Download presentation
1
Chromosomes Dr Pupak Derakhshandeh, PhD
Ass Prof Medical Science of Tehran University
2
What are chromosomes? Chromosomes are the structures that hold our genes Genes are the individual instructions that tell our bodies how to develop and function They govern our physical and medical characteristics, such as hair color, blood type and susceptability to disease. Each chromosome has a p and q arm; p is the shorter arm and q is the longer arm. The arms are separated by a pinched region known as the centromere
4
How many chromosomes do humans have?
The typical number of chromosomes in a human cell is 46 - two pairs of 22 + XX/XY Holding an estimated 30,000 to 35,000 genes. One set of 23 chromosomes is inherited from the biological mother (from the egg), and the other set is inherited from the biological father (from the sperm).
5
study of the chromosomes
with a microscope , then Stainning The chromosomes look like strings with light and dark "bands" A picture, or chromosome map, of all 46 chromosomes is called a karyotype The karyotype : identify chromosome abnormalities: that are evident in either the structure or the number of chromosomes.
6
Study of the chromosomes
The first 22 pairs of chromosomes are called "autosomes" Final pair is called the "sex chromosomes." The sex chromosomes an individual has determines that person's gender; females have two X chromosomes (XX), and males have an X and a Y chromosome (XY)
8
Karyotype 46), Xy)
10
How Chromosome Abnormalities Happen?
Meiosis Mitosis Maternal Age Environment
11
Meiosis
12
Meiosis
14
Chromosome abnormalities
Abnormality of chromosome number or structure: Numerical Abnormalities Structural Abnormalities
15
Numerical Abnormalities
When an individual is missing either a chromosome from a pair (monosomy) or has more than two chromosomes of a pair (trisomy). An example: Down Syndrome, also known as Trisomy 21 (an individual with Down Syndrome has three copies of chromosome 21, rather than two). Turner Syndrome is an example of monosomy the individual is born with only one sex chromosome, an X. Kleinfelter Syndrome is an example of trisomy the individual is born with three sex chromosome, XXY.
16
Trisomy 18, 47 Ch.
17
Trisomy 18, 47 Ch. incidence of about 1 in 3,000
There is a 3:1 preponderance of females to males Thirty percent of affected newborns die within the first month 50% by two months and 90% by one year. severe mental retardation microcephaly overlapping fingers, and rocker bottom feet Neurologically they are hypertonic Other common malformations include congenital heart, kidney, .... abnormalities.
18
Trisomy 18, 47 Ch.
20
Trisomy 13 (XX/XY, 47 Ch) has an incidence of 1 in 5,000
Forty-four percent of affected newborns succumb in the first month of life and 69% by six months Only 18% of the babies born with trisomy 13 survive the first year microcephaly microophthalmia (small eyes) cleft lip or cleft palate polydactyly (extra fingers) congenital heart defects urogenital defects brain malformations severe mental retardation.
21
Turner Syndrome ( 45, X) 45, X
22
Turner Syndrome (45, X)
23
Turner syndrome Only females One X chromosome
Or has two X chromosomes but one is damaged Short stature Delayed growth of the skeleton Sometimes heart abnormalities Usually infertile due to ovarian failure Diagnosis is by blood test (karyotype) 1 out of every 2,500 female live births worldwide Short neck with a webbed appearance
24
Kleinefelter XXY
25
Kleinefelter/47XXY
26
Klinefelter syndrome (47, XXY)
In boys and men 47 chromosomes with XXY sex chromosomes XXY is one of the most common chromosomal abnormalities 1 in 500 male births the most common genetic cause of male infertility Often : undiagnosed : variation in clinical presentation Small testes , insufficient production of testosterone , and infertility
27
Klinefelter syndrome (47, XXY)
Breast enlargement, lack of facial and body hair, a rounded body type , to be overweight , and be taller than their fathers and brothers Learning and/or behavioral problems Testosterone replacement corrects the symptoms of androgen deficiency
28
Fragile X Syndrome 1 in 3,600 males and 1 in 4,000 to 6,000 females with the full mutation worldwide It is estimated that 1 in 250 females and 1 in 700 males are carriers of the premutation. It is second only to Down Syndrome as a cause of mental retardation Fragile X syndrome appears in children of all ethnic, racial and socio-economic backgrounds
29
Fragile X Syndrome most common inherited form of familial mental retardation (CGG)n trinucleotide expansion in the FMR1 gene leading to the typical Martin-Bell phenotype Clinical features vary depending on age and seX Expansion of a (CCG)n repeat in the FMR2 gene corresponds to the FRAXE fragile site which lies distal to FRAXA and is also associated with mental retardation, but it is less frequent and lacks a consistent phenotype
30
Fragile X Syndrome
31
Fragile X Syndrome
32
Down Syndrome (Trisomy 21( Trisomy 13 & 18
33
Down Syndrome (Trisomy 21(
34
Down Syndrome (Trisomy 21(
35
Down syndrom) Trisomy 21, 46)
critical region: A region on the long (q) arm of chromosome 21 Down syndrome causes mental retardation, a characteristic facial appearance, and multiple malformations Associated with a major risk for heart malformations a small but still significant risk of acute leukemia . 3 copies of chromosome number 21
36
incidence of 1 in 660 and is by far the most common chromosomal abnormality
Slight flattening of the face A low bridge of the nose (lower than the usually flat nasal bridge of the normal newborn) An epicanthal fold (a fold of skin over top of the inner corner of the eye, which can also be seen less frequently in normal babies) A ring of tiny harmless white spots around the iris mental retardation
37
Down Syndrome
38
Down Syndrome: Prenatal Risk
The risk of trisomy 21 is directly related to maternal age Patients who will be 35 years or older on their due date should be offered chorionic villus sampling or second-trimester amniocentesis
39
The use of ultrasound to estimate gestational age improves the sensitivity and specificity of maternal serum screening. (Am Fam Physician 2000;62:825-32,837-8.)
40
Etiology and Clinical Manifestations
Trisomy 21 is present in 95 percent of persons with Down syndrome. Mosaicism, a mixture of normal diploid and trisomy 21 cells, occurs in 2 percent.
41
Etiology and Clinical Manifestations
The remaining 3 percent have a Robertsonian translocation in which all or part of an extra chromosome 21 is fused with another chromosome.
42
Robertsonian translocation
The reciprocal transfer of the long arms of two of the acrocentric chromosomes: 13, 14, 15, 21 or 22 On rare occasions, other non-acrocentric chromosomes undergo Robertsonian translocation
43
Robertsonian translocation
a reciprocal transfer of the whole long or short arms close to the centromere A relatively common Robertsonian translocation is between chromosome 14 and chromosome 21 In meiosis, a trivalent is formed.
44
Frequency of Dysmorphic Signs in Neonates with Trisomy 21
Dysmorphic sign Frequency (%) Flat facial profile Poor Moro reflex Hypotonia Hyperflexibility of large joints Loose skin on back of neck Slanted palpebral fissures 80
45
Frequency of Dysmorphic Signs in Neonates with Trisomy 21
Dysmorphic sign Frequency (%) Dysmorphic pelvis on radiograph 70 Small round ears Hypoplasia of small finger 60
46
Persons with Down syndrome usually have mild to moderate mental retardation
School-aged children with Down syndrome often have difficulty with language, communication Adults with Down syndrome have a high prevalence of early Alzheimer's disease
47
Adult Down Syndrome
48
Incidence of Some Associated Medical Complications in Persons with Down Syndrome Disorder Incidence (%) Mental retardation >95 Growth retardation >95 Early Alzheimer's disease % by age 60 Congenital heart defects (atrioventricular canal defect, ventricular septal defect, atrial septal defect
49
Disorder Incidence (%)
Hearing loss to 75 Ophthalmic disorders (congenital cataracts, glaucoma( Epilepsy to 10 Gastrointestinal malformations (duodenal atresia, Hirschsprung disease) 5 Hypothyroidism Leukemia
50
Disorder Incidence (%)
Increased susceptibility to infection (pneumonia, otitis media, sinusitis, pharyngitis( 1-6 Infertility >99% in men anovulation in % of women
51
Estimated risk of Down syndrome according to maternal age
. . . Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â FIGURE 1. Estimated risk of Down syndrome according to maternal age. Data from reference 8. Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â FIGURE 1. Estimated risk of Down syndrome according to maternal age. Data from reference 8. Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â Â FIGURE 1. Estimated risk of Down syndrome according to maternal age. Data from reference 8. Estimated risk of Down syndrome according to maternal age Maternal Serum Screening Maternal Serum Screening Maternal Serum Screening
52
The risk of having a child with Down syndrome
1/1,300 for a 25-year-old woman; at age 35, the risk increases to 1/365 At age 45, the risk of a having a child with Down syndrome increases to 1/30
53
Maternal Serum Screening
If all pregnant women 35 years or older chose to have amniocentesis about 30 percent of trisomy 21 pregnancies would be detected Women younger than 35 years give birth to about 70 percent of infants with Down syndrome
54
The risk of having a child with Down syndrome
Maternal serum screening (multiple-marker screening) can allow the detection of trisomy 21 pregnancies in women in this younger age group.
55
Maternal Serum Screening "triple test" or "triple screen" "Multiples of the Median (MoM)"
Alpha-fetoprotein (AFP) unconjugated estriol human chorionic gonadotropin (hCG)
56
"Multiples of the Median (MoM)"
AFP is produced in the yolk sac and fetal liver. Unconjugated estriol and hCG are produced by the placenta. The maternal serum levels of each of these proteins and of steroid hormones vary with the gestational age of the pregnancy.
57
"Multiples of the Median (MoM)"
With trisomy 21, second-trimester maternal serum levels of AFP and unconjugated estriol are about 25 percent lower than normal levels maternal serum hCG is approximately two times higher than the normal hCG level
58
Maternal Serum Screening "triple test" or "triple screen"
The triple test can detect approximately 60 percent of the pregnancies affected by trisomy 21, with a false-positive rate of about 5 percent.
59
Recurrence Risk and Family History
If a patient has had a trisomy 21 pregnancy in the past, the risk of recurrence in a subsequent pregnancy increases to approximately 1-3 percent above the baseline risk determined by maternal age
60
Diagnosis of a chromosome-21 translocation in the fetus or newborn is an indication for karyotype analysis of both parents If both parents have normal karyotypes, the recurrence risk is 1 to 3 percent
61
Ultrasonographic Findings Associated with Fetal Down Syndrome
Chorionic villus sampling 10 to 12 weeks 0.5 to 1.5 % Early amniocentesis 12 to 15 weeks 1.0 to 2.0 % Second-trimester amniocentesis 15 to 20 weeks 0.5 to 1.0 %
62
a woman having amniocentesis
63
Counseling Aspects Women who will be 35 years or older on their due date should be offered chorionic villus sampling or second-trimester amniocentesis. Women younger than 35 years should be offered maternal serum screening at 15 to 18 weeks' gestation.
64
Ultrasound During the first trimester of the majority of pregnancies, it is possible to measure the size of the fluid area at the back of the fetus’s neck, known as the nuchal translucency or NT The increasing size of the NT indicates a greater risk of the fetus having Down’s syndrome.
65
Ultrasound
66
Fluorescent In Situ Hybridisation techniques
67
female fetus with trisomy-21
chromosomes 18 (aqua), X (green), and Y (red). chromosomes 13 (green), and 21 (red)
68
Quantitative fluorescent polymerase chain reaction
2:1 ratio (Down's Syndrome) 1:1 ratio (normal fetus)
69
Chromosome abnormalities
Abnormality of chromosome number or structure: Numerical Abnormalities Structural Abnormalities
70
Structural Abnormalities
Deletions: A portion of the chromosome is missing or deleted (>5 Mb). Paraderwilli Syndrome (Ch 15) Angleman Syndrome (Ch 15) Imprinting effect
71
Deletion refers to the loss of a segment of a chromosome
DELETIONS Deletion refers to the loss of a segment of a chromosome This can be terminal (close to the end of the chromosome on the long arm or the short arm) or it can be interstitial (within) ig.DGS II
72
DELETIONS
73
Structural Abnormalities
Duplications: A portion of the chromosome is duplicated, resulting in extra genetic material. Oncogenes (c-onc, c-fos, c-myc)
74
DUPLICATIONS refers to an extra chromosomal segment within the same homologous chromosome or an extra chromosomal segment on another nonhomologous chromosome. Again, the clinical findings are highly variable depending upon the chromosomal segments involved. Gene expantion: in Huntington Disease/ Fragile X, ….
75
DUPLICATIONS
76
Structural Abnormalities
Translocations: When a portion of one chromosome is transferred to another chromosome.
77
There are two main types of translocations.
In a reciprocal translocation, segments from two different chromosomes have been exchanged. In a Robertsonian translocation, an entire chromosome has attached to another at the centromere.
78
TRANSLOCATIONS
79
Balanced reciprocal translocation
81
Robertsonian translocation
The reciprocal transfer of the long arms of two of the acrocentric chromosomes: 13, 14, 15, 21 or 22 On rare occasions, other non-acrocentric chromosomes undergo Robertsonian translocation a reciprocal transfer of the whole long or short arms close to the centromere A relatively common Robertsonian translocation is between chromosome 14 and chromosome 21 In meiosis, a trivalent is formed.
82
Robertsonian translocation
85
Structural Abnormalities
Inversions: A portion of the chromosome has broken off, turned upside down and reattached, therefore the genetic material is inverted. eg Ch9 inv in Iran
86
involve only one chromosome
Inversions involve only one chromosome the intervening segment is rejoined in an inverted or opposite manner. Since there is no loss nor gain of chromosomal material, inversion carriers are normal Paracentric: does not include the centromere pericentric:inverted segment contains the centromere In meiosis, the normal chromosome and the inverted chromosome will form a loop to allow pairing of specific DNA sequences that occur within the inversion loop result in gametes with both deletions and duplications inversion carriers have a relatively low risk of having abnormal offspring.
87
Inversions
89
Rings: A portion of a chromosome has broken off and formed a circle or ring. This can happen with or without loss of genetic material.
90
Ring
91
Oncology Chronic Myelogenous Leukemia (CML)
a clonal expansion of transformed hematopoietic progenitor cells: Myeloid Monocytic Erythroid Megakaryocytic lymphoid lineages
92
Hematology Bone marrow
93
Chronic myelogenous leukemia (CML)
15% to 20% of leukemias in adults incidence of 1 to 2 cases per 100,000 population
94
Chronic myelogenous leukemia
occurs more frequently in males than in females (ratio of 1.3 to 1) Incidence: increases with age the median age at presentation is between 45 and 55 years Up to 30% of patients with CML are 60 years or older which is an important consideration for the selection of therapeutic strategies stem-cell transplantation treatment with interferon-alfa (Intron A, Roferon-A)
96
The Philadelphia Chromosome
a reciprocal translocation between the long arms of chromosome 9 and chromosome 22 the large segment of the c-abl gene from chromosome 9q34 to the part of the bcr gene on chromosome 22q11 in a head-to-tail fashion creating a hybrid bcr-abl gene that is transcribed into a chimeric bcr-abl mRNA
99
Role of the bcr-abl Fusion Gene in CML Pathogenesis
Ch 9: c-abl gene :a proto-oncogene Encodes: a nonreceptor tyrosine kinase with a molecular mass of 145 kd (p145c-abl) It is localized in both cytoplasm and nucleus It consists of 11 exons 230 kilobases (kb)
100
Role of the bcr-abl Fusion Gene in CML Pathogenesis
c-abl gene : Exon 1 has two alternative forms 1a and 1b In most cases, the breakpoint : within the segment between exons 1a and 1b creating a bcr-abl fusion mRNA of 8.5 kb The fusion mRNAs are translated into a 210-kd chimeric protein called p210bcr-abl
101
Detection of bcr-abl Cytogenetic analysis
Ph chromosome in 90% of patients with CML Such analysis is tedious and time-consuming allows the examination of only 20 to 25 metaphases per bone marrow sample misses the 5% of patients who are Ph-negative but bcr-abl-positive
102
Molecular tools important for detecting the molecular abnormalities associated with Ph for monitoring the course of disease during treatment These include polymerase chain reaction (PCR)
103
RT-PCR Quantitative reverse transcriptase–polymerase chain reaction
following patients with CML after stem-cell transplantation Its use for monitoring patients receiving interferon-alpha
104
FISH Fluorescence in situ hybridization
allows for the analysis of metaphase and nondividing interphase cells Results of FISH studies are easily quantifiable
105
fluorescence in situ hybridization (FISH)
106
fluorescence in situ hybridization (FISH)
107
FISH Bcr Abl Abl-Bcr
108
Abl-Bcr
Similar presentations
© 2025 SlidePlayer.com. Inc.
All rights reserved.