillbirth/neonatal Stillbirth/neonatal deathdeath

• Infertility/history of Infertility/history of pregnancy losspregnancy loss

• NeoplasiaNeoplasia

How is a karyotypeHow is a karyotype （（核型）核型） prepared?prepared?

• Sample: blood, skin, amnio, CVS Sample: blood, skin, amnio, CVS

• Cells grown in cultureCells grown in culture

• Blocked in metaphase using colchicineBlocked in metaphase using colchicine

• Spread on slide and stainedSpread on slide and stained

• Abnormalities detected by number, Abnormalities detected by number, morphology and banding patternmorphology and banding pattern

Chromosome AnatomyChromosome Anatomy• Centromere placementCentromere placement

• p (short arm)p (short arm)

• q (long arm)q (long arm)

• SizeSize

• Banding pattern (Giemsa stain)Banding pattern (Giemsa stain)– Heterochromatin Heterochromatin 异染色质异染色质

(inactive, condensed) - dark(inactive, condensed) - dark

– Euchromatin Euchromatin 常染色质常染色质 (active, decondensed) - light(active, decondensed) - light

Interphase & Metaphase Interphase & Metaphase NucleiNuclei

Giemsa Staining (G-banding)Giemsa Staining (G-banding)

Normal Human Male KaryotypeNormal Human Male KaryotypeIndividual Chromosomes Cut from Metaphase SpreadIndividual Chromosomes Cut from Metaphase Spread

Ideogram of Human Male G-banded Metaphase ChromosomesIdeogram of Human Male G-banded Metaphase Chromosomes

(400 bands per haploid karyotype)(400 bands per haploid karyotype)

Abnormalities of Abnormalities of Chromosome NumberChromosome Number

• HeteroploidHeteroploid （异倍体）（异倍体）– Any chromosome number other than 46Any chromosome number other than 46

(1) Euploid (1) Euploid （整倍体）（整倍体）– An exact multiple of the haploid An exact multiple of the haploid

chromosome number (n), where n = 23chromosome number (n), where n = 23

(2) Aneuploid (2) Aneuploid （非整倍体）（非整倍体）– Any chromosome number that is not an Any chromosome number that is not an

exact multiple of the haploid number (n)exact multiple of the haploid number (n)

TriploidyTriploidy （（三倍性）三倍性）• Most often due to fertilization by two sperm Most often due to fertilization by two sperm

(dispermy) or occasionally a diploid sperm or (dispermy) or occasionally a diploid sperm or eggegg

• Partial hydatidiform moles (remnants of Partial hydatidiform moles (remnants of placenta placenta ± small atrophic fetus)± small atrophic fetus): triploid with : triploid with extra paternal set extra paternal set – Mole: from the Latin Mole: from the Latin molamola,, for false conception for false conception

• Extra maternal set: early spontaneous Extra maternal set: early spontaneous abortionsabortions

Molar pregnanciesMolar pregnancies

• Partial mole:Partial mole: remnants of fetal remnants of fetal tissue (embryonic tissue (embryonic and/or and/or extraembryonic)extraembryonic)

• Triploid, paternalTriploid, paternal

• Complete mole:Complete mole: no no fetal tissuesfetal tissues

• Risk for ovarian Risk for ovarian teratoma or teratoma or choriocarcinomachoriocarcinoma

• Diploid but all Diploid but all chromosomes are chromosomes are maternal or paternal, maternal or paternal, respectivelyrespectively

AneuploidyAneuploidy （（非整倍性）非整倍性）• TrisomyTrisomy （（三体）三体） :: three copies three copies

– 47,XY+21: Down syndrome47,XY+21: Down syndrome• Monosomy Monosomy （（单体）单体） : one copy: one copy

– 45,X: Turner syndrome45,X: Turner syndrome• NondisjunctionNondisjunction （（不分离）不分离） :: failure of a failure of a

pair of chromosomes to separate (to pair of chromosomes to separate (to disjoin) normally in meiosis I or IIdisjoin) normally in meiosis I or II

Different Consequences to the Gamete Different Consequences to the Gamete of Nondisjunction at of Nondisjunction at

Meiosis I or Meiosis IIMeiosis I or Meiosis II

both parental both parental 21s present21s present

2 copies of one2 copies of one parental 21parental 21

Abnormal Male Karyotype:Abnormal Male Karyotype:47,XY +2147,XY +21

Down syndrome• Most common

trisomy 1:800 in new born

• Most common sever mental retardation

• Related with advanced maternal age

Down syndrome

Trisomy 18 （ Edward syndrome ）

• 1:7500 in liveborn and more common in abortion and stillbirth

• Severe mental retardation and multiple structural anomalies

Trisomy 18

Trisomy 13（ Patau syndrome ）

• 1:20,000 in liveborn and more common in abortion and stillbirth

• Severe structural anomalies lead to death in one month

Trisomy 13

Monosomy

• Almost all monosomy for an entire chromosome is lethal

• Turner syndrome: 45,X, the only monosomy can be born and survive

Turner syndrome

XXY, Klinefelter syndrome

• 1:1,000 in male liveborn

• Hypogonadism

• Infertility

Abnormalities of Abnormalities of Chromosome StructureChromosome Structure

• Balanced: nothing gained or lostBalanced: nothing gained or lost

• Unbalanced: material gained or lostUnbalanced: material gained or lost

Balanced RearrangementsBalanced Rearrangements（平衡性重排）（平衡性重排）

• Individuals with balanced rearrangements Individuals with balanced rearrangements appear normalappear normal

• Therefore, they may not be detected until:Therefore, they may not be detected until:– Birth of a child with an unbalanced Birth of a child with an unbalanced

rearrangementrearrangement– Infertility evaluation (recurrent pregnancy loss)Infertility evaluation (recurrent pregnancy loss)

Balanced and Unbalanced Translocations（平衡易位、非平衡易位）

• Reciprocal ~

（相互易位）

Resulted from breakage of nonhomologous chromosomes, with reciprocal exchange of the broke-off segments

Translocation

Reciprocal Translocation (9;22)

Robertsonian Translocation（罗氏易位）

• Two acrocentric chromosomes fuse near the centromere region with loss of the short arms, which carry multiple copies of genes for rRNA.

• Only 45 chromosomes with balanced karyotype and phenotype

45, XX, rob ( 13q14q)

Balanced translocation in meiosis

High Risk to

produce unbalanc

ed offspring

Translocation Down SyndromeTranslocation Down Syndrome

• 4% of all Down cases4% of all Down cases• One chromosome is a One chromosome is a

Robertsonian translocationRobertsonian translocation• 21q + q of another 21q + q of another

acrocentric chromosome, acrocentric chromosome, usually 14 or 22usually 14 or 22

• 46,XX,rob(14;21),+21 or 46,XX,rob(14;21),+21 or 46,XY,rob(14;21),+2146,XY,rob(14;21),+21

Down syndrome:21/21 t

Offsprings

Down syndrome: t

The Tools:Cytogenetic Analysis

ConventionalKaryotyping

SKY(spectral karyotyping)

What is FISH?What is FISH?

• Fluorescence Fluorescence in situin situ hybridizationhybridization

• Detects a specific Detects a specific position or gene on an position or gene on an intact chromosomeintact chromosome

• Can be used to detect Can be used to detect numeric problems or numeric problems or rearrangements rearrangements – Banding could not be detected < 4Mb

141521.121.221.322.122.222.32324

25

26.126.226.3

q

13 12 11.2 11.1 11.111.212

13

p

11.212

13

Normal chromosome 15

Duplication chromosome 15

13 12 11.2 11.1 11.111.21213141521.121.221.322.122.222.323

24

25

26.126.226.3

p

q

Fluorescence In Situ Hybridization （ FISH ）

• Using DNA probe labeled with a certain marker

• Hybridizing with DNA in chromosomes and nuclei on slides

• Probes hybridized with the fragment in chromosome are detected by signals from the labeled markers

Cs+ Probe Co-denature Anneal,hybridize

Down syndrome----FISH

Chromosome Painting

Specific Cytogenetic Changes in CancerSpecific Cytogenetic Changes in Cancer

• Association of cytogenetic changes with specific Association of cytogenetic changes with specific forms of cancerforms of cancer

• Breakpoints may be associated with structural Breakpoints may be associated with structural rearrangements of oncogenesrearrangements of oncogenes

• Cytogenetic changes in cancer are numerous Cytogenetic changes in cancer are numerous and diverseand diverse– Many seen repeatedly in same type of tumorMany seen repeatedly in same type of tumor

– Evaluate by FISH and chromosomal paintingEvaluate by FISH and chromosomal painting

Philadelphia Chromosome in Chronic Myelogenous Leukemia

Ph Chromosome FISH

嵌合体： Mosaic and chimera

Mosaic

Chimera

Aberration

Aberration

Submicroscopic polymorphic chromosome region copy number

variants are increasingly being detected by high-resolution techniques such as aCGH.

Array Comparative Genomic Hybridization (aCGH)

chromosomal disorders 张咸宁 [email protected] tel ： 13105819271; 88208367 office: a705,...

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