MEDICAL GENETICSMEDICAL GENETICS

Chapter 3pChromosomal Aberrations

Abnormalities of chromosomes may be either ynumerical or structural and may involve one or more autosomes, sex chromosomes, or both simultaneouslysimultaneously.

Numerical Aberrations

Structural AberrationsStructural Aberrations

i A iNumerical Aberrations A chromosome complement with anyA chromosome complement with any chromosome number other than 46 is said to be numerical aberrations.Numerical aberrations involve the loss and/or gain of a whole chromosome or chromosomes and can include both autosomes and sexand can include both autosomes and sex chromosomes.

EuploidEuploid

A l idAneuploid

EuploidEuploidAn exact multiple of the haploidchromosome number (n) is called euploid.

•Haploid•Haploid•Germ cells (egg and sperm) have 23 chromosomes: one copy of each autosome pyplus a single sex chromosome. This is referred to as the haploid number.

•Triploid•A condition in which there is an extra copy f h

69，XXX 69，XXY 69 XYYof every chromosome.

•Tetraploid•A condition in which there are two extra

69，XYY

92 XXXX•A condition in which there are two extra copies of every chromosome.

92，XXXX92，XXYY

i l idTriploid

From cancer genetics and cytogenetics 143(2003):169-171

AneuploidAneuploidAn clinically significant chromosome abnormality which number due to an extra or missingwhich number due to an extra or missing chromosome.1. Hyperdiploidyp p– Somatic cells in which chromosome numbers are more than

46.Those cells with an extra chromosome show trisomy for the– Those cells with an extra chromosome show trisomy for the chromosome involved.

– Trisomy is the most common type.47 XX(XY) 21 (D S d )– e.g. 47, XX(XY), +21 (Down Syndrome)

2. Hypodiploid– Somatic cells in which chromosome numbers are less than– Somatic cells in which chromosome numbers are less than

46.– Cells which have lost a chromosome are monosomy for that

chromosomechromosome. – e.g. 45, X (Turner Syndrome)

Multicolor FISH analysis ofMulticolor FISH analysis of interphase amniotic fluid cells

47,XX,+18 (trisomy 18) cellChromosome 18 aqua, X q ,chromosome green

trisomy 21cellsCh 13 hChromosome 13 green, chromosome 21 red

Mechanism of numerical aberration

1. Diandry and digyny2 E d li i d

The reason for triploid2. Endoreplication and

endomitosis3 M i i di j i

The reason for tetraploid

3. Meiotic nondisjunction4. Mitotic nondisjunction

The reason for aneuploid

The reason for mosaicism5. Loss of chromosome Also the reason for mosaicism

Structural Aberration

Quantities and positions of genetic material altered.M h i Ch b k f lMechanism: Chromosomes were broken, fragments lost or connected to a wrong position.Description: number sex chromosomes abnormalitiesDescription: number, sex chromosomes, abnormalities– Brief pattern：using the breakpoints– Detailed pattern：using the form of the bands in rearrangedDetailed pattern：using the form of the bands in rearranged

chromosomes

symbols：– p、q、 ter、 pter、qter、cen、t、inv、:、::、del、der、i、

fra、rob etc.

Some abbreviations

Abbreviation Meaning cendel

centromeredeletion

used for description of h

delderdic

dup

deletionderivativedicentric chromosomeduplication

chromosomes frai

insi

fragile siteisochromosomeinsertioni iinv

marmat

p

inversionmarker chromosomematermal originshort arm of chromosomep

patqr

short arm of chromosomepaternal originlong arm of chromosomering chromosome

rcprob

tter

reciprocal translocationRobertsonian translocationtranslocationterminuster

+-:

terminusgain ofloss ofbreak

::/

b eabreak and joinmosaicism

Common structural aberrations

Deletion, delRing chromosome, rT l iTranslocation, tInversion, inv,Dicentric chromosome, dicIsochromosome, i

Deletion delDeletion,del

• Deletions involve loss of material from a single chromosome. The effects are gtypically severe since there is a loss of genetic materialgenetic material.

Terminal deletion

Interstitial deletionInterstitial deletion

Terminal deletion

A terminal segment of a chromosome is deleted.

i l d l iTerminal deletion

lloss

Brief pattern：– 46, XX(XY), del(1)(q21)46, XX(XY), del(1)(q21)

Detailed pattern：– 46, XX(XY), del(1)(pter→q21:)

Notice:NThe detailed description usually begins from the terminal of short arm (pter), but when

i d l d i h ld b i f hpter is deleted, it should begins from the terminal of long arm (qter).E g Cri du chat syndromeE.g. Cri du chat syndrome– Brief pattern：46, XX(XY), del(5)(p14)– Detailed pattern：46 XX(XY) del(5)(qter→p14:)Detailed pattern：46, XX(XY), del(5)(qter→p14:)

i i l d l iInterstitial deletion

An intermediary segment, i.e., excluding a centromere and terminal ends (telomeres), of a chromosome is deleted.

I i i l d l iInterstitial deletion

q21

q31loss

Brief pattern：– 46, XX(XY), del(1)(q21q31)

Detailed pattern：– 46, XX(XY), del(1)(pter→q21::q31 →qter)

Chromosomal Microdeletions:Chromosomal Microdeletions:

Prader-Willi and AngelmanSyndromesSyndromes

Gene imprinted (turned off)

Gene not imprinted (turned on)Gene not imprinted (turned on)

D Dele

ele

ted

tedd d

PaternalDNA

MaternalDNA

Prader-WilliSyndrome

AngelmanSyndromey y

Prader-Willi Syndrome

Cause:•Usually caused by micro deletion in region q11-13 of the paternally

transmitted chromosome 15.•Several genes in this region are genomically imprinted in the maternal•Several genes in this region are genomically imprinted in the maternal

chromosome.•Hence, if there is a paternal deletion in this region, there are no active genes.

Symptoms:•Short stature•Mental retardation, learning difficulties•Decreased muscle tone

y p

•Decreased muscle tone•Hypogonadism•Emotional lability•Unregulated appetite or hyperphagia ( obesity)Unregulated appetite or hyperphagia ( obesity)

Prader Willi Syndromey

Tanis, a girl with PWS

Angelman SyndromeAngelman Syndrome

Cause:Cause:Microdeletion of region q11-13 of chromosome 15 that deletes agene(s) that is paternally imprinted.

•Normal development until 6-12 months then delayed development

Symptoms:

•Normal development until 6-12 months, then delayed development•Disproportionate head growth microcephaly•Abnormal EEG, seizures•Marked deficit in language (no words to a few words) but betterMarked deficit in language (no words to a few words) but better

communication using nonvebral methods (e.g., facial expressions)•Motoric problems (balance problems, ataxia of gait, hypermotoric actions)•Attention problems (short attention span)p ( p )•Emotional exuberance (frequent laughter, smiling)

AngelmanSyndromeSyndrome

Angelman Syndromeg y

i hRing chromosome, r

Two broken ends of a chromosome have j i d t f i lik t tjoined to form a ring-like structure.

loss

p21

q31

loss

Brief pattern: Notice:p– 46, XX(XY), r(2)(p21q31)

Detailed pattern:

Notice:

No ::p– 46, XX(XY), r(2)(p21→q31)

T l i Translocation, t

Translocations involve is the transfer of chromosomal materialexchange ofchromosomal materialexchange of material between two or more chromosomeschromosomes.

Reciprocal translocation

Robertsonian translocationRobertsonian translocation

Reciprocal translocationReciprocal translocation

R i l t l tiReciprocal translocationis a translocation in which the segments of h h b h dchromosomes have been exchanged.

i l l iReciprocal translocation

2q21

der(2)der(2)

2

5q31

d (5)

5

Brief pattern: – 46，XX(XY)，t(2;5)(q21;q31)

der(5)

Detailed pattern: – 46，XX(XY)，t(2;5)(2pter→2q21::5q31 →5qter ; 5pter →5q31::2q21 →2qter)

Notice:In reciprocal translocation between autosomes, the larger one should be described antecedently;In reciprocal translocation between sex chromosomes and autosomes, the sex chromosome should be described antecedentlydescribed antecedently.

e g 46 XX t(X; 2)(q21; 2q31)e.g. 46，XX，t(X; 2)(q21; 2q31)

The best-known tumor-specific rearrangement produces the Philadelphia (Ph1) chromosome, a very small acrocentric chromosome seen in 90% of patients with chronic m eloid le kemiachronic myeloid leukemia.

T(9;22)(q34;q11), The breakpoint on chromosome 9 isT(9;22)(q34;q11), The breakpoint on chromosome 9 is within an intron of the ABL oncogene.

The translocation joins most of the ABL genomic sequence onto a gene called BCR (breakpoint cluster region) on chromosome 22 creating a novel fusion geneon chromosome 22, creating a novel fusion gene .

This chimeric gene is expressed to produce a tyrosine This chimeric gene is expressed to produce a tyrosine kinase related to the ABL product but with abnormal transforming properties

A metaphase cell positive for the bcr/abl rearrangement using FISH

Burkitt's lymphoma is a childhood tumor common in y pmalarial regions of Central Africa and Papua New Guinea.

M i d E i B i b li d lMosquitoes and Epstein-Barr virus are believed to play some part in the etiology, but activation of the MYC oncogene is a central eventis a central event.

A characteristic chromosomal translocation, t(8;14)(q24;q32) is seen in 75~ 85% of patients .

E h f th t l ti t th MYC lEach of these translocations puts the MYC oncogene close to an immunoglobulin locus, IGH at 14q32.

MYC is expressed at an inappropriately high level.

Pairing at meiosis

q21q23

q

Alternate: ①3，21 ②3*，21*Alternate: ①3，21 ②3 ，21

Karyotypes of offspring:① ②

Karyotypes of offspring:

① 46，XX（XY） Normal ① 46，XX（XY）

② 46 XX（XY） t(3;21) (q23;q21)Balanced translocation, phenotypically normal

② 46，XX（XY），t(3;21) (q23;q21)

Adjacent 1：③ 3，21* ④ 3*，21Adjacent 1：③ 3，21* ④ 3*，21

③ ④

Karyotypes of offspring:

③ ④

y yp p g

③46,XX（XY）, -21 , +der(21) (21pter 21q21::3q23 3qter)

unbalanced translocation, abnormal(21pter →21q21::3q23 →3qter)

④46 XX（XY） 3 +der(3)

abnormal

b l d l i④46,XX（XY）, -3 , +der(3) (3pter→3q23::21q21 →21qter)

unbalanced translocation, abnormal

Adjacent 2： ⑤ 3，3* ⑥ 21，21*Adjacent 2： ⑤ 3，3 ⑥ 21，21

Karyotypes of offspring:

⑤ ⑥

Karyotypes of offspring:

⑤ 46,XX（XY）, -21 , +der(3) (3pter →3q23::21q21 →21qter)⑤ , , , ( ) ( p q q q )⑥ 46,XX（XY）, -3 , +der(21) (21pter→21q21::3q23 →3qter)

Both are unbalanced translocation, abnormal

Robertsonian translocationRobertsonian translocation

Translocations involving the centromeric regions and with both long arms ofregions and with both long arms of acrocentric chromosomes. C t i f iCentric fusionBalanced translocation

b i l iRobertsonian translocation

loss

lossBrief pattern：

45,XX(XY),rob(14;21)(p11;q11)

Detailed pattern：

45,XX(XY),rob(14;21)(14qter→14p11::21q11 →21qter)

2012年4月6日星期五

2012年4月6日星期五

④⑤ ⑥③②①

• Karyotypes of offspring：

④⑤ ⑥③②①

Phenotypes：

Normal ① 46, XX(XY)

yp

Balanced translocationDown syndrome

M 21

② 45, XX(XY), rob(14;21) (p11; q11)③ 46, XX(XY), -14, + rob(14;21) (p11; q11)④ 45 XX(XY) 21 Monosomy-21

Be similar to trisomy-14Monosomy-14

④ 45, XX(XY), -21⑤ 46, XX(XY), -21, + rob(14;21) (p11; q11)⑥ 45, XX(XY), -14

2012年4月6日星期五

Monosomy 14⑥ 45, XX(XY), 14

FISH detection of balanced translocation between chromosomes 11FISH detection of balanced translocation between chromosomes 11 (yellow) and 16, using a painting probe for chromosome 11.

Karyotype is 46,XY,t(11;16)(q24;q23)

2012年4月6日星期五

FISH detection of a cryptic translocation in a developmentally delayed proband, using specific probes for the telomere of chromosome 3pp g p p pand chromosome 11q.

An unbalanced translocation between 3p and 11q carrying partial trisomy for 3p and partial monosomy for 11q

2012年4月6日星期五

trisomy for 3p and partial monosomy for 11q.

I i iInversion , inv

Inversions occur when there are two breaks within a single chromosome and the broken segment flips 180° (inverts) g p ( )and reattaches to form a chromosome that is structurally out-of-sequencethat is structurally out of sequence. – Paracentric Inversion– Pericentric Inversion

Paracentric inversion

An inversion of a chromosome segment that excludes the centromereexcludes the centromere.

Brief pattern: 46 XX(XY) i (2)( 13 24)– 46, XX(XY), inv(2)(p13p24)

Detailed pattern: 46 XX(XY) inv(2)(pter→p24::p13→ p24::p13 →qter)– 46, XX(XY), inv(2)(pter→p24::p13→ p24::p13 →qter)

i i i iPericentric inversion

An inversion of a chromosome segment that includes the centromere.

1

2

p p13q31p13

1

q31p 3

2q

q31p13

q31

3q31

Brief pattern:2

– 46, XX(XY), inv(2)(p13q31)Detailed pattern:– 46, XX(XY), inv(2)(pter→p13::q31→ p13::q31 →qter)

• Although an inversion carrier may be completely• Although an inversion carrier may be completely normal, they are at a slightly increased risk for producing a chromosomally unbalanced embryo. This is because an inverted chromosome has difficulty pairing with it's normal homolog during meiosis which can result in gametes containingmeiosis, which can result in gametes containing unbalanced derivative chromosomes if an unequal cross-over event occurs.unequal cross over event occurs.

Inversion looploop

i i h diDicentric chromosome, dic

A chromosome with two centromeres.

Dicentric chromosome, dic

di t i Xdicentric X

Normal X

Combined FISH and centromere analysis in a 46,X,idic(X) patient, with a dicentric isochromosome of the X chromosome.BLUE h i d i h DAPIBLUE– chromosomes stained with DAPIGREEEN– functional centromeres, as detected with antibodies against a protein specific for active centromeres/kinetochores.RED– X centromeres detected by FISH using a specific alpha satellite probe from the X.

h iIsochromosome , i

The two arms of the hchromosome are

identical to each thother.

46,X, i(Xp) 46,X, i(Xp)(pter→cen →pter), , ( p)(p p )

46,X, i(Xq)46 X i(Xq)(qter cen qter)46,X, i(Xq)(qter→cen →qter)

DiandryA condition that

Diandry

one egg fertilized by two sperms. y p

23X69，XXX

69 XXY23X

69，XXY

23X 69，XYY23X

In meiosis Ⅱof oogenesis, the secondary oocyte for someDigyny secondary oocyte, for some unknown reasons, fails to exclude the 2nd polar body. Then fertilization occurs

Digyny

Then fertilization occurs between it and a normal sperm.

23X23X

69，XXY

23X 69，XXX23X

Endoreplication

Chromosomes duplicate twice in a single cell di i idivision.

EndomitosisAlthough chromosomes duplicate once normally in interphase, the nuclear envelope doesn’t break up until metaphase resulting in tetraploidmetaphase, resulting in tetraploid.

Meiotic nondisjunction

Nondisjunction can occur either in meiosis Ⅰi i ior in meiosis Ⅱ.

– All the gametes will be produced abnormally due to the disjunction in meiosis Ⅰ namely disjunction of homologousdisjunction in meiosis Ⅰ, namely disjunction of homologous chromosomes.

– Half of the gametes will be produced abnormally due to the Ⅱdisjunction in meiosis Ⅱ, namely disjunction of sister

chromatids

Meiotic nondisjunction

Nondisjunction in meiosis Ⅰ Nondisjunction in meiosis Ⅱ

Mitotic nondisjunctionThe types of the cell lines in mosaicism and their proportions are related to the time of disjunction in mitosis and viabilities of themmitosis and viabilities of them.

– The earlier disjunction occurs, the moreThe earlier disjunction occurs, the more abnormalities are.

– The later disjunction occurs, the less abnormalities are.

Vi bilit f h di l id i t– Viability of hyperdiploid is stronger; – Viability of hypodiploid is poorer.

46 46

47 45 46 46

46 46 47 4547 47 45 45

47/45 or 47 46/47/45 or 46/47

Nondisjunction in 1st Nondisjunction in 2ndNondisjunction in 1st segmentation

Nondisjunction in 2nd segmentation

Loss of chromosomes

During mitosis, some chromosome cannot move normally to any pole of the cell because of not attaching to microtubules of gthe mitotic spindle or delayed movement resulting in loss or being digestedresulting in loss or being digested.

46

loss

46 45

46 46 45 4546 46 45 45

e.g. 46，XY/45，X