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- 18

- Rawan Almujaibel

- Talal Al-Zabin

- Dr. Belal

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In the last lecture we started talking about human disorders due to

alteration. These alterations are divided into 3 main groups:

1-Structural abnormalities.

2-Autosomal Aneuploidy.

3-Sex chromosomal Aneuploidy.

In this sheet will be continue talking about the clinical cases in each

group of chromosomal alterations.

LET'S GET STARTED!!

The Dr. started his lecture with a quick revision of Down syndrome and

he added some extra information that will be included below in this

sheet.

Down syndrome: Non-disjunction of chromosomes 21, this disjunction

happened in meiosis 1 or it can be happened in meiosis 2.

Non-disjunction happens:

-During egg formation (94% maternally).

-During spermatogenesis (5% paternally).

The Dr. asked question; how I could know the non-disjunction if it's

caused of maternal or paternal (the extra chromosome does it came

from the mother or the father?).

Answer:

The Chromosomes are consisting of DNA and proteins. DNA has many

regions. Some of them have genes and the others are not having any

genes (non coding regions). These two regions are about 2% of the

whole DNA (coding +non-coding).

[The DR. mentioned that about 30% of human DNA is the same as viral

DNA such as same nucleotides sequences. He justifies that by saying

some regions in DNA during evolution have integration sites from

viruses.]

Also, there is another region of DNA in chromosomes, which has tetra or

hexa nucleotides that are repeated several times on that specific region

on the chromosome. These numbers of repeats are different from

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person to person. So I can differentiate between people by these

repeats. They are considered as a maker for each person.

Coming back to our question above; in the picture below it represents

mother’s chromosomes with the fathers and their child’s who has Down

syndrome.

The circle refers to the mother and the square refers to the father and

the other circle beneath them refers to a baby girl, beside each symbol

their chromosomes. We are going to take a specific region from

chromosome 21 to know the extra chromosome 21 is paternal or

maternal. Let’s say, we will look at region A in chromosome 21 in both

parents. So in the father, the repeat in that region A is (A= 3, 4. which

means that the hexa or tetra nucleotides is repeated 3 times in the first

paternal chromosome and 4 times in the second paternal chromosome)

and the mother (A= 1, 2. Here the nucleotides are repeated once at the

first maternal chromosome and twice at the second maternal

chromosome). If we look to the same region in the child who has 3

chromosomes (A=1, 2, 3) we will notice that 2 repeats were from the

mother and 1 repeat was from the father. This is because the father has

4 repeats of A, which is not present in the child.

Notice that probe B is not informative here, because both the mother

and the father have one repeat of it.

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The Dr. said I might give you another example with different

representation by polymorphic Markers; we should be familiar with it.

Another way:

A proband is defined as an individual that brings the family to clinical

attention. In other words, the person who auto-connect with the

clinician. Sometimes it is not necessary to be the patient. (It’s important

to know that)

We are looking at the signals, there is a tetra repeat (4 nucleotides

repeated several times). The region we are investigating in chromosome

21 is called (D21S1432) – we can look into more than one region -.

The proband has 3 signals (143, 144 & 145), the father has 2 signals

(141& 145) and the mother has 2 signals (143, 144).

So if we compare the results we will find that 2 signals are same as the

mother and 1 signal is the same as the father. So we know that the extra

chromosome is maternal.

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Here is another way with gel electrophoresis, refer to the picture

below:

"Revision: as we know from the previous lectures that DNA is negatively

charged, so when we expose DNA with electrical current immediately it

will migrate to positive charge (anode). Also, the bigger size DNA

fragments will move slower than smaller one. That is what basically the

electrophoresis does to DNA".

P = Proband, F= Father, M= Mother, S= siblings.

There are 3 arrows in the left; each of them refers to a double band (In

other words: the proband has 3 chromosomes). So the 1st & 2nd arrows

from the top are showing bands that are from the mother and the last

arrow is from the father. So again, the extra chromosome is maternal. As

the sibling’s have only two bands, they’re normal.

Partial trisomy (21q):

There is a rare case of dawn syndrome called Partial down syndrome

(21q). It is very confusing when we diagnosis it by karyotyping because

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the patient has 46 chromosomes instead of 47 chromosomes despite

that the clinical picture of him is clearly down syndrome.

How patients get this type of disease (partial Down syndrome)?

Do you remember in the previous lecture when we said that

chromosome 21 is one of the 5 acrocentric chromosomes (13, 14, 15, 21,

22). Those chromosomes, as we said before, have P arms without clinical

consequences if not present.

Look at the picture, the 1st chromosome 21 on the left is normal, as it

has a p & q arms separated by centromere. However, the other one has

an q arm on the top instead of p arm and after the centromere there is

another q arm ( 2 q arms on one chromosome). That change causes the

partial trisomy Down syndrome. Also, it is differentiated from the

normal trisomy as there are 46 chromosomes but with 3 q arms in

chromosome21.

Note that in both the normal trisomy and partial trisomy, there’re both 3

q arms.

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Trisomy 18 (Edward Syndrome), kayrotyping (47, XY,

+18):

It is the 2nd most common viable trisomy after Down syndrome, has

extra chromosome in 18 chromosomes.

Clinical features:

-95% of cases have congenital heart disease (CHD).

-Failure to thrive (FTT): means their development is slower than their

actual ages (very small sizes compared to their ages).

-Growth retardation and mental retardation.

-Hypertonic.

-They have unusual hand position (clenched fist).

-Prominent occiput (their occipital bone very big).

-dr. added their own clinical notice that they usually have lower set ears

(near mandible bone).

-The sternum is smaller and shorter.

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-They have problems with intestine.

-they have rocker bottom feet.

Trisomy 13, Patau syndrome, kayrotyping (47, XX, +13):

It's 3rd (the last) viable trisomy (autosomal trisomy).

Clinical features:

-85% has CHD.

-Mental retardation.

-Microcephali (the size of the head very small comparable to their age,

their size is deviated out of the normal head size range).

-Scalp defect.

-Small eyes.

-Low set and malformed ears.

-Cleft lip and/or palate (they are facial and oral malformations, also

physical split or separation of the two sides of the upper lip and appears as

a narrow opening or gap in the skin of the upper lip. This separation often

extends beyond the base of the nose and includes the bones of the upper

jaw and/or upper gum.) –We took that with Dr. Heba in details!

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-Polydactyly and syndactyly (polydactyle is an extra digit in the hands or

feet, while syndactyle means fused digits together)

-Polycystic kidney disease.

-Rocker bottom feet.

These are cases of viable numerical abnormalities (autosomal) that have

been mentioned by the Dr. that have trisomy chromosomal

abnormalities. Also, Dr. mentioned that there is no viable monosomy

case.

Now we will move to sex chromosomes:

Sex chromosome:

Let's have a look on some numbers, look at the red box in the picture

below.

-Every 1000 of male newborn will have one case that has extra X or Y

chromosome. It will be either 47, XXY or 47, XYY.

-Every 5000 of female newborn will have one case that has a missing X

chromosome, 45, X0.

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-Every 1000 female newborn will have one has extra X chromosome, 47,

XXX.

Now have a look on the sex chromosome; refer to the picture below.

On the left, we will notice that the Y chromosome is smaller than X

chromosome. So as a matter of fact either Y compares to X is small, that

means most regions in the X chromosome does not have homologues in

Y chromosome.

At the moment we will be focusing on Y chromosome first:

Y chromosome is very small; if you notice the picture on the right, the

lower part has gray colour, which is considered as heterochromatin. No

RNA is made from it so it is non-coding. Also, there is a specific region at

P arm called "SRY". The point is that in the embryonic development, we

will get developed by default to female (specifically because of this

region-SRY), unless if there is a Y chromosome, it becomes a male.

Another region in the chromosome is called "AZF a, b, or c". These 3

regions play an important role in fertility (either he has sperms, or small

amount of sperms or he does not have any sperms). So if a male has a

problem with fertility, it could be related to these regions. Moreover, Y

chromosome has 70-200 genes compared to X, which has 900-1600.

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Dr. Mentioned that some of the genes in the sex chromosomes have

nothing to do with sex at all, for example:

- DMD (distal Muscular dystrophy), is weakness in the muscle when

mutation is happened in one of the genes in sex chromosome (

ي العضالت .(ضمور ف

- Hemophilia is a hematological disease, which has nothing to do

with sex.

- Color blindness as well has nothing to do with sex chromosome.

Some clinical cases that have abnormal sex chromosome:

Kleinfelter's syndrome (or klinefleters), kayrotyping (47, XXY):

Of course it’s a male; in the kayrotyping their chromosomes are longer

than usual.

Clinical features:

-the primary sexual organs are underdeveloped

-Small testes

-They are infertile (absent of the sperms)

- The secondary sexual organs such as the breasts are developed more

than normal (look like female breast)

-Scars body hair distribution (no facial hair)

-Osteoporosis

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-Fat distribution around the hips and thighs which usually seen in

females.

-They are very tall and have huge bodies.

Turner syndrome:

It is the only known viable monosomy in humans, monosomy X is known

which produces X0 females who are sterile.

In kayrotyping written 45, X (in some books written as 45, X0).

Clinical features:

-Average height is 143 cm (that does not mean that every female with a

height of 143 cm has turner syndrome)

-Wiped neck

-Spots distribution on the whole body

-Under developed secondary sexual organs such as breast development

and wide spaced nipples

-Unusual elbow position (noticed during anatomical position)

-Rudimentary ovaries or gonadal streak

-Big and prominent cletrus

- Constriction of aorta

So, we finished talking about the sex chromosomes abnormalities, now

we will move to structural chromosomal abnormalities.

The first example on structural chromosomal abnormalities is:

Cri Du Chat syndrome:

Cri Du chat means in English (cry of the cat), so if you listen to a baby

who has Cri Du Chat cry, you will not be able to distinguish between the

cat's cry and the baby's cry, (distinguish feature to the syndrome).

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This syndrome has 46 chromosomes but their structure is changed in

chromosome 5. Look at the picture below:

The P arm in chromosome 5 has a deletion which is the main cause of

this classical disease. Numerically speaking there are normal but

structurally there is a deletion (partial deletion).

Symptoms of Cri Du Chat syndrome is mostly those of looks:

-Small heads (microcephaly)

-Unusual round face

-Low nasal bridge

-Folds of the skin over their eyes

-The distance of the eyes is far apart

Other clinical features:

-Heart defect

-Muscle problems (core muscle tone)

-Vision problems and hearing problems

-They have difficulty to talk and walk

-Some have psychological problems (aggressiveness)

-Hyperactivity

-Severe mental retardation

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So who has Cri Du Chat syndrome, usually die before they complete 1

year after birth (around 90%), and the reasons behind this is that they

have problems in the heart and respiration. As a result, they get

Pneumonia, CHD and respiratory distress syndrome. However 10% live

longer due to contemporary medicine that help them in heart defects

and respiratory problems as well.

The end ....

I advise you to go back to the slides as the doctor did not mention some

of the information were in the slide.

Sorry for any mistake ..

"I can accept failure, but I can't accept not trying",

Micheal Jordan