Genetics 5 Voice
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Genetics 5 Voice


Autosomal Aneuploidy is a case,
when the cell doesn’t contain a multiple of 23 chromosomes, and that way, it will
become aneuploid cells, and aneuploidy can occur in any chromosome.
However, only 13,18 and 21st chromosome can be presented in live births, otherwise the
chromosomes aneuploidy will not be in a live birth. For example, trisomy 16,
is quite common. However, unfortunately the baby is not viable, and the birth
isn’t live, and the most common example of Aneuploidy is Down syndrome, and the
frequency is one out of 800 life births. Down syndrome was first described by Langdon Down, who described the disease in 1866. Since then, there is a great body of
research conducted on Down syndrome, and one of the biggest findings we have now,
it’s that, incidence of Down syndrome will vastly increase with maternal age,
for instance, after 45 year old maternal age, that risk can be as high as 5%,
probability of having a baby with Down syndrome is as high as 5%.
The explanation is fairly simple in this case, because a woman is born with all of
her maternal egg cells, which are held in a dormant state, and during the dormant
state, they may accumulate damage from influences from external factor
and the damage occurs in cellular proteins that govern the meiosis, which
at the end, may lead to nondisjunction and non disjunction of course, here may
result in trisomy 21, and down syndrome. What’s the role of paternal age
in all of this, there are great speculations that, paternal age plays a
role in development of Down syndrome, however, there is no steady evidence that
will point on paternal age. The famous Columbia University research conducted
in 2003, collected data from births of infants from 1983 to 1997, approximately
3,400 cases were examined, and it was conducted in New York State, and paternal
age was found that, it also may influence somewhat, the results of having
the baby with Down syndrome. So, when babies born with Down syndrome, there is
a chance of mental retardation and the degree of mental retardation may vary
significantly. Again, the people with Down syndrome may present with significantly
high IQ, and there were cases described in literature that person diagnosed with
Down syndrome was able to enter and complete the college, and be successful
in professional employment. However, over all the patients, or people with Down
syndrome may present with relatively low IQ. So physical features
will include, low nasal bridge, epicanthal folds will be present and protruding
tongue, muscle tone will be poor. Patients with Down syndrome, may present
with increased risk of heart disease, congenital heart disease. It’s important
to screen a baby for congenital heart disease, can have GI disorders, and may
have a higher risk of developing leukemia, and again, because of the
development of the health sciences, nowadays, the management of Down syndrome
and consequences is much more elaborate, and people who are diagnosed with Down
syndrome, or were born with Down syndrome may have much higher quality of life, and
enjoy themselves, compared to several decades ago. Trisomy 13 and 18 or other
trisomies that can be present in live births, but unfortunately, the patients
with trisomy 13 and 18, will present with much more significant and severe
complications, than the person with trisomy 21. The relativity of having more, or the
probability of having more profound deficits is much higher, and the mental
retardation can be present, as well as the physical disorders may be present,
and again, other chromosomal trisomies will not survive to term,
and again, trisomy 16 is the most common one in spontaneous abortions, and it’s
never seen in live births. Partial trisomies also may occur, when extra
portion of chromosome is present in each cell. So, when we have a partial trisomy,
that consequences of it, it’s not as severe as complete trisomy is. Remember,
what we were saying before talking about complete trisomy, is that, most of them do
not result in live births, and the ones that result in live births, the
patients may present with significant disorders, but in this case, when we are
talking about partial trisomy, it’s not as severe as in complete trisomies, and
individuals who are affected with this, are considered chromosomal mosaics- that means
that, the body has several cell lines and by that, we mean that (by cell lines
differences), we mean that, each cell line has a different karyotype, and mosaics of
course, are formed by early mitotic nondisjunction, and which can occur in
one embryo cell, but not in other embryos cells. So again, the take-home message in
here, is that, partial trisomy isn’t as severe, and partial trisomy- it’s only a
portion of chromosome is present in the cell. So there is something left, it’s not
complete trisomy. So again, remember the statement, or the sentence, or that says
that more genetic material is better than less. So missing a chromosome, is
worse case scenario, than having a part of chromosome. Sex chromosome aneuploidy,
is similar to autosomic chromosomal aneuploidy. However, the consequences are
less severe. For example, when we are having an abnormality related to Y chromosome, the
consequences may be relatively insignificant, the explanation is the
small amount of genetic material carried by the Y chromosome, and it’s
approximately for the genes located on it. When we’re having X chromosome aneuploidy,
and they may be more serious consequences. For instance, when
we have no X chromosome, only Y chromosome, chances of survival are non-existent. The zygote obviously,
won’t survive if there is no X chromosome. So, instead of two X
chromosomes, some times, some females may have three x chromosomes, or even four X
chromosomes.There is a term describing this phenomenon. They call
it metafemale. So, what being ‘metafemale’ is means, from the physical standpoint, this may represent no physical abnormalities, obviously visible,
but sometimes, the patient, the female with three chromosomes may
have sterility, menstrual irregularity, abnormal menstrual cycle,
and some mental retardation, but again, being a metafemale it’s not a verdict.
For all of these abnormalities, or all of these disorders, and obviously mental
retardation, it’s not always seen, or I can say that, it’s seen very seldom. On
the other hand, when the number of X chromosome increases, the chances of
developing disorders, especially mental retardation is increasing, and with five
chromosomes, the chances are even higher. So, we can say that the presentation of
the disorders will increase, and will be more severe with each additional X
chromosome. Turner syndrome is a disorder, when there is only one X chromosome
present. So with only one X chromosome, the life and survival is still possible,
but again, without X chromosome, the survival is impossible.
So, when individual who has only 45 chromosomes in turner syndrome, and it’s
only one x chromosome, there is no conjoined or corresponding, I’m sorry
‘conjoined’ is not a correct word here, corresponding X chromosome or Y
chromosome. The gender of the individual will be female obviously, and
but in this case, the lady will be presenting with absence of ovaries and
sterility, the short height and webbing of the neck is one of the characteristic
signs for this, and patients may have some edema, they can have coarctation of the aorta,
newborns will have edema in lower extremities, and you know, when I
said the ovaries are absent, it’s actually gonadal streaks like unformed
ovaries, it’s like undeveloped ovaries, they are not fertile, but still, they
still can be susceptible to neoplasm, still can develop neoplasm, this should
be monitored and should be taken care of, if there is a suspicion for cancer.
Turner syndrome will have relatively high mortality rate presented as
spontaneous abortion, but again, survival rate is relatively high, and the individual will present with all the
symptoms described here. One last thing I want to say, X chromosome will be
inherited from mother, the paternal X chromosome will not be present.
So basically, father in this case, doesn’t donate anything, anymore.
So Turner syndrome is possible with only one X chromosome. Klinefelter’s
syndrome is another sex chromosome aneuploidy and patient may have at least
two X chromosomes and one Y chromosome. So basically, it’s the excess of X
chromosomes, so patient will have male appearance and karyotype can be
described as 47 XXY karyotype, and basically, the patient will have all the
consequences of having excess in X chromosomes. Some of the individuals will
have symptoms of sterility, they will have still testicles , but they won’t be
developed, patient may have gynecomastia, long limbs, and sparse body hair. Some
patients may have 3 X chromosomes, or even 4 X chromosomes, but again, with more
and more X chromosomes, the abnormalities rate will increase. In addition to, losing or gaining a
chromosome, sometimes, parts of chromosome can be lost, or interchanged or duplicated.
When you the sex cells are formed, and the arrangement may be altered, because
of this, although again, there’s small amount of genetic material involved in
this. So the consequences, may not be as serious, as when we are having changes that
involve the entire chromosome, and sometimes, in this case is when we have
this type of disorder, we may not even notice any representation in the patient,
or in the individual, the smaller the part that was involved in the chromosome,
the best chances we have usually of it, being resulting in some kind of disorder.
On the other hand, if abnormalities of the chromosome are present, they can
produce a serious disease in some cases, and also may influence the children and
again, as if it’s some type of sex transfer trait, and it may show up in the
next generation. So, deletion is very simple process to describe it, when
chromosome loses part of the DNA, and and it results in deletion. So, we have a
gamete with deletion, and probability of uniting with a another gamete with
deletion is very low. So, usually the gamete with deletion
unites with a gamete, with a normal gamete. So, one chromosome in this zygote
will be normal, okay? zygote with the normal complement genes, and one
will be with missing gene, because in this case, many genes may be lost in
deletion. We may have big consequences, serious consequences, because we may have
genes that are influencing and governing vital functions and the consequences
again, will be serious. Inversion is another type of alteration in
chromosomal structure, when the rearrangement occurs of the segment of
chromosome, basically that segment flips around, and is reversed end to end. The deletion can result in Cri du chat syndrome.
Translocation can be described, as an exchange of genetic material between
chromosomes, and what happens, the genetic material from one chromosome, a segment
of chromosome is transferred to another and between many types of translocations,
it’s worth to mention Robertsonian translocation. In this case, long arms of
two chromosomes, they would fuse at the centromere, and they will form single
chromosome. Robertsonian translocation can happen in chromosomes 13, 14, 15, 21
and 22 for the reason, because short arms of these chromosomes are very small, tiny
and they really don’t have any essential genetic material. So, when this happens,
when the translocation happens in Robertsonian case, the short arms are lost
completely, during the next cell divisions. So, in Robertsonian
translocation, can happen is that, there is loss of no important genetic material,
and your individual will have only 45 chromosomes in each cell, and they will
present as normal individuals, they won’t present with any disorder, because again,
there is no essential material lost in this case. On the other hand, their
offspring can have monosomies and trisomies.
Common Robertsonian translocation that I want to talk about is, the fusion of
the arms of chromosome 21 and 14, and when the baby is born from someone who
has this, can receive an extra copy of the long arm of chromosome 21, and of
course, when we’re talking about chromosome 21, we are talking about Down
syndrome, and yes! the baby will develop Down syndrome.So, to talk about this more,
Robertsonion translocations, are responsible for quite significant number.
Ringchromosome occurs, when the telomers of each chromosomal arm have been
deleted, and the broken arm joined together, and form a ring. The drastic
consequence of this one is, the ring chromosome can actually trigger series
of breakage and fusion, bridge events, which will cause continuous DNA breakage,
is like a chain reaction and recombination of the chromosomal
material. So, because of these, the ring by itself, it’s not a big danger, but because
of the chain reactions, it can cause problems. The ring, patients with
ring syndrome may display very diverse symptoms, resulting from DNA breakage and
recombination, basically deletions of the chromosomal material will occur,
duplications and the diverse presentation is just very very different,
but they always, they have something in common, and
doesn’t matter how they present, the patients with congenital or in
chromosomes they show failure to thrive, and failure to thrive is a consequence
of the fact that, cells may not proliferate normally, and that will
result in failure to thrive, and there is some school of thought that suggests
that mitotic instability of the ring, will prevent somatic cells. Again to
proliferate normally, basically again, ring by itself, it’s not a big danger, but
the consequences or that happens after formation of the ring that may cause
diverse presentation of the symptoms, and the main thing is that, patients will
present with failure to thrive. Chromosomal breakage occurs again, like
in previously was said, physiological mechanisms trying to repair the break,
but unfortunate part of this, that the break would heal differently than
original chromosome, and again like in ring chromosome case, this may result in
diverse presentation of different abnormalities. However, this may be very
mild, or this can be very drastic, very very unfortunate for the individual
with this. So, what can cause it, and ionizing radiation is notorious for this,
chemicals, viruses, but again, this may affect chromosome in autosomal
structures, and verses sex cells, but regardless of this, this breakage when it happens
in a chromosome, the healing part unfortunately result of distortion of
the structure of the chromosome, and distortion of the DNA, and what I’m
trying to say is that healing isn’t always good, because, it continues to alter the
structure of the chromosome. Duplication is a relatively rare occurrence, in
alterations in chromosomal structure. What happens?
the repeated gene, or gene sequence, I’m sorry, occurs, and let’s say
a duplication occurred, the consequences (physical consequences) should be much
less severe, than let’s say, deletion. How to explain it?, again we are going back to
the beginning of the lecture, when we were saying that more genetic material
is much better than less. So, when we are deleting something, of course, having a
viable infant is, a viable fetus is much more difficult than adding something,
like in trisomy 21. So, one of the examples of duplications, what can happen
again, in the short arm of chromosome 5, and you all remember that, it was the
Cri du chat syndrome, and actually found a French speaker to say,
and again it’s Cri du chat, and in Cri du chat syndrome, we remember that not
only mental retardation was happening, but several physical abnormalities, such
as microcephaly. If duplication occurs in this short arm, of chromosome 5, there will be no physical presentation, but the infant
still will have physical, I’m sorry infant still will present with mental
retardation. So, if it’s duplication in a short arm of chromosome 5. Fragile
sites are sites that the breaks or gaps within chromosome, and actually those can
be seen by a microscope, when the cells are cultured or developed, and there is
really no evidence that this may be related to some disorder, in most of the
fragile sites, however, you may already heard about fragile chromosome X
syndrome, or fragile X syndrome. So most important feature of this is
presentation of mental retardation, it’s fairly prevalent in population. One in
4,000 males will develop it, and one in 8000 females. Why there is such distinct
ratio between male and females, 4000 versus 8000, this can be explained by the
fact that females have two X chromosomes versus males have only one, so in fragile
X chromosome, females will inherit the mutation, they do not necessarily express
the disease, but the male who inherits the disease, will express
the condition, because the male has again only one chromosome. So, that’s why the
prevalence is two times more in males versus females, and again, the female who
carries fragile X syndrome or may not present it herself, but can pass it to
the next generation. So to finish this statement, or this slide, again most of
the fragile sites will not be presenting any relation to the disease, only fragile
X chromosome. So when fragile X chromosome occurs, it occurs on the long
side of X chromosome, will be related to mental retardation, and again it’s one of
the most common genetic disorders, and it will occur, it will be second, compared to
Down syndrome, and again the highlight of this slide is that males will have higher
occurrence, because there is only one X chromosome.

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