Chromosomal Abnormalities IISDK

October 28, 2013

II- STRUCTURAL CHROMOSOMAL ABNORMALITIES

Theses are group of problems that is caused by the structural abnormalities of the chromosomes.

Structural abnormalities may be Balanced or unbalancedBalanced. Where there is no loss or gain of chromosome materialUn Balanced. An `unbalanced’ abnormality means that an

individual has more or less chromosomal material than usual.(Loss or gain of genetic materail)

Structural abnormalities may occure in Germ cell or Somatic cells. Those that happen in germ line cause difficulties in egg or sperm development and

normal development of a zygote. This can be transferred to next generations

Those happen in Somatic cells can cause Cancer but are not transferred to next generation.

II- STRUCTURAL ABNORMALITIES

1. Translocation 1. Reciprocal transloations

2. Robertsonian Translocation

2. Deletion and microdeletion

3. Duplication

4. Inversion 1. Pericentric inversion

2. Paracentric inversio

5. Insertion

6. Ring chromosome

7. Isochromosome

8. Chromosomal breakage/Instability: (e.g. Fanconi anemia, Bloom syndrome)

Types of Structural Abnormalities

Types of Structural Abnormalities

1. Translocation

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

Translocation are of 2 typesReciprocal translocationsRobertsonian translocations

In a reciprocal translocation, two non-homologous chromosomes break and

exchange fragments.

Individuals carrying such abnormalities still have a balanced complement of

chromosomes and generally have a normal phenotype that is no symptoms.

May have some symptoms and varying degrees of subnormal fertility if break

occur in the area where some important genes are present..

However most of the DNA are Junk DNA do not code for any thing only 5%

DNA is functional Coding DNA. However this person can be a carrier and can transfer problem to next

generation.

a- Reciprocal translocations

From Balanced to unbalanced Translocation

• An unaffected carrier(Parents) of a `balanced’ translocation may have two kinds of offspring's

• Child may have the same `balanced’ chromosomal translocation in their cells as their parent.

• Child may have an unbalanced chromosomal translocation in their cells as compare to their parent

Examples of Reciprocal Abnormalities

• Reciprocal Translocation of Chromosome 9 and 22(Produces Philadelphia Chromosome). This is because that the break occurred at an important gene which is actually an oncogene called “abl” oncogene this leads to CML(Chronic Myeloid Leukemia)

• Reciprocal Translocation between Chromosome 8 and 14 result in overproduction of “myc” oncogene this leads to Burkitts Lymphoma.

It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood.

CML is a clonal bone marrow stem cell disorder in which proliferation of mature granulocytes (neutrophils, eosinophils, and basophils) and their precursors take place.

CML(Chronic Myeloid Leukemia) Philadelphia Chromosome

Epidemiology

• CML occurs in all age groups, but most commonly in the middle-aged and elderly.

• Its annual incidence is 1–2 per 100,000 people, and slightly more men than women are affected.

• CML represents about 15–20% of all cases of adult leukemia in Western populations.

• The only well-described risk factor for CML is exposure to ionizing radiation; for example, increased rates of CML were seen in people exposed to the atomic bombings of Hiroshima and Nagasaki.

Genetic Link

• CML was the first malignancy to be linked to a clear genetic abnormality, the chromosomal translocation known as the Philadelphia chromosome.

• This chromosomal abnormality is so named because it was first discovered and described in 1960 by two scientists from Philadelphia, Pennsylvania.

The Philadelphia chromosome:

T (9:22) translocation.The Ph chromosome is a shortened chromosome 22, which result from Reciprocal translocation between the long arms of chromosomes 9 & 22.The result is a hybrid bcr-abl gene (fusion protein)

with increased tyrosine Kinase actinity and resulting in leukemic transformation.

BCR-ABL Gene

• This exchange brings together two genes: – The BCR (breakpoint cluster region) gene on chromosome

22 and the

– Proto-oncogene ABL (ableson leukemia virus) on chromosome 9.

• The resulting hybrid gene BCR-ABL codes for a fusion protein with tyrosine kinase activity, which activates signal transduction pathways, leading to uncontrolled cell growth.

The clinical manifestations of Chronic Myeloid Leukemia (CML)

The clinical manifestations of Chronic Myeloid Leukemia (CML) are insidious and are often discovered incidentally when an elevated White Blood Cells (WBC) count is revealed by a routine blood count or when an enlarged spleen is revealed during a general physical examination.

Prognosis: Patient usually die within 6 months -- 2 years but may live for 5 years or more

• AGE: CML is a disease of young adults ( ) 20 - 45 years, but may occur at any age.

• Onset: Gradual.

• Course : Spontenous remissions and exacerbations. The disease generally terminates in marrow transformation (AML) or failure associated with fibrosis.

• Prognosis Patient usually die within 6 months --> 2 years but may live for 5 years or more.

CML(Chronic Myeloid Leukemia) Philadelphia Chromosome

Ultimate diagnosis of CML

Ultimately, CML is diagnosed by detecting the Philadelphia chromosome.By routine cytogenetics, By fluorescent in situ hybridization, or by PCR for the bcr-abl fusion gene

Treatment

• Chronic phase CML is treated with inhibitors of tyrosine kinase

• Bone marrow transplantation

• Stem cell transplantation

Burkitt’s Lymphoma

Burkitt's lymphoma (BL) is a tumor which was first described in 1958 by Denis Burkitt, a surgeon working in Africa.

It is a solid tumor of B Lymphocytes which form part of the white cell population in the blood and lymph glands.

It is one form of non-Hodgkin's lymphoma. The type of cell affected in Burkitt's lymphoma is the B lymphocyte which is normally involved in fighting infection by producing antibodies.

* In most (approximately 90%) of the cases of Burkitt's lymphoma, a reciprocal translocation has moved the proto-oncogene c-myc from its normal position on chromosome 8 to a location close to the enhancers of the antibody heavy chain genes on chromosome 14.

 

Burkitt’s Lymphoma

* Here is an actual karyotype of a cell from the tumor of a patient with Burkitt's lymphoma. The long (q) arm of the resulting chromosome 8 is shorter (8q-) than its normal homologue; the long arm of translocated chromosome 14 longer (14q+).

 

Burkitt’s Lymphoma

b- Robertsonian translocations

In Robertsonian translocations two different non homologous

chromosome get stuck together.

This only occur between two acrocentric chromosomes.Robertsonian translocations (centric fusion)is a translocation in which the centromeres of two acrocentric chromosomes fuse to generate one large

metacentric chromosome.

The karyotype of an individual carrying a centric fusion has one

less than the normal diploid number of chromosomes.

Robertsonian translocations

Down Syndrome

Traditional type(95%) that is trisomy 21 an extra 21 chromosome due to non

disjunction.

Robertsonian Translocation Trisomy 21(5%). that is an extra q arm of

chromosome 21 on chromosome 14.

These translocational Down’s cases are heritable: several children in the same

family can have the disease.

The translocation joins the long arms together on one centromere and the

short arms is usually lost. The individual thus has a normal chromosome 14, a

normal chromosome 21, and a translocation chromosome, called t(14;21).

In this case one of the parent may have Robertsonian

Translocation and this is the cause of repeated abortions and

miscarriage(Pregnancy loss).

So a female with a down child and repeated abortions might

have Robertsonian Translocation .

Down Syndrome

Incidence of Down Syndrome Increases with Maternal Age

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A portion of one chromosome is lost during cell

division.

That chromosome is now missing certain genes.

When this chromosome is passed on to offspring the

result is usually lethal due to missing genes.

2. Deletion

Cri Du Chat: A specific Terminal deletion of a small portion of “chromosome 5”

These children have severe mental retardation, a small head with unusual facial features, and a cry that sounds like a distressed cat.

Terminal Deletion/ Cri Du Chat

WAGR syndrome is a rare genetic syndrome in which affected children are predisposed to develop Wilms tumour (a tumour of the kidneys),

Aniridia (absence of the coloured part of the eye, the iris),

Genitourinary anomalies, and mental Retardation. The G is sometimes instead given as "gonadoblastoma,"

since the genitourinary anomalies are tumours of the gonads (testes or ovaries).

The condition results from a deletion on chromosome 11 resulting in the loss of several genes

Aniridia-Wilms Tumor Syndrome

Aniridia-Wilms Tumor Syndrome

• 1 in 50,000,000 births46 chromosomes.XY or XX

• 11 Deletion of upper arm• Symptoms:

• Mentally retarded

• Growth retarded

• Blindness

• Tumors on kidneys

• Short lifespan

Eighteen Q Deletion Syndrome

Distal 18q- is a genetic condition caused by a deletion of genetic material within one of the two copies of chromosome 18. The deletion involves the distal section of 18q and typically extends to the tip of the long arm of chromosome 18.

1 in 10,000,000 births

#18 Deletion of lower arm

Eighteen Q Deletion Syndrome

Mentally retardedHeart diseaseAbnormal hands and feetLarge eyesLarge earsNormal lifespan

maed-05-135.pdf paper2010.pdf

Eighteen Q Deletion Syndrome

Wolf- Hirschhorn Syndrome

Interstitial Deletion

• Prader-Willi and Angelman Syndrome

• Deletion at chromosome 15.

Angelman, Prader-Willi syndromes

• Usually caused by large (megabase+) interstitial deletions of 15q11-q13

• Delete maternal chromosome = AS

• Delete paternal chromosome = PWS

Symptoms of Angelman Syndrome

• Developmental delay

• Functionally severe Speech impairment

• Movement or balance disorder

• Behavioral uniqueness: any combination of frequent laughter/smiling; apparent happy demeanor; easily excitable personality, often with hand flapping movements

• Short attention span

What is Prader-Willi Syndrome

Prader-Willi syndrome is caused by the absence of normally active genetic material on the long arm of chromosome 15. Deletion on the paternal chromosome 15

Prevalence: 1:12,000- 15,000 (both sexes, all races)

Symptoms of Prader-Willi Syndrome

• Poor weight gain in infancy

• Excessive or rapid weight gain between 1 and 6

• Delayed sexual maturity

• Mild to moderate mental retardation

• Obsession with food

Williams Syndrome

• Autosomal dominant disorder

• Occurs in approximately one of every 20,000 births

Genetic Cause

Spontaneous deletion on chromosome band 7q11.23.

Deletion removes more than 20-25 genes that encode

for different functions.

This also involves deletion of elastin gene (ELN).

Most deletions are not detected through standard

karyotyping but rather through fluorescent in situ

hybridization (FISH).

Clinical features of Williams Syndrome?

• Mild to moderate mental retardation

• Short stature compared to family

• Attention deficit (ADD)

• Heart and blood vessel problems

• Hypercalcemia (elevated blood calcium levels)

• Joint stiffness

• Dental abnormalities

• Personality traits include being overly friendly trusting strangers, fear of loud sounds or physical contact, and an affinity for music

Why it is William Syndrome is calledcontiguous gene deletion syndrome.

• Williams syndrome is not solely caused by elastin haploinsufficiency;

• the deletion involves a region that spans more than 25 genes and, hence, is considered a contiguous gene deletion syndrome.

• The cardiovascular findings, part of the connective tissue pathology, and facial dysmorphology are attributed to the elastin gene haploinsufficiency.

Problems associated with WS

• Heart & Blood Vessel Defects– Supravalvular aortic stenosis

– High blood pressure

– Hypertension

– Hypercalcemia

Problems associated with WS

• Vascular & Connective Tissue Deficiency– Gene that encodes for elastin is deleted

• Kidney Defects– Stenosis of the renal arteries

• Hernias– Groin & umbilical hernias are more frequent in WS

patients.

Psychological Effects

• Mental Retardation

• Behavior Characteristics– “Cocktail Party” personality

• Memory loss

• Learning Disabilities

• Neurological Problems

• Auditory & Verbal – Sensitive hearing

– Amazing musical abilities

Hyperacusis (sensitive hearing) 

• Children with Williams syndrome often have more sensitive hearing than other children;

• Certain frequencies or noise levels can be painful an/or startling to the individual. This condition often improves with age.

Diagnosis

• FISH (fluorescent in situ hybridization)– Most common method of testing for WS– Analyzes specialized chromosomes by using

specially prepared elastin probes– The FISH test will show only one copy of the

elastin gene in patients with WS.– Detects deletion of the gene more than 98% of the

time

Treatment

• No actual cure• Support groups,

including the Williams Syndrome Association

• Therapies (music, horseback riding, etc.)

• Special teacher & parent info

www.williams.ngo.hu/ udvozlet/zsofi.jpg

3. Duplications Genes are duplicated if there is more than one copy present

in the haploid genome. Some duplications are “dispersed”, found in very different

locations from each other. Other duplications are “tandem”, found next to each other. Tandem duplications is easy to generate extra copies of the

duplicated genes through the process of unequal crossing over.

Unequal crossing over is a type of gene duplication or deletion event that deletes a sequence in one strand and replaces it with a duplication from its sister chromatid in mitosis or from its homologous chromosome during meiosis.

15q Duplication Syndrome

Chromosome 15q Duplication Syndrome (Dup15q) is a results from duplications of chromosome 15q11-13

These duplications most commonly occur in one of two forms. 1. These include an extra isodicentric 15 chromosome, abbreviated

idic15,

2. or an interstitial duplication 15.

When the extra genetic material comes from the paternal chromosome a child may have normal development. However, when the duplicated material comes from the maternal chromosome, developmental problems are often the result.

Interstitial Duplication 15

People born with the typical 46 chromosomes, but who have a segment of duplicated material within chromosome 15, are said to have an interstitial duplication chromosome 15.

Most often this is the same section (15q11-q13) that makes up the extra chromosome in idic(15).

For this reason, people with interstitial duplications of 15q and those with idic(15) share similar characteristics.

However, people with interstitial duplication 15 tend to have milder symptoms than those with idic(15).

Duplications In Chromosome 15

Small duplications in chromosome 15 cause no symptoms Large duplication (with inversion) causes seizures and

mental retardation

Duplication/ Fragile X Syndrome

If the fragment joins the homologous chromosome, then that region is repeated

Example Fragile X: one of the most common form of mental retardation.

The X chromosome of some people is unusually fragile at one tip - seen "hanging by a thread" under a microscope.

Duplication/ Fragile X Syndrome

Duplication/ Fragile X Syndrome

• Moderate to sever mental retardation

• Speech delay, short attention, hyperactivity

• Poor motor coordination and mouthing objects

• Poor socialization, temper tantrum

• Mood disorder (bipolar), schizophrenia

Duplication/ Fragile X Syndrome

4. Inversion

Types of inversion• Two types

1. Peri-centric. When inversion include the centromere is called peri-centric inversion.

2. Para-centric. When inversion do not include the centromere is

called para-centric inversion.

Peri-centric Inversion of chromosome 16 & Small Partial trisomy of 16q.

• A male infant born with full term pregnancy has• Hypospadiasis

• Ambiguous genitalia

• Poor sucking reflex

• Poor growth

• Microcephaly

• Wide set eyes and depressed nasal bridge.

• This baby father was suffering from Peri-centric inversion of chromosome 16 that leads to his son with double material at 16q causing small partial trisomy.

An insertion (also called an insertion mutation) is the addition of one or more nucleotide base pairs into a DNA sequence.

Insertions can be anywhere & of any in size, from one base to a section of one chromosome inserted into another.

Insertions can be particularly hazardous if they occur in an exon, the amino acid coding region of a gene.

Insertion causes frame shift mutation and usually with the presence of premature stop codon.

This result in abnormal protein.

5. Insertion

5. Insertion

6. Ring chromosome

A ring chromosome is a chromosome whose arms have fused together to form a ring.

Ring chromosomes may form in cells following genetic damage by mutagens like radiation, they may also arise spontaneously during development.

7. Isochromosome

An isochromosome is a chromosome that has lost one of its arms and replaced it with an exact copy of the other arm.

In a Robertsonian translocation fusion occurs at the:

A. Telomeres.

B. Centromeres.

C. Histones.

D. Ends of the long arms.

B. Centromeres.

Dysmorphic features and/or developmental delay 

Fetal / neonatal death, with multiple congenital malformations or dysmorphic features. 

Indeterminate gender or ambiguous genitalia, amenorrhoea, infertility etc. 

Recurrent miscarriages - if a couple have had 3 or more miscarriages - both members of the couple should be tested.

When karyotyping is needed

Known or suspected family history of chromosome abnormality (e.g. Down syndrome or Edwards syndrome), where the karyotype of the affected individual is not known or not available. 

Known familial chromosome rearrangements e.g. Robertsonian or reciprocal translocations. 

Terminated fetus, for confirmation of an abnormal cytogenetic result diagnosed previously. 

Raised maternal/ paternal age. Ultrasound marker(s) indicative of chromosome

abnormality Previous fetus/child with chromosome

abnormality. Parent is known to carry a chromosome

rearrangement. Positive maternal serum or ultrasound screening

for Down syndrome.

Indications for fetal karyotyping

A common example is chromosome analysis of amniotic fluid.

Amniotic fluid is the developing baby’s urine and trophoblastic secretions and therefore contains cells from the baby.

Chromosome analysis can also be performed on blood, skin cells, and other tissues.

How to do Chromosome Analysis

Summary• In each human cell, except the egg and sperm cells, there are 46 paired

chromosomes of varying size

• • One chromosome of each pair is inherited from each parent

• • The autosomes are chromosomes numbered 1-22 (largest to smallest)

• • The two sex chromosomes are called X and Y

• • Egg cells contain 23 chromosomes, made up of 22 autosomes and an X

• • Sperm cells contain 23 chromosomes, made up of 22 autosomes and an X or a Y

• • When the egg and sperm join at conception, the baby will have 46 chromosomes in its cells, just like the parents

• • Changes in the number, size or structure of chromosomes in the cells of an individual may cause a chromosomal condition that affects growth, development and health

• A particular type of chromosomal structural change is called a translocation. There are two different types of translocations:

• Reciprocal translocation - material is exchanged between any of the chromosomes and involves pieces of any size

• Robertsonian translocation - material is exchanged between chromosomes 13, 14, 15, 21 and 22

• Where there does not appear to have been any loss or gain of chromosome material, the translocation is described as balanced

• An unbalanced translocation means that an individual has more or less chromosomal material than usual

Summary

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