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 2 Trisomy 16 15 Trisomy 18 3 Trisomy 21 5 Other Trisomy Monosomy X Triploidy 15 Tetraploidy 5 Other 10 25 20 .

Chromosome abnormalities • Triploidy • Trisomy 16 → rare at birth – lethal → Most common in spontaneous miscarriages → Completely lethal. probably mosaic survive • Trisomy 13 &18 • Trisomy 21 • Klinefelters • 45X . Cause unknown → 95% miscarry → 80% miscarry → 50% miscarry → 1% at conception → 98% miscarry.

.5% HAVE major anomaly • 2 or more major anomalies may represent genetic syndrome or chromosomal abnormalities(10%).When to suspect it…continue • Presence of congenital anomalies – 45% have minor single anomalies – 9% 3 minor anomalies – 1.

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 .

Forms of Chromosomal Non-Disjunction Euploidy Triploidy complete extra set of chromosomes .Down / Tri 13 / Tri 18 / Klinefelter Monosomies Trisomies .92 caused by a failure of the first zygotic division Tetraploidy Aneuploidy gain or loss of a single chromosome failure in meioses (usually) loss of a chromosome – Turner syndrome autosomal monosomies are lethal sex monosomies survive gain of a chromosome .69 caused by fertilization of an egg by more than one sperm or an egg that failed to divide complete extra diploid set of chromosome .

Types of Polyploidy • Triploidy – three sets of chromosomes 23 x 3 = 69 • Tetraploidy – four sets of chromosomes 23 x 4 = 92 .

How does polyploidy arise? Triploidy .lethal .most die within one month Teraploidy .observed in 5% of spontaneous abortions .most result from dispermy . 69XYY .99% die before birth .about 1% of all conceptions are triploid .often due to failure of cytokinesis .69XXX.can have a haploid sperm fertilize a diploid egg . 69XXY.triploidy seen in about 1 in 10.000 live births .

defect is a change in the number of copies of genes present in the genome Mechanisms .mitosis/cytokinesis mismatch .dispermy . .in humans – it is lethal.meiosis/cytokinesis mismatch .it is the duplication of the entire set of chromosomes .does not involve mutation of any gene per se .Polyploidy .Summary .

XYY Syndrome . Trisomy 18 3.Aneuploidy in Humans • When aneuploidy occurs in humans. Trisomy 13 2. Examples include the following: 1. Down Syndrome 3. Turner Syndrome 4. syndromes can result. Klinefelter Syndrome 5.

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 .

• The result is a trisomy or a monosomy.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. .

some gametes receive two of the same type of chromosome (disomy) and another gamete receives no copy (nullisomy).• As a consequence of nondisjunction. • Offspring results from fertilization of a normal gamete with one after nondisjunction will have an abnormal chromosome number or aneuploidy. aneuploidy typically leads to a distinct phenotype. – 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 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 .

18.Aneuploidy • As women age – some chromosomes exhibit non-disjunction in oocytes • • • • 13. 21 associated with age 16 and X only first meiotic division associated with age Most chromosome abnormalities incompatible with life Will miscarry .


or even viruses may cause chromosomes to break. • Chromosomal mutations include inversion. leading to mutations. organic chemicals. translocation. • Radiation. • A change in chromosome structure is a chromosome mutation. . and duplication.Changes in Chromosome Structure • A mutation is a permanent genetic change. deletion.

a chromosomal segment has been transferred from one chromosome to extra copy of a chromosomal segment Translocations .Deletions . Two types Reciprocal translocations Robertsonian translocation Inversions .loss of a chromosomal segment Duplication .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 .

– This chromosome will be missing certain genes. • A deletion occurs when a chromosome fragment lacking a centromere is lost during cell division. • A duplication occurs when a fragment becomes attached as an extra segment to a sister chromatid. .• Breakage of a chromosome can lead to four types of changes in chromosome structure.

• An inversion occurs when a chromosomal fragment reattaches to the original chromosome but in the reverse orientation. others are not. • In translocation. . a chromosomal fragment joins a nonhomologous chromosome. – Some translocations are reciprocal.

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

deficiency .Deletion .

15q11. 13q14 Prader-Willi. 22q11. 5p15 • Wolf-Hirschhorn.2 DiGeorge. 15q11.2 . – microdeletion (FISH) • • • • Retinoblastoma.Deletions • Terminal • Cri du chat.2 Angelman.2. 7q11. 4p36 • Interstitial • Williams.

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


two non-homologous acrocentric chromosomes break at the centromere and long arms fuse.two non-homologous chromosomes exchange information Robertsonian translocation . . Two major types Reciprocal translocation .Translocations Translocation is a exchange of chromosomal segments between two. nonhomologous chromosome. The short arms are often lost.

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

Chromosome Abnormalities: Structural • Chromosome breakage with subsequent reunion in a different configuration Reciprocal translocation .

gene disruption) • reproductive consequences .Chromosome Translocations – Balanced Reciprocal Translocations • no loss or gain of genetic information • position change • no phenotype consequences (position effect.

Reciprocal Translocation . individuals appears normal (no phenotype) .if one of the breaks occurs in a gene .if no genes are broken.individuals are translocation carriers .two non-homologous chromosomes exchange information .gene can be disrupted .can have a phenotype .no gain or loss of genetic information .

embryonic deaths .translocation carriers .unbalanced gametes produce abnormaloffspring.have high risk of producing unbalanced gametes during meiosis because of chromosomal pairings problems -nondysjunction .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 translocation 3:1 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) .

why? .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.

17)(q21.q25.3.2) .Reciprocal Translocation 46.XX.t(2.

involving 2 or more chromosomes .Balanced Reciprocal Translocation: A closer look normal 17 der (2) der (17) normal 2 *der = derivative chromosome that is structurally rearranged.

Reciprocal Translocations: Points to consider • Referring to the previous slide: – What is the modal chromosome number? 46 – Is there a rearrangement present? Yes. – How many derivative chromosomes do you see? Two. a reciprocal translocation. – 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 .

the modal number is reduced from 46 to 45 chromosomes. n = 46 n = 45 With a balanced Robertsonian translocation.Robertsonian Translocation Fusion of two acrocentric chromosome occurs (A) to form a single derivative chromosome (B). .

two short arms of each chromosome are lost Example .Robertsonian Translocation . .occurs most frequently with acrocentric chromosomes (13.22).Down’s syndrome .14. .produce one new large chromosome made from the two long arms of two different chromosomes.21.15.

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? .

der(13q.Robertsonian Translocation 45.XX.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. . – 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. two acrocentric chromosomes have joined at or near the centromere. the acrocentric long arms have joined to form a single derivative chromosome. – How many derivative chromosomes do you see? One.

Robertsonian Translocation: Points to consider (2) • What material has been lost with this rearrangement. there is no phenotype effect. . Since the p arms contain ribosomal genes that are found on the short arms of other acrocentric chromosomes. if any? The acrocentric p arms of chromosomes 13 and 14 have been lost with this rearrangement.

?inheritance Can result in Down syndrome .Robertsonian Translocations Other chromosomal forms of Down syndrome .

Segregation of chromosomes at meoisis in a 1421 translocation carrier .

Robertsonian translocation .

and 2 were male carrier .miscarry • 6 families described – 21 Down children – 12 miscarriages – 4 families female carrier.21:21 fusion • At meiosis cannot form normal gametes – Either disomy or nullisomy • Never give normal offspring Down – Trisomy 21 – Monosomy 21 lethal .

Reciprocal Translocation .Common form of structural rearrangements Robertsonian Translocation vs.

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* .



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

pericentric if it excludes the centromere .Structural Aberrations Balanced rearrangements No visible loss or gain of genetic material: Inversions ( peri.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* .and paracentric) a piece of chromosome flipped around and reinserted if it includes the centromere .

. http://www.htm Pericentri inversion Paracentric Inversion .

Other forms of chromosome abnormalities • deletions • duplications • insertions • rings • isochromosomes WHY?? Deletions 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 .

and translocation . inversion. birth defects and cancer • Chromosome breakage can lead to rearrangements that can produce genetic disorders or cancer – Four types of rearrangement are deletion.8.23 Connection: Alterations of chromosome structure can cause miscarriage. duplication.

> background • increased risk of miscarriage • increased risk of offspring with – mental retardation – congenital anomalies • WHY? .Consequences Of Balanced Structural Rearrangements • Balanced carriers • phenotypic risks .low • reproductive risks .

Chromosome Abnormalities: Structural • Unbalanced Rearrangements – loss or gain or chromosome material – many different types • Isochromosomes • Deletions • Duplications – abnormal phenotype association .

q34.1. XY del (7q) 47. XY t (7. X 47.9) (p21.1 and long arm of chromosome 9 band 34.1) What it means Normal male Normal female Turner syndrome female Klinefelter syndrome male Jacobs syndrome male Male missing part of long arm of chromosome 7 Female with trisomy 21 Male with translocation between short arm of chromosome 7 band 21. XX+21 46.Chromosomal shorthand Abbreviation 46. XX 45. XXY 47.1 . XY 46. XYY 46.

Female with a duplication of short arm of chromosome 5.+21 47. with a no rmal 13 and normal 14 missing.Karyotype nomenclature Table 1. del(4)(p14) 46.+21 / 46. Karyotype Nomenclature Karyotype 46. because it includes the centromere this is a pericentric inversion. A female with one normal X and one ring X chromosome. -13. t(13q. -14.XY 47. Female with one normal X chromosome and and isochromsome of the long arm of the X. Down Syndrome. dup (5p) 45. XY.22)(q23. . Male mosaic for trisomy 21 and normal cells Male with distal deletion of the short arm of chromosome 4 band designated 14. XY. XY 46. Male with a b alanced Robertsonian translocation of chromosome 13 and 14. XX. Male with a balanced reciprocal translocation Female with an i nversion on chromosome 3 from p21 to q13. X. t(11.q13) 46.XX.q22) 46. XX. i(Xq) Description Normal male Female with trisomy 21. inv(3)(p21. X.XX.14q) 46.r(X) 46. XY.

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 .

U/S abn etc • Neoplasia .Clinical Indications for Chromosome Analysis • Problems of early growth and development • Stillbirth/neonatal death • Fertility problems • Family history of chromosome rearrangement • Pregnancy indications – LMA.

Fate of human implanted embryos .

Case 3 • Clinical referral: – complex cyanotic congenital heart defect requiring multiple surgeries – borderline mental retardation – short stature – Turner syndrome? .

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

duplications .Microdeletion Identification: Locus Specific Probes • Unique sequences localized within a chromosome band – microdeletion screen – microduplication screen – identification of chromosome region • structural rearrangements • deletions.

.2q11.XX.Locus Specific Probe: 22q11.?del(22)(q11.2 46.2).

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 – m

Genetic Follow-up:
• Genetic counseling • Parental chromosome studies • Extended family studies for inherited chromosome rearrangement • Prenatal diagnosis options for future pregnancies

Sex Determination

46,XY female

SRY on Xp - XX male