A 6 year old boy presents to
the clinic with his mother.
The mother reports that her son’s appetite has become
progressively more insatiable over the past year.
As a result, he has
gained a lot of weight.
His diet is generally balanced and
healthy but he is not very active.
The boy’s mother also states that her son has
been having more temper tantrums at home lately.
He attends a special
education program at school.
As an infant, the boy had feeding difficulties,
weak muscle tone, and developmental delay.
Physical examination is noticeable for a short, obese
child with a narrow forehead, and almond-shaped eyes.
Which of the following genetic abnormalities is
the most likely to have caused this condition?
Answer choice (A) -
Answer choice (B) - maternal
Answer choice (C) - paternal
and answer choice (D) -
Now take a moment to come to your own
conclusion before we go through it together.
Now let's jump in to this question.
What we have here is a
medical genetics question.
we're discussing disomy,
chromosomal deletion, trisomy;
we're discussing different types of dysmorphic
facial features, this is classic medical genetics.
Now this is a 2-step question.
We first have to determine the child's diagnosis and then determine the genetics behind it.
And in this case, the stem is absolutely
required given the intricate clinical vignette,
the facial dysmorphism and
the clinical history.
So let's walk through
the question together.
Well for step 1, we need to
determine child's diagnosis.
In the vignette, we were told that the child when he was
younger, had hypotonia - which is weak muscle tone,
generalized developmental delay and in his older
age, he has been having hyperphagia or eating more.
Now in the story we also learned that the boy has dysmorphic facial
features, notable for a narrow forehead and almond-shaped eyes.
Now this constellation of symptoms and history is
consistent with the diagnosis of Prader-Will syndrome.
Now for step 2, we need to determine the
genetic mechanism behind the disorder.
Prader-Willi Syndrome results from a dysfunction
related to something known as 'genomic imprinting'.
This is an extremely high-yield
principle to understand.
Now genomic imprinting is a process in which certain alleles are physiologically silenced in a parent-specific manner.
Meaning that whether that allele is
inherited from the mother of a father,
it can be silenced due to a process
called genomic imprinting.
Now for Prader-Willi Syndrome, the affected regions
are the SNRPN and NDN of 15q13- that's chromosome 15
in which the alleles inherited from the mother are
silenced through the process of genomic imprinting.
That means that these alleles will always be quiet for the
mom and the paternal ones are the ones to be expressed.
And in the condition in which the
paternal allele may have a deletion,
there are no alleles to be expressed in that region and
that will result in the condition of Prader-Willi Syndrome.
Now let's refer to our image to
help us better understand this.
Here we see images of chromosome 15 and
the region boxed is the section q13
to help us understand where the allele is, where
it's deleted and how it's being expressed.
In the normal case, we have the paternal
chromosome coming from the father
and the maternal chromosome in this
orange color coming from the mother.
And the allele is boxed in that
section - that's in normal condition,
the mother's component will be silenced by genomic
imprinting and then the father's will be expressed.
Now in the paternal deletion, which is the
condition that produce the Prader-Willi Syndrome,
you have a deletion of that region and then
there is absolutely no allele expression
because the maternal one is silenced
through the process of genomic imprinting
and the father's is deleted and that
produces Prader-Willi Syndrome.
So the correct answer in this case is paternal
chromosome deletion - answer choice (C).
Now let's dicuss some high-yield facts regarding
genomic imprinting, Prader-Willi Syndrome
and we'll discuss why genomic imprinting is important for
other condtions outside of simply Prader-Willi Syndrome.
So let's first start
with genomic imprinting.
Now this is a physiologic process that affects less
than one percent of all genes in the human genome.
And this slightly mentioned previously describes the
silencing of certain alleles in a parent-specific manner,
that is contingent upon if you obtain it from the mother
or the father, it can be physiologically silenced,
which leaves only the other
parent's allele to be expressed.
Now a very significant disorder of this chromosome in which
the paternal deletion occurs produces Prader-Willi Syndrome.
Now let's say in this case,
we had maternal deletion.
In this case, we would have what is known
as the condition 'Angelman Syndrome'.
And then mnemonic there, this is the
same case as having genomic imprinting,
for Angelman Syndrome is that 'Your mother is an angel,
thus she has a deletion producing the Angelman Syndrome.
Now let's discuss Prader-Willi
Syndrome in a little bit more detail.
Now this is a rare genetic disorder
that typically presents during infancy.
And you will see a child with hypotonia or weak muscle
tone, feeding diffciulties and gross developmental delay.
You will see a physiological, or in this case a
physical abnormalities of a narrow forehead,
almond-shaped eyes, hypogonadism
and small hands and feet.
And for the genetics, the affected regions in
Prader-Willi are the SNRPN and NDN of 15q13
that causes genomic imprinting with
the deletion of the father's alleles.