1. Chap 4 Chromosomal abnormalities

2. objectives At the end of the session you should be able to
Describe the common chromosome anomalies such as Down syndrome.
Explain the consequences of chromosome rearrangements such as inversions or translocations.

3. Chromosome Abnormalities: Introduction
An important part of genetic problems
One of the most specific causes for genetic referral
Incidence of chromosome abnormalities (0.5%)
Leading to malformation syndromes, reproductive losses, or infertility

4. Newborn Infants: Chromosomal Abnormalities
Incidence /200
Autosomal trisomies 1/700
>90% of trisomy 13 and 18 are aborted
65-80% of trisomy 21 are aborted
Sex chromosomal abnormalities /500
>95% of 45,X are aborted
Structural abnormalities 1/500
molecule

5. Spontaneous abortions:
Spontaneous Abortions/Stillbirths: Incidence of Chromosomal Abnormalities
Spontaneous abortions:
All %
Before 12 weeks %
12-20 weeks %
Stillbirths %

6. Human Metaphase spread

7. karyotype
Karyotype: array of photographs of chromosomes ordered according to their length and relative position of their centromeres.
Karyotype: trisomy diploid analysis

8. Postmortems malignancy 慢性粒细胞白血病 chronic amniocyte viili

9. Naming of parts telomere p arm à centromere heterochromatin à q arm à

10. Numerical abnormalities
euploidy
The category of chromosome changes which involve the addition or loss of complete sets of chromosomes.
triploidy
The possession of one complete extra set of chromosomes.
Usually caused by polyspermy, the fertilisation of an egg by more than one sperm.
Such embryos will usually spontaneously abort.
tetraploidy
Usually the result of a failure of the first zygotic division. It is also lethal to the embryo.
Any other cell division may also fail to complete properly and in consequence a very small proportion of tetraploid cells can sometimes be found in normal individuals.
Zygote category

11. Triploidy karyotype (69, XXY)

12. endoreduplication

13. Numerical abnormalities
Aneuploidy
The category of chromosome changes which do not involve whole sets. It is usually the consequence of a failure of a single chromosome to complete division.
monosomies
All autosomal monosomies are lethal in very early embryogenesis. They do not even feature in the table of frequencies which follows because they abort too early even to be recognised as a conception.
Down syndrome, trisomy 21
The incidence of trisomy 21 rises sharply with increasing maternal age.
maternal

14. Down syndrome
CVS=②chorionic villus sampling绒膜绒毛取样, a kind of early prenatal diagnosis, doctors take chorionic villus cells from uterus of pregnant woman, then culture them for several days, harvest metaphase chromosomes for
karyotyping an analysis. If the chromosome of DS be found, abortion is suggested. So that, incidence of DS at CVS is about a half of those at birth.

15. Numerical abnormalities
Aneuploidy
Down syndrome, trisomy 21
Most cases arise from nondisjunction in the first meiotic division, the father contributing the extra chromosome in 15% of cases.
A small proportion of cases are mosaic and these probably arise from a non disjunction event in an early zygotic division.
About 4% of cases arise by inheritance of a translocation chromosome from a parent who is a balanced carrier.
The symptoms include characteristic facial dysmorphologies, and an IQ of less than 50. Down syndrome is responsible for about 1/3 of all cases of moderate to severe mental handicap.
Homologous chromosomes, same chromosomes, for example, two number 21 chromosome, one comes from father’ sperm, another comes from mother’s ovum. In meiotic division, homologous chromosomes will synapsis in zygotene of prophase one, which means homologous chromosomes associate with each other. In anaphase one of meiotic division, homologous chromosomes will separate o and move toward two opposite polar of the cell. If nondisjunction happens, will result in one of daughter cell has the extra number 21 chromosome, and that another lacks number 21, if the latter be fertilized , the zygote will can not develop, this means lethal.
In an early zygotic division, mitosis, sister chromosomes separate towards opposite polar of cell in anaphase. If a nondisjunction happens, this will result in mosaic cells.
What’s a balanced carrier? Because no genetic material be increased or decreased obviously, a person with the karyotype looks no clinical symptom

16. Nondisjunction leading to aneuploidy

17. Free Trisomy 21 47, XX, +21

18. Translocation Down Syndrome: 46, XY, der(14;21) (q10;q10), +21
Derivative chromosome abviation

19. Translocation Down Syndrome: 46, XY, der(14;21) (q10;q10), +21

20. Balanced Robertsonian Translocation: 45, XY t (14q;21q)

21. Synapse formation and a Robertsonian translocation chromosome
“Triradial” synapse
An example of meiotic segregation of a Robertsonian translocation. In a few of cases (about 2%-4%). Down syndrome is the result of Robortsonian translocation. In other words, one parents is a Robertsonian tanslocation carrier( possesses a balanced translocation between two acrocentic chromosomes), In this case, may be produce a offspring with an unbalanced chromosomes. The chromosome of Robortsonia translocation of carrier may segregate abnormally in meiotic division. Note that during meiosis, the two normal chromosomes pair with the translocation chromosome in an unusual “ triradial” synapse. There are three different ways that the triradial synapse may be resolved, one “ alternate” segregation, and two different “ adjacent” segregation. Notice that the gametes produced by alternate (balanced) segregation have the normal amount of genetic material and would lead to normal phenotype, when fertilized by a normal gamete. Those gametes produced by either adjacent (unbalanced) segregation have either too much or too little genetic material and after fertilization, would yield an abnormal trisomic and monosomic phenotype, respectively. Only the first three possibilities are viable, whereas monosomy 21, trisomy14, and monosomy 14 rarely survive, in other word, they are lethal. Although the first three conception are compatible with survival, they are not seen in equal frequency. The empirically observed recurrence risk for a Robertsonia translocation mother is 10% to 15%, whereas in the father it is 1% to 2%. This observed frequency is always less than the predicted frequency. Therefore, it is important to always obtain a karyotype on a child with a clinical diagnosis of Down syndrome.
Synapse formation and a Robertsonian translocation chromosome

22. Prenatal FISH: 21 Trisomy
chorionic villus sampling represent

23. DS: Infant
Sloping forehead
Upslanting eyes
Flat nasal bridge
Small nose
Protruding tongue
Small chin
Small ears
Proximated nipples

24. Down Syndrome: DS child Upslant eyes Flat nasal bridge Small nose
Open mouth
Protruding tongue
Small chin
Small ears

25. DS: Adult
Mental handicap
Upslanting eyes
Mid-facial hypoplasia

26. DS Ear
Typical DS small ear
Overfolded helix

27. DS Hand
Transverse palmar crease (simian crease)
Clinodactyly

28. Numerical abnormalities
Aneuploidy
Trisomy 13, Patau syndrome
The incidence is about 1 in 5000 live births.
50% of these babies die within the first month and very few survive beyond the first year. There are multiple dysmorphic features.
Most cases, as in Down's syndrome, involve maternal non-disjunction.
Again, a significant fraction have a parent who is a translocation carrier.
Trisomy 18, Edwards Syndrome
Incidence ~1 in 3000.
Again most babies die in the first year and many within the first month.

29. Trisomy 13 Microcephaly Microphthalmia Cleft lip/palate Short neck
malformation
Microcephaly
Microphthalmia
Cleft lip/palate
Short neck
Polydactyly
Trisomy 13

30. Trisomy 13
Infant with trisomy 13
Scalp defect
Polydactyly

31. Trisomy 13
Karyotype

32. Infant with trisomy 18 Microcephaly Hypertelorism Microphthalmia
Low set, malformed ears
Short sternum
Abnormal finger grasping pattern

33. Trisomy 18 fetus
Arthrogryposis
Distinct finger grasping pattern

34. Trisomy 18
Abnormal finger grasping pattern
Nail hypoplasia

35. Trisomy 18
Rocker-bottom feet

36. Trisomy 18 Karyotype

37. Numerical abnormality
sex chromosome aneuploidies
Because of X inactivation and because of the paucity of genes on the Y chromosome, aneuploidies involving the sex chromosomes are far more common than those involving autosomes.
Turner syndrome 45,X
The incidence is about 1 in 5000 female births but this is only the tip of the iceberg because 99% of Turner syndrome embryos are spontaneously aborted.
Individuals are very short, they are usually infertile. Characteristic body shape changes include a broad chest with widely spaced nipples ,ovarian dysgenesis , delayed puberty and may include a webbed neck,.
IQ and lifespan are unaffected.
Most common karyotype is 45,X. Clinical findings include proportionate short
stature, ovarian dysgenesis and delayed puberty, and characteristic
malformations. These include a “webbed” neck, prominent ears, mild
downslanting of the palpebral fissures, and a broad chest. Lymphedema is
common at birth; many of the physical findings are thought to be related to
lymphedema in fetal life and its sequelae. About 20% have congenital heart
disease, with coarctation of the aorta being most common.
Mosaicism is common (30-40% of patients).
Common in spontaneous abortions (15-20% of chromosomally abnormal
abortuses have 45,X karyotype). It is estimated that 99% of affected fetuses are
lost prenatally. Incidence at livebirth is 1/2500-1/4000 females. Most are
caused by a meiotic error in spermatogenesis.

38. Turner Syndrome Short neck Webbed neck Low posterior hair line
Abnormal ears

39. Turner Syndrome: Fetus
Severe cystic hygroma

40. Turner Syndrome Short neck Webbed neck Low posterior hair line
Short stature
Short neck

41. Turner Syndrome: Chest
Shield-like chest
Increased inter-nipple distance

42. Turner Syndrome
Lymph edema
Nail hypoplasia

43. Turner Syndrome: Karyotype (45,X)

44. Numerical abnormality
Kleinfelter’s syndrome 47,XXY
The incidence at birth is about 1 in 1000 males.
Testes are small and fail to produce normal levels of testosterone which leads to breast growth (gynecomastia) in about 40% of cases and to poorly developed secondary sexual characteristics.There is no spermatogenesis.
These males are taller and thinner than average and may have a slight reduction in IQ. Many Kleinfelter males lead a normal life.
Very rarely more extreme forms of Kleinfelter's syndrome occur where the patient has 48, XXXY or even 49, XXXXY karyotype. These individuals are generally severely retarded.
Karyotype: 47,XXY. Incidence: about 1/1000 males. Most common finding:
postpubertal testicular failure and infertility. May see “eunuchoid” body habitus,
gynecomastia. Birth defects not common. May have IQ in the normal range,
or may see learning disabilities and mild mental retardation. Severe mental
retardation is rare. Some patients may have social pathology.

45. Klinefelter Syndrome: A Child
Slightly long arms and legs
Otherwise normal phenotype
adolescence

46. Klinefelter syndrome: Gynecomastia
adolescence

47. Klinefelter Syndrome: External Genitalia
Female type distribution of pubic hair
Testicular dysgenesis

48. physical characteristic
gonad development q
physical characteristic
gonad development
Genes Distribution on X Chromosome

49. Structural aberrations
Inversions
In an inversion, a piece of chromosome has been lifted out, turned around and reinserted.
If this includes the centromere then the inversion is termed pericentric.
If it excludes the centromere then it is a paracentric inversion.
About 1 in 1000 individuals carries an inversion. Inversions are balanced structure rearrangements and inversion carriers are usually phenotypically normal, no loss or gain of genetic material. However, carriers are at risk to produce offspring with deletion or duplication and abnormal phenotype. During paring of homologous chromosomes in meiosis, a chromosome with an inversion will from a loop to line up correctly with its homolog. If crossing over occurs within the loop, resultant gametes may have duplication or deletion of chromosome material. Individuals with a pericentric inversion have a 5 per cent to 15 per cent risk of producing a child with an abnormal phenotype. This risk is much less( <1%) for those individuals carrying a paracentric inversion, because most abnormal chromosomes are dicentric or acentric and lead to a nonviable conception.

50. Structural aberrations
Translocations
In a balanced translocation there is no net gain or loss of chromosomal material, two chromosomes have been broken and rejoined in the wrong combination

51. Structural aberrations
Genetic consequence of a reciprocal translocation...
The carrier of a reciprocal translocation is usually phenotypically normal( unless a gene or genes have been disrupted by the translocation). However, carriers have an increased risk for unbalanced gametes and abnormal phenotype in their offspring.
Aneuploid gametes

52. Alternate Adjacent1 Adjacent2 normal balanced unbalanced
“quadriradial” synapse
Alternate
Adjacent1
Adjacent2
An example is shown in the figure, of the meiotic segregation patterns that are possible in the carriers of a balanced, reciprocal translocation. Notice that the two translocation chromosomes form an unusual “ quadriadial” synapse with the normal homolog of chromosomes, here, one is marked blue, another is red. This pattern of synapse may be resolved in one of three ways. Alternate segregation yields one gamete with a normal complement of chromosomes and another gamete containing the pair of reciprocally balanced translocation chromosomes. Each of these gametes should produce an individual with phenotype following fertilization by a normal gamete of the opposite sex. However, either of adjacent segregation pattern yields unbalanced gametes. Each gamete contains a partial trisomy and partial monosomy, and is expected on fertilization to produce an abnormal phenotype or the embryo with the abnormalities is not developed, means lethal.
normal
balanced
unbalanced

53. Robertsonian translocations
Involves the acrocentric chromosomes
Remember the acrocentric chromosomes are 13, 14, 15, 21 and 22.

54. Robertsonian translocations
Fusion of two chromosomes with the loss of the short arms
Carriers of a Robertsonian translocation are usually normal because short arms of acrocentric chromosomes contain redundant copies of ribosomal RNA genes, and no essential genetic material is lost. However, carriers are at risk for producing conceptions with monosomy or trisomy. Look next slide.
第四章%20染色体畸变和染色体病.ppt#15. Numerical abnormalities⒈ ⒉

55. Deletions
Deletions may either be either interstitial or terminal. If big enough to be visible a deletion must be removing many genes and will probably give rise to a severe phenotype
A well known recurrent terminal deletion involves the loss of material at the end of the short arm of chromosome 5. It causes “Cri di Chat” syndrome.

56. Cri du Chat (5p-) A round face Hypertelorism Cat-like cry Miaow Infant
Named for the unusual shrill cry characteristic of affected newborns. Most cases
are “sporadic”, but 10-15% of affected infants are the offspring of a balancedcarrier
parent.
Clinical findings - Newborn period: Microcephaly, rounded face, hypertelorism,
epicanthal folds, flat nasal bridge, downslanting palpebral fissures, single
transverse palmar crease, hypotonia.
Later: Profound mental retardation; survival in childhood is relatively high.
A round face
Hypertelorism
Cat-like cry