Structural Abnormalities of Chromosomes

Slide 1 · Structural Abnormalities of Chromosomes

Chromosomal mechanisms, cytogenetic nomenclature, and clinicopathologic consequences

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish chromosome number abnormalities from structural rearrangements.

Explain how breakage, loss, fusion, and inversion alter chromosomes.

Interpret core translocation, deletion, ring, and isochromosome notation.

Connect balanced or unbalanced architecture to phenotype and reproductive risk.

Slide 3 · Two categories of cytogenetic disorder

A numerical abnormality changes chromosome complement.

A structural abnormality alters one or more chromosomal segments.

Both may influence survival, development, and clinical phenotype.

Numerical changes

Change in chromosome count

Structural changes

Rearrangement or loss of chromosome segments

Slide 4 · The normal human chromosome complement

Chromosome complements are conventionally stated as 46,XX or 46,XY.

The chromosome count alone does not establish structural normality.

Band-level notation identifies rearranged arms and breakpoints.

46,XX or 46,XY

46,XX,t(2;5)(q31;p14)

The total count can remain unchanged despite rearrangement

Slide 5 · Reading a chromosome: P arm and q arm

P denotes the short arm; Q denotes the long arm.

The centromere is the reference point for numbering regions.

Regions, bands, and sub-bands are numbered outward from it.

P arm

Q arm

P3

P2

P1

Q1

Q2

Q3

Centromere separates short (p) and long (q) arms

Region → band → sub-band

Slide 6 · Interpreting a cytogenetic address

Xp21.2 identifies a specific segment on the X chromosome.

The address gives arm, region, band, then sub-band.

Precise breakpoint descriptions localize structural changes.

P3

P2

P1

Q1

Q2

Q3

X p 2 1 . 2

Chromosome X • short arm • region 2 • band 1 • sub-band 2

Slide 7 · Routine banding has finite resolution

Routine banding requires an alteration of approximately 2–4 Mb to be visible.

A visually normal karyotype cannot exclude smaller structural changes.

Fluorescence in situ hybridization can resolve selected kilobase-scale targets.

Banded karyotype

Large changes (~2–4 Mb) visible in routine banding

Fluorescence in situ hybridization

Selected loci: Changes detectable at kilobase scale

Slide 8 · Genomic test choice depends on the question

Karyotyping demonstrates chromosome counts and large rearrangements.

FISH interrogates selected loci at higher resolution.

Sequencing and emerging methods can identify structural changes not resolved by banding.

Chromosomal count and gross pattern

Locus-specific rearrangement or loss

Higher-resolution sequence-level analysis

Slide 9 · Euploidy and aneuploidy

Copy number is distinct from rearrangement.

Euploid: An exact multiple of the haploid chromosome number (23).

Aneuploid: A complement that is not an exact multiple of 23.

A structural rearrangement may be present with a count of 46.

Slide 10 · Nondisjunction creates abnormal gametes

Failed separation during gametogenesis creates n + 1 and n − 1 gametes.

With a normal gamete, fertilization can yield trisomy or monosomy.

This numerical mechanism provides context for chromosomal disorders.

Failure of chromosome separation

Gamete n + 1

Gamete n − 1

Zygote 2n + 1

Zygote 2n − 1

Slide 11 · Anaphase lag differs from nondisjunction

A homolog or chromatid lags behind during cell division.

It may be excluded from the daughter nucleus.

The result may be one normal cell and one monosomic cell.

One chromatid / homolog lags

Normal complement

Monosomic daughter

Slide 12 · Chromosomal dosage influences viability

Autosomal monosomy generally removes too much genetic information for survival.

Some autosomal trisomies permit live birth but cause major abnormalities.

Sex-chromosome aneuploidies can have variable, compatible-with-life phenotypes.

Autosomal monosomy

Usually incompatible with live birth / embryogenesis

Selected autosomal trisomies

Slide 13 · Mosaicism: Two chromosome complements

A mitotic error after fertilization can create distinct cell populations.

Each population contributes descendants to developing tissues.

Phenotypic expression depends in part on which cells and tissues are affected.

Early postzygotic mitotic error

Cell population A

46,XY

Cell population B

47,XY,+21

Descendants maintain their respective complements

Slide 14 · Sex chromosome mosaicism as an example

45,X/47,XXX is a postzygotic numerical mosaic.

A division error can produce descendants with one or three X chromosomes.

The populations coexist in a single individual.

The distribution of 45,X cells influences Turner-spectrum expression.

Slide 15 · Mosaic trisomy 21 as an example

46,XY/47,XY,+21

Early mitotic error may create a trisomic and a normal cell population.

A monosomic lineage may be nonviable and disappear during development.

Down-syndrome expression varies with the proportion of trisomic cells.

Slide 16 · Timing matters in postzygotic mosaicism

An early event can affect a broader descendant cell population.

The lineage and tissue distribution shape clinical expression.

Somatic chromosome change can also occur later in life.

Loss of Y is described as a common acquired event in older males.

Slide 17 · Structural chromosome abnormalities arise after breakage

Chromosome breaks may be followed by loss of DNA.

Broken segments can also be rejoined in a different configuration.

The type of rearrangement determines gene dosage and genomic architecture.

Intact chromosomal segment

A

B

C

D

E

F

Breakage followed by loss or rearrangement

A

B

D

E

F

Slide 18 · Structural rearrangements: Main families

Rearrangement

Defining structural event

Reciprocal translocation

Exchange between chromosomes

Robertsonian translocation

Centric fusion of acrocentrics

Isochromosome

One arm lost; remaining arm duplicated

Inversion

Reinsertion of an inverted interval

Deletion

Loss of an interval or terminal segment

Ring chromosome

Fusion of broken chromosome ends

Slide 19 · Balanced and unbalanced are not synonyms for benign and harmful

Balanced rearrangement: Usually no or very little net DNA loss.

Unbalanced rearrangement: Missing or extra chromosomal material.

Balanced carriers can still have reproductive risk or breakpoint-related effects.

Rearrangement with no major DNA loss

Loss, duplication, or breakpoint disruption

Slide 20 · Balanced rearrangements can change chromosome morphology

Balanced reciprocal translocations can retain a total count of 46.

A karyotype can disclose rearranged derivative chromosomes.

Chromosome number and chromosome organization must be evaluated separately.

46,XX or 46,XY

46,XX,t(2;5)(q31;p14)

The total count can remain unchanged despite rearrangement

Slide 21 · A structural breakpoint may interrupt a gene

Copy-neutral does not guarantee no biological effect.

Inversions usually preserve DNA copy number.

Exception: A breakpoint interrupts a critical gene.

Phenotype depends on what is disrupted as well as the overall DNA amount.

Slide 22 · Translocation means transfer between chromosomes

A segment from one chromosome becomes attached to another.

Reciprocal exchange is one important form.

The chromosome products can be cytogenetically identifiable.

Before: Two different chromosomes

A1

A2

A3

A4

B1

B2

B3

B4

After: Reciprocal exchange of distal segments

A1

A2

B3

B4

B1

B2

A3

A4

Slide 23 · Reciprocal translocation: Two chromosome breaks

A break occurs in each of two different chromosomes.

The resulting chromosome segments exchange partners.

Two derivative chromosomes may be produced.

Before: Two different chromosomes

A1

A2

A3

A4

B1

B2

B3

B4

After: Reciprocal exchange of distal segments

A1

A2

B3

B4

B1

B2

A3

A4

Slide 24 · Balanced reciprocal translocation preserves most DNA

Exchange typically causes no or very little genetic material loss.

Many carriers are phenotypically normal.

Rearranged chromosome structure still influences meiotic segregation.

Before: Two different chromosomes

A1

A2

A3

A4

B1

B2

B3

B4

After: Reciprocal exchange of distal segments

A1

A2

B3

B4

B1

B2

A3

A4

Slide 25 · Reciprocal translocation notation is structured

46,XX,t(2;5)(q31;p14) describes a balanced exchange.

T(2;5) identifies the participating chromosomes.

Q31 and p14 specify the breakpoint bands on chromosomes 2 and 5.

46,XX or 46,XY

46,XX,t(2;5)(q31;p14)

The total count can remain unchanged despite rearrangement

Slide 26 · Derivative chromosomes are not identical to normal homologs

One rearranged chromosome contains material from chromosome 2 and chromosome 5.

Its reciprocal partner contains the exchanged complementary material.

The two derivatives together may preserve the overall DNA complement.

Before: Two different chromosomes

A1

A2

A3

A4

B1

B2

B3

B4

After: Reciprocal exchange of distal segments

A1

A2

B3

B4

B1

B2

A3

A4

Slide 27 · Meiosis creates risk for unbalanced gametes

A carrier may produce a gamete with a normal chromosome and the wrong derivative.

That gamete may gain some sequences and lack others.

Balanced somatic phenotype therefore does not remove reproductive risk.

Translocation carrier — simplified chromosome products

A1

A2

B3

B4

B1

B2

B3

B4

Unbalanced gamete: Duplicated B material

And missing part of A

Slide 28 · An unbalanced zygote has abnormal gene dosage

Fertilization of an unbalanced gamete produces an unbalanced conceptus.

The missing and duplicated regions alter genetic dosage.

Possible outcomes include pregnancy loss or birth of an affected child.

Translocation carrier — simplified chromosome products

A1

A2

B3

B4

B1

B2

B3

B4

Unbalanced gamete: Duplicated B material

And missing part of A

Slide 29 · Carrier phenotype and offspring risk are different questions

Question

Balanced carrier

Possible unbalanced offspring

Net gene dosage

Usually preserved

Extra and/or missing segments

Typical phenotype

Often clinically normal

May have developmental malformations

Main assessment

Carrier structural karyotype

Specific segmental imbalance

Slide 30 · Robertsonian translocations involve acrocentrics

Applicable human acrocentric chromosomes: 13, 14, 15, 21, and 22.

Breaks occur near their centromeres.

The long arms can become united in a centric fusion.

Acrocentric chromosomes: Relatively short p arms

P

Q

P

Q

Fusion of long arms; Small p-arm product usually lost

Q (chromosome A)

Q (chromosome B)

Slide 31 · Robertsonian translocation: Centric fusion

Long arms from two acrocentric chromosomes form one large product.

A small product containing the short arms is often lost.

The retained fused chromosome contains two q arms.

Acrocentric chromosomes: Relatively short p arms

P

Q

P

Q

Fusion of long arms; Small p-arm product usually lost

Q (chromosome A)

Q (chromosome B)

Slide 32 · Why loss of acrocentric short arms can be tolerated

Some material is genomically redundant.

The small p-arm product can carry redundant sequences.

Examples include genes encoding ribosomal RNA.

Its loss may be compatible with an apparently normal phenotype.

Slide 33 · Balanced Robertsonian carriers: Clinical context

Robertsonian translocations occur in approximately 1 in 1000 apparently normal individuals.

The person may be phenotypically normal despite altered chromosome architecture.

The principal concern is the possible production of abnormal progeny.

Slide 34 · Robertsonian translocation and trisomy 21 risk

Segment dosage in offspring is the clinically important issue.

A translocation involving chromosome 21 can produce gametes with extra 21q material.

A resulting child may have translocation-associated Down syndrome.

Distinguish an affected child from the phenotype of a balanced parental carrier.

Slide 35 · Reciprocal versus Robertsonian translocations

Property

Reciprocal

Robertsonian

Chromosome partners

Two chromosomes

Two acrocentric chromosomes

Main event

Segment exchange

Fusion of two long arms

Material lost

Often little or none

Small p-arm product often lost

Carrier issue

Unbalanced gametes

Unbalanced gametes

Slide 36 · Isochromosomes duplicate one chromosome arm

One chromosome arm is lost.

The remaining arm is duplicated.

The abnormal chromosome contains two copies of the same arm.

A normal chromosome has a p and a q arm

P

Q

Isochromosome: Two copies of the same arm

Q

Q

Slide 37 · Isochromosome structure changes regional dosage

The two arms have the same gene complement.

Sequences on the lost arm are deficient.

Sequences on the duplicated arm are present in excess.

A normal chromosome has a p and a q arm

P

Q

Isochromosome: Two copies of the same arm

Q

Q

Slide 38 · An Xq isochromosome is a characteristic example

I(X)(q10) as the commonest isochromosome seen in live births.

The rearranged X carries two long arms.

Its cytogenetic shorthand specifies an X chromosome and q-arm duplication.

A normal chromosome has a p and a q arm

P

Q

Isochromosome: Two copies of the same arm

Q

Q

Slide 39 · Dosage effect of i(X)(q10)

Loss of the original Xp contributes monosomy of Xp genes.

Duplication of Xq creates a trisomic dosage for Xq genes across the complement.

The phenotype reflects this asymmetric gene dosage.

Rearrangement with no major DNA loss

Loss, duplication, or breakpoint disruption

Slide 40 · Inversion reverses an intrachromosomal segment

Two breaks occur within a single chromosome.

The intervening segment is reinserted in reverse orientation.

No DNA copy-number change is required to form an inversion.

Inversion entirely on one side of the centromere

A

B

C

D

E

F

A

C

B

D

E

F

Two breakpoints in one arm; Centromere not inside inverted segment

Slide 41 · Paracentric inversion excludes the centromere

Both breakpoints lie within one chromosome arm.

The inverted segment does not contain the centromere.

Orientation changes; Total segment dosage may be preserved.

Inversion entirely on one side of the centromere

A

B

C

D

E

F

A

C

B

D

E

F

Two breakpoints in one arm; Centromere not inside inverted segment

Slide 42 · Pericentric inversion includes the centromere

Breakpoints occur on opposite sides of the centromere.

The inverted interval includes the centromere.

The p–q arm configuration is altered by the reversal.

Inversion crosses the centromere

A

B

C

D

E

F

A

D

C

B

E

F

The inverted interval includes the centromere

Slide 43 · Inversions are often compatible with normal development

Many inversions retain the full chromosome complement.

An unaffected phenotype is common when gene function is preserved.

Breakpoints interrupting essential genes are clinically important exceptions.

Rearrangement with no major DNA loss

Loss, duplication, or breakpoint disruption

Slide 44 · Paracentric and pericentric inversion compared

Feature

Paracentric

Pericentric

Break locations

Within one arm

On opposite arms

Centromere within inversion

No

Yes

DNA copy number

Often unchanged

Often unchanged

Major distinction

Position of reversed interval

Centromere included in interval

Slide 45 · Deletion removes chromosomal DNA

A chromosome loses a segment of genetic material.

Interstitial and terminal deletions are two principal types.

Loss of segmental dosage can alter phenotype.

Normal sequence

A

B

C

D

E

F

Interstitial deletion: Loss of internal C–D segment

A

B

E

F

Slide 46 · Interstitial deletion: Two breaks within an arm

Two intrachromosomal breaks delimit an internal interval.

The material between them is lost.

Remaining proximal and distal ends rejoin.

Normal sequence

A

B

C

D

E

F

Interstitial deletion: Loss of internal C–D segment

A

B

E

F

Slide 47 · How to read a cytogenetic deletion

46,XY,del(16)(p11.2p13.1)

46,XY specifies the remaining overall chromosome count and sex complement.

Del(16) identifies the chromosome carrying the deletion.

P11.2 and p13.1 specify the short-arm breakpoint bands.

The chromosomal material between the breakpoints is missing.

Slide 48 · Terminal deletion: Loss from a chromosome end

A break produces a distal, acentric fragment.

The fragment is lost at a subsequent cell division.

The retained chromosome now has an exposed broken end.

Normal chromosome arm

A

B

C

D

E

F

Acentric terminal fragment is lost

A

B

C

D

E–F lost

Slide 49 · Terminal deletions require end protection

Telomeric protection stabilizes a broken chromosome end.

The retained shortened chromosome must acquire protective telomeric sequences.

Without effective end protection, sister chromatids may fuse after replication.

Such fusion may initiate a breakage–fusion–bridge process.

Slide 50 · Breakage–fusion–bridge cycle

Unprotected sister chromatid ends can join to form a dicentric chromosome.

Segregation may produce chromosomal bridging and breakage.

Repeated cycles can perpetuate structural instability.

Telomere not restored

Exposed chromosome end

Sister-chromatid fusion

Dicentric chromosome

Segregation and breakage

Bridge–break cycle

Conceptual breakage–fusion–bridge sequence

Slide 51 · Interstitial versus terminal deletion

Property

Interstitial

Terminal

Typical breaks

Two in one chromosome arm

One within the chromosome arm

Lost material

Internal interval

Distal arm fragment

Broken-end issue

Flanking ends rejoin

New terminal end needs protection

Consequence

Segmental deletion

Deletion with possible end instability

Slide 52 · Deletion consequences depend on the missing interval

Loss can encompass multiple genes and regulatory regions.

The extent and genomic content of the deletion determine the dosage deficit.

Banding may miss deletions below its approximately 2–4 Mb resolution.

Targeted FISH can identify selected smaller deletions.

Slide 53 · Ring chromosomes result from end-to-end fusion

Breaks occur near both chromosome ends.

Terminal fragments are lost.

The broken chromosome ends fuse into a ring structure.

Loss of both terminal fragments

A

B

C

D

E

Broken ends rejoin to form a ring; Schematic

Slide 54 · Ring chromosomes may be clinically consequential

Loss of clinically important terminal DNA can create an abnormal phenotype.

Ring chromosomes may behave abnormally during cell division.

Robbins characterizes their consequences as usually serious.

Loss of both terminal fragments

A

B

C

D

E

Broken ends rejoin to form a ring; Schematic

Slide 55 · Chromosome ring notation

46,XY,r(14) indicates a ring involving chromosome 14.

The chromosome count and sex complement precede the rearrangement.

The r identifies ring formation; Chromosome 14 is in parentheses.

Loss of both terminal fragments

A

B

C

D

E

Broken ends rejoin to form a ring; Schematic

Slide 56 · Structural alterations: Dosage and architecture

Class

Primary architectural effect

Dosage status

Reciprocal translocation

Exchange between chromosomes

Can be balanced

Robertsonian translocation

Fusion of acrocentric long arms

Often balanced in carrier

Isochromosome

Duplication of one arm

Arm-specific imbalance

Inversion

Reversal within chromosome

Often copy-neutral

Deletion

Loss of chromosomal segment

Deficit

Ring chromosome

Fusion of damaged ends

Often terminal loss

Slide 57 · Chromosome notation: Fast recognition

Notation

Interpretation

46,XX,t(2;5)(q31;p14)

Reciprocal translocation involving chromosomes 2 and 5

i(X)(q10)

Isochromosome consisting of X long arms

46,XY,del(16)(p11.2p13.1)

Deletion of the specified interval on 16p

46,XY,r(14)

Ring chromosome 14

Slide 58 · What a conventional karyotype can show

Total chromosome number and sex-chromosome complement.

Large translocations, inversions, deletions, and ring forms.

Chromosome arm and cytoband locations of visible changes.

Not necessarily small, sub-band-scale rearrangements.

Slide 59 · FISH improves locus-specific detection

Fluorescent probes identify specific chromosome sequences.

FISH can detect changes as small as kilobases.

It is particularly useful when the clinically suspected region is known.

Banded karyotype

Large changes (~2–4 Mb) visible in routine banding

Fluorescence in situ hybridization

Selected loci: Changes detectable at kilobase scale

Slide 60 · Sequencing can reveal additional structural change

Molecular resolution complements cytogenetic morphology.

DNA sequencing and newer genomic approaches can identify rearrangements.

Choice of method depends on the genomic question and diagnostic context.

A structurally normal banded karyotype does not establish DNA-level normality.

Slide 61 · Structural chromosome results need two interpretations

Cytogenetic interpretation

Clinical interpretation

What is rearranged?

Is genetic material missing or extra?

Where are the breakpoints?

Could a critical gene be disrupted?

Is the carrier balanced?

What is the potential offspring risk?

What assay resolved the change?

What are the limits of that assay?

Slide 62 · Chromosomal abnormalities are selected against in development

The textbook estimates chromosome abnormalities in approximately 7.5% of conceptions.

Most of those conceptions do not survive to live birth.

An estimated 0.5%–1.0% of live-born infants have chromosomal abnormalities.

These figures cover chromosome disorders broadly, not only structural rearrangements.

Slide 63 · Case: Normal carrier with an abnormal offspring risk

A phenotypically normal adult has 46,XX,t(2;5)(q31;p14).

Why can a balanced carrier have a child with chromosomal imbalance?

Reciprocal translocation changes chromosome structure without necessarily changing total dosage.

Meiotic segregation can transmit one derivative without its complementary partner.

The conceptus may have missing and duplicated chromosome segments.

Slide 64 · Case: Interpret a deleted chromosome segment

A karyotype is reported as 46,XY,del(16)(p11.2p13.1).

Which chromosome and arm are involved, and what is missing?

Chromosome 16 carries the deletion; P specifies the short arm.

The lost interval lies between the reported p-arm breakpoints.

The chromosome count alone does not quantify the lost DNA.

Slide 65 · Case: Distinguish inversion types

Two chromosome breaks occur on opposite sides of a centromere; The interval reinserts in reverse orientation.

What type of inversion is described?

Pericentric inversion.

The inverted segment includes the centromere.

Copy-number neutrality does not exclude breakpoint disruption.

Slide 66 · Case: A chromosome with two identical long arms

A chromosome is identified with two long arms derived from the X chromosome.

Name the structural lesion and predict dosage changes.

I(X)(q10) is the Xq isochromosome.

Genes on Xp are deficient; Genes on Xq are represented in excess.

This is different from a copy-neutral inversion.

Slide 67 · Case: Terminal deletion without telomere restoration

A terminal chromosome break leaves an unprotected end after distal-fragment loss.

What cell-cycle process can sustain chromosome instability?

Sister chromatids can fuse after replication.

The fusion forms a dicentric chromosome.

Segregation and breakage can repeat as a breakage–fusion–bridge cycle.

Slide 68 · Core distinctions for pathology practice

Chromosome architecture and DNA dosage both matter.

Reciprocal and Robertsonian translocations can be balanced in a carrier but reproductive-risk relevant.

Isochromosomes, deletions, and many rings alter regional gene dosage.

Inversions are often copy-neutral but may disrupt critical genes.

Karyotype, FISH, and sequence-level methods address different resolution scales.

Slide 69 · References

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th edition (2026). Chapter 5: Genes and Human Diseases, pp. 145–146.

Structural Abnormalities of Chromosomes: chromosomal breakage, rearrangement, and cytogenetic notation.

Related context in the same chapter: cytogenetic disorders and Trisomy 21, pp. 145–147.