6-year-old (male) with dysmorphic facial features

00:02 A 6 year old boy presents to the clinic with his mother.

00:05 The mother reports that her son’s appetite has become progressively more insatiable over the past year.

00:11 As a result, he has gained a lot of weight.

00:14 His diet is generally balanced and healthy but he is not very active.

00:18 The boy’s mother also states that her son has been having more temper tantrums at home lately.

00:24 He attends a special education program at school.

00:27 As an infant, the boy had feeding difficulties, weak muscle tone, and developmental delay.

00:33 Physical examination is noticeable for a short, obese child with a narrow forehead, and almond-shaped eyes.

00:41 Which of the following genetic abnormalities is the most likely to have caused this condition? Answer choice (A) - paternal disomy Answer choice (B) - maternal chromosomal deletion Answer choice (C) - paternal chromosomal deletion and answer choice (D) - autosomal trisomy Now take a moment to come to your own conclusion before we go through it together.

01:07 Now let's jump in to this question.

01:09 What we have here is a medical genetics question.

01:12 we're discussing disomy, chromosomal deletion, trisomy; we're discussing different types of dysmorphic facial features, this is classic medical genetics.

01:23 Now this is a 2-step question.

01:25 We first have to determine the child's diagnosis and then determine the genetics behind it.

01:30 And in this case, the stem is absolutely required given the intricate clinical vignette, the facial dysmorphism and the clinical history.

01:39 So let's walk through the question together.

01:41 Well for step 1, we need to determine child's diagnosis.

01:45 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.

01:59 Now in the story we also learned that the boy has dysmorphic facial features, notable for a narrow forehead and almond-shaped eyes.

02:07 Now this constellation of symptoms and history is consistent with the diagnosis of Prader-Will syndrome.

02:14 Now for step 2, we need to determine the genetic mechanism behind the disorder.

02:19 Prader-Willi Syndrome results from a dysfunction related to something known as 'genomic imprinting'.

02:25 This is an extremely high-yield principle to understand.

02:29 Now genomic imprinting is a process in which certain alleles are physiologically silenced in a parent-specific manner.

02:37 Meaning that whether that allele is inherited from the mother of a father, it can be silenced due to a process called genomic imprinting.

02:46 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.

03:03 That means that these alleles will always be quiet for the mom and the paternal ones are the ones to be expressed.

03:10 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.

03:21 Now let's refer to our image to help us better understand this.

03:25 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.

03:36 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.

03:46 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.

03:56 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.

04:15 So the correct answer in this case is paternal chromosome deletion - answer choice (C).

04:20 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.

04:33 So let's first start with genomic imprinting.

04:36 Now this is a physiologic process that affects less than one percent of all genes in the human genome.

04:41 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.

04:57 Now a very significant disorder of this chromosome in which the paternal deletion occurs produces Prader-Willi Syndrome.

05:07 Now let's say in this case, we had maternal deletion.

05:11 In this case, we would have what is known as the condition 'Angelman Syndrome'.

05:16 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.

05:27 Now let's discuss Prader-Willi Syndrome in a little bit more detail.

05:31 Now this is a rare genetic disorder that typically presents during infancy.

05:35 And you will see a child with hypotonia or weak muscle tone, feeding diffciulties and gross developmental delay.

05:42 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.

05:53 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.