Chromosomal abnormalities

Lecture Summary

• Chromosome rearrangements associated with:– abnormal phenotype (unbalanced) – reproductive consequences

• Abnormalities identified by– metaphase chromosome analysis– molecular cytogenetic techniques

Chromosome abnormalities in humans

• Spermatozoa 10%

• Mature oocytes 25%

• Spontaneous miscarriage 50%

• Live births 0.5-1%

• Most due to maternal meiotic non disjunction

• Strongly related to maternal age

When to suspect it

• Unexplained infertility/ balanced translocation

• Multiple abortion >2

• Prior case of defective baby

Incidence

• The earlier the abortion the more likely to be chromosomal

• 50% of spontanous abortion are chromosomal abnormal

• Mostly triploidy, 45 XO, trisomy 16• 98% of fetus with turner abort• Generally 6/1000 the incidence of

chromosomal abnormalities

Chromosome abnormalities in miscarriages

Incidence %

Trisomy 13 2Trisomy 16 15Trisomy 18 3Trisomy 21 5Other Trisomy 25

Monosomy X 20Triploidy 15Tetraploidy 5Other 10

• Triploidy

• Trisomy 16

• Trisomy 13 &18

• Trisomy 21

• Klinefelters

• 45X

→ rare at birth – lethal

→Most common in spontaneous miscarriages

→Completely lethal. Cause unknown

→95% miscarry

→80% miscarry

→50% miscarry

→1% at conception→98% miscarry, probably mosaic survive

Chromosome abnormalities

When to suspect it…continue

• Presence of congenital anomalies– 45% have minor single anomalies– 9% 3 minor anomalies– 1.5% HAVE major anomaly

• 2 or more major anomalies may represent genetic syndrome or chromosomal abnormalities(10%).

Variations in Chromosomal Number

• Euploidy – the normal number and sets of chromosomes

• Polyploidy – the presence of three or more complete sets of chromosomes

• Aneuploidy – the presence of additional or missing individual chromosomes

EuploidyTriploidy complete extra set of chromosomes - 69 caused by fertilization of an egg by more than one sperm or an egg that failed to divide

Tetraploidy complete extra diploid set of chromosome - 92

caused by a failure of the first zygotic division

Aneuploidy gain or loss of a single chromosomefailure in meioses (usually)

Monosomies loss of a chromosome – Turner syndrome autosomal monosomies are

lethal sex monosomies survive

Trisomies gain of a chromosome - Down / Tri 13 / Tri 18 / Klinefelter

Forms of Chromosomal Non-Disjunction

Types of Polyploidy

• Triploidy – three sets of chromosomes

23 x 3 = 69

• Tetraploidy – four sets of chromosomes

23 x 4 = 92

Triploidy - 69XXX, 69XXY, 69XYY- most result from dispermy- can have a haploid sperm fertilize a diploid egg- about 1% of all conceptions are triploid - 99% die before birth- triploidy seen in about 1 in 10,000 live births- most die within one month

Teraploidy- observed in 5% of spontaneous abortions- often due to failure of cytokinesis - lethal

How does polyploidy arise?

Summary - Polyploidy

- does not involve mutation of any gene per se- it is the duplication of the entire set of chromosomes- defect is a change in the number of copies of genes

present in the genome

Mechanisms- meiosis/cytokinesis mismatch- mitosis/cytokinesis mismatch- dispermy

- in humans – it is lethal.

Aneuploidy in Humans

• When aneuploidy occurs in humans, syndromes can result. Examples include the following:

1. Trisomy 132. Trisomy 183. Down Syndrome3. Turner Syndrome4. Klinefelter Syndrome5. XYY Syndrome

Aneuploidy caused by• Non-disjunction

– failure of homologous chromosomes to separate in anaphase I

– failure of sister chromatids to separate at meiosis II

• Anaphase lag– Chromosomal loss via micronucleus formation

caused by delayed movement of chromosome/chromatid during anaphase

• results in daughter cell deficient of that chromosome or chromatid

Changes in Chromosome Number

• Nondisjunction occurs during meiosis I when the members of a homologous pair both go into the same daughter cell or during meiosis II when the sister chromatids fail to separate and both daughter chromosomes go into the same gamete.

• The result is a trisomy or a monosomy.

• As a consequence of nondisjunction, some gametes receive two of the same type of chromosome (disomy) and another gamete receives no copy (nullisomy).

• Offspring results from fertilization of a normal gamete with one after nondisjunction will have an abnormal chromosome number or aneuploidy.– Trisomic cells have three copies of a particular

chromosome type – Monosomic cells have only one copy of a particular

chromosome type and have 2n - 1 chromosomes.

• If the organism survives, aneuploidy typically leads to a distinct phenotype.

Aneuploidy

Autosomal monosomy is rarely observed in spontaneously aborted fetuses or in live births.

Most autosomal trisomies are also lethal

 

Nondisjunction in meiosis I

Nondisjunction in meiosis II

Aneuploidy

• As women age – some chromosomes exhibit non-disjunction in oocytes

• 13, 18, 21 associated with age• 16 and X only first meiotic division associated with

age • Most chromosome abnormalities incompatible

with life• Will miscarry

Changes in Chromosome Structure

• A mutation is a permanent genetic change.• A change in chromosome structure is a

chromosome mutation.• Radiation, organic chemicals, or even

viruses may cause chromosomes to break, leading to mutations.

• Chromosomal mutations include inversion, translocation, deletion, and duplication.

Deletions - loss of a chromosomal segment

Duplication - an extra copy of a chromosomal segment

Translocations - a chromosomal segment has been transferred from one chromosome to another.

Two types Reciprocal translocationsRobertsonian translocation

Inversions - order of a chromosome segment has been reversed

Single Chromosome Disorders

1.Deletion

• Genetic material is missing

2. Duplication

• Genetic material is present twice

3. Inversion

• Genetic material is “flipped”

Two Chromosome Disorders(Both types are called “translocation”)

Insertion (unreciprocal translocation)

• Genetic material is added from another chromosome

Reciprocal Translocation

• Material is swapped with another chromosome

• Breakage of a chromosome can lead to four types of changes in chromosome structure.

• A deletion occurs when a chromosome fragment lacking a centromere is lost during cell division.– This chromosome will be missing certain

genes.

• A duplication occurs when a fragment becomes attached as an extra segment to a sister chromatid.

• An inversion occurs when a chromosomal fragment reattaches to the original chromosome but in the reverse orientation.

• In translocation, a chromosomal fragment joins a nonhomologous chromosome.– Some translocations are reciprocal, others are

not.

Deletions

• Deletions occur when a single break causes a lost end piece, or two breaks result in a loss in the interior.

• An individual who inherits a normal chromosome from one parent and a chromosome with a deletion from the other parent no longer has a pair of alleles for each trait, and a syndrome can result.

Deletion - deficiency

Deletions

• Terminal• Cri du chat, 5p15• Wolf-Hirschhorn,

4p36

• Interstitial• Williams, 7q11.2,

– microdeletion (FISH)

• Retinoblastoma, 13q14

• Prader-Willi, 15q11.2• Angelman, 15q11.2 • DiGeorge, 22q11.2

Deletions

• Deletions are rare, as are monosomies

• Can be de novo or inherited – due to translocation or inversion in parent

• Would not reproduce

• Duplication results in a chromosome segment being repeated in the same chromosome or in a homologous chromosome, producing extra alleles for a trait.

• An inverted duplication in chromosome 15 causes inv dup 15 syndrome with poor muscle tone, mental retardation, and related symptoms.

Translocations 

Translocation is a exchange of chromosomal segments between two, nonhomologous chromosome.

Two major types

Reciprocal translocation - two non-homologous chromosomes exchange information

Robertsonian translocation - two non-homologous acrocentric chromosomes break at the centromere and long arms fuse. The short arms are often lost.

Translocation

• Translocation: a fragment of a chromosome is moved ("trans-located") from one chromosome to another - joins a non-homologous chromosome.

• The balance of genes is still normal (nothing has been gained or lost) but can alter phenotype as it places genes in a new environment.

• Can also cause difficulties in egg or sperm development and normal development of a zygote.

Chromosome Abnormalities: Structural

• Chromosome breakage with subsequent reunion in a different configuration

Reciprocal translocation

Chromosome Translocations

– Balanced Reciprocal Translocations• no loss or gain of genetic information• position change• no phenotype consequences (position effect, gene

disruption)• reproductive consequences

Reciprocal Translocation - two non-homologous chromosomes exchange

information

- if no genes are broken, individuals appears normal (no phenotype)

- no gain or loss of genetic information- individuals are translocation carriers

- if one of the breaks occurs in a gene- gene can be disrupted- can have a phenotype

translocation carriers

- have high risk of producing unbalanced gametes during meiosis because of chromosomal pairings problems

-nondysjunction

- unbalanced gametes produce abnormaloffspring, embryonic deaths

- What might you suspect in a family observed to have offspring with multiple birth defects and many spontaneous abortion?

- may be a translocation carrier

Reciprocal Translocations 

Reciprocal translocation

• 2:2 segregation– Two chromosomes per gamete– Could produce normal, balanced or unbalanced

gametes

• 3:1 segregation– Three chromosomes to 1 gamete– One chromosome to other gamete– All will be unbalanced

Reciprocal translocation

2:2 segregation• Pachytene

quadrivalent

• Alternate

gives normal or balanced gametes

Reciprocal translocation

2:2 segregation• Adjacent 1 gives unbalanced

• Adjacent 2 gives unbalanced

Reciprocal translocation3:1 segregation

• Pachytene quadrivalent

• A, C, D together – trisomy for material on C• B alone – monsomy for material on B

"Philadelphia chromosome" Translocation 9:22

• Translocation

Figure 8.23Bx

Spectral Karyotype (SKY) of a breast cancer cell

Paul Edwards (Cambridge)

Reciprocal Translocations: Points to consider

• Look at the karyotype following this slide:– What is the modal chromosome number?– Is there a rearrangement present? – How many derivative chromosomes do you

see?– Is this a balanced karyotype and if so, why?

Reciprocal Translocation

46,XX,t(2;17)(q21.3;q25.2)

Balanced Reciprocal Translocation: A closer look

der (2)

normal 2

normal 17

der (17)

*der = derivative chromosome that is structurally rearranged, involving 2 or more chromosomes

Reciprocal Translocations: Points to consider

• Referring to the previous slide:– What is the modal chromosome number? 46– Is there a rearrangement present? Yes, a reciprocal

translocation. – How many derivative chromosomes do you see?

Two.– Is this a balanced karyotype and if so, why? There

is no apparent cytogenetic loss or gain of chromosome material, just a repositioning effect.

Robertsonian Translocation

• Joining of the long arm of two acrocentric chromosomes to form a single derivative chromosome

• loss of p arm material without phenotype effect

• modal chromosome number 45 in balanced carriers

Robertsonian Translocations

Robertsonian Translocation

n = 46 n = 45

Fusion of two acrocentric chromosome occurs (A) to form a single derivative chromosome (B).

With a balanced Robertsonian translocation, the modal number is reduced from 46 to 45 chromosomes.

Robertsonian Translocation - occurs most frequently with acrocentric chromosomes (13,14,15,21,22).

- produce one new large chromosome made from the two long arms of two different chromosomes.

- two short arms of each chromosome are lost Example - Down’s syndrome

Robertsonian Translocation: Points to consider

• Look at the karyotype following this slide:– What is the modal chromosome number?– Is there a rearrangement present? – How many derivative chromosomes do you see?– Is this a balanced karyotype and if so, why?– What material has been lost with this rearrangement,

if any?

Robertsonian Translocation

45,XX,der(13q;14q)

Robertsonian translocation of chromosomes 13 and 14

Robertsonian Translocation: Points to consider (1)

• Referring to the previous slide: – What is the modal chromosome number? 45– Is there a rearrangement present? Yes, two

acrocentric chromosomes have joined at or near the centromere.

– How many derivative chromosomes do you see? One, the acrocentric long arms have joined to form a single derivative chromosome.

– Is this a balanced karyotype and if so, why? Yes, There is no loss of clinically relevant euchromatin with the formation of a single derivative chromosome.

Robertsonian Translocation: Points to consider (2)

• What material has been lost with this rearrangement, if any? The acrocentric p arms of chromosomes 13 and 14 have been lost with this rearrangement. Since the p arms contain ribosomal genes that are found on the short arms of other acrocentric chromosomes, there is no phenotype effect.

Robertsonian Translocations

Other chromosomal forms of Down syndrome - ?inheritance

Can result in Down syndrome

Segregation of chromosomes at meoisis in a 14-21 translocation carrier

Robertsonian translocation

21:21 fusion

• At meiosis cannot form normal gametes– Either disomy or nullisomy

• Never give normal offspring– Trisomy 21 Down– Monosomy 21 lethal - miscarry

• 6 families described– 21 Down children– 12 miscarriages– 4 families female carrier, and 2 were male carrier

Robertsonian Translocation Reciprocal Translocationvs.

Common form of structural rearrangements

Reciprocal vs Robertsonian:

• Reciprocal -> 2 derivative chromosomes, 46 chromosomes total

• Robertsonian -> 1 derivative chromosome • 45 = balanced• 46 = unbalanced

Either may or may not be inherited*

Inversion

• Inversion involves a segment of a chromosome being turned 180 degrees; the reverse sequence of alleles can alter gene activity.

• Crossing-over between inverted and normal chromosomes can cause recombinant chromosomes due to the inverted chromosome needing to form a loop to align.

Inversion

Inversion of Chromosome 16

Structural Aberrations Balanced rearrangements No visible loss or gain of genetic material:

Inversions ( peri- and paracentric)

a piece of chromosome flipped around and reinsertedif it includes the centromere - pericentricif it excludes the centromere - paracentric

These have slightly different genetic consequences as a result of meiotic pairing

Can result in abnormal pregnancies and SAB

May or may not be inherited*

Inversions

Pericentriinversion

ParacentricInversion

http://www.tokyo-med.ac.jp/genet/cai-e.htm

Other forms of

chromosome abnormalities

• deletions• duplications

• insertions• rings

• isochromosomes

Deletions

WHY?? part of being human

Ring chromosomes

• Often unstable in mitosis

• Often only find ring in proportion of cells

• Other cells usually monosomic as lack ring

Ring chromosomes

Ring X chromome.

Isochromosomes

Isochromosome

Fragile X

• Chromosome breakage can lead to rearrangements that can produce genetic disorders or cancer– Four types of rearrangement are deletion,

duplication, inversion, and translocation

8.23 Connection: Alterations of chromosome structure can

cause miscarriage, birth defects and cancer

Consequences Of Balanced Structural Rearrangements

• Balanced carriers phenotypic risks - low reproductive risks - > background

• increased risk of miscarriage• increased risk of offspring with

– mental retardation– congenital anomalies

• WHY?

Chromosome Abnormalities: Structural

• Unbalanced Rearrangements– loss or gain or chromosome material– many different types

• Isochromosomes• Deletions• Duplications

– abnormal phenotype association

Chromosomal shorthand

Abbreviation What it means

46, XY Normal male

46, XX Normal female

45, X Turner syndrome female

47, XXY Klinefelter syndrome male

47, XYY Jacobs syndrome male

46, XY del (7q) Male missing part of long arm of chromosome 7

47, XX+21 Female with trisomy 21

46, XY t (7;9) (p21.1;q34.1)

Male with translocation between short arm of chromosome 7 band 21.1 and long arm of chromosome 9 band 34.1

Karyotype nomenclature

Table 1. Karyotype Nomenclature

Karyotype Description46,XY Normal male47, XX,+21 Female with trisomy 21, Down Syndrome.47, XY,+21 / 46, XY Male mosaic for trisomy 21 and normal cells46, XY, del(4)(p14) Male with distal deletion of the short arm of

chromosome 4 band designated 14.46,XX, dup (5p) Female with a duplication of short arm of

chromosome 5.45, XY, -13, -14, t(13q;14q) Male with a b alanced Robertsonian translocation

of chromosome 13 and 14, with a normal 13 andnormal 14 missing.

46, XX, t(11;22)(q23;q22) Male with a balanced reciprocal translocation46,XX, inv(3)(p21;q13) Female with an inversion on chromosome 3 from

p21 to q13; because it includes the centromere thisis a pericentric inversion.

46, X.r(X) A female with one normal X and one ring Xchromosome.

46, X, i(Xq) Female with one normal X chromosome and andisochromsome of the long arm of the X.

Summary: Why do we study human chromosomes?

• Chromosome disorders - major category of genetic disease– Responsible for >100 identifiable syndromes– More common than all mendelian single gene

disorders!– 1% livebirths– 2% pregnancies

Clinical Indications for Chromosome Analysis

• Problems of early growth and development

• Stillbirth/neonatal death

• Fertility problems

• Family history of chromosome rearrangement

• Pregnancy indications – LMA, U/S abn etc

• Neoplasia

Fate of human implanted embryos

Case 3

• Clinical referral:– complex cyanotic congenital heart defect

requiring multiple surgeries– borderline mental retardation– short stature– Turner syndrome?

46,XX,?del(22)(q11.2q11.2)

Microdeletion Identification: Locus Specific Probes

• Unique sequences localized within a chromosome band– microdeletion screen– microduplication screen– identification of

chromosome region• structural rearrangements• deletions, duplications

Locus Specific Probe: 22q11.2

46,XX,?del(22)(q11.2q11.2).

Microdeletion 22q11.2

• Velocardiofacial Clinical Spectrum– cleft palate– cardiac - VSD, Tetralogy of Fallot– typical facies: prominent nose, narrow palpebral

fissures, slightly retruded mandible– learning disabilities– slender hands and digits– minor auricular anomalies– overlap with DiGeorge syndrome– http://www.around.ntl.sympatico.ca/~a815/

chr22.htm

Genetic Follow-up:

• Genetic counseling

• Parental chromosome studies

• Extended family studies for inherited chromosome rearrangement

• Prenatal diagnosis options for future pregnancies

Sex Determination

46,XYfemale

SRY on Xp - XX male