Inheritance and expression of Marfan syndrome
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Inheritance and expression of Marfan syndrome
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[post_date] => 2024-12-23 10:30:14
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[post_content] => Practice Passage (Question 1-6)
*This passage is the property of Khan Academy and has been reformatted into an AAMC-style interface in their entirety by MedLife Mastery. MedLife Mastery does not endorse and is not an affiliate of Khan Academy.
Marfan syndrome is a fairly common (1 in 5,000) genetic disorder that is characterized by a myriad of symptoms affecting connective tissues. The predominant genetic defect is in the FBN1 gene, which codes for the glycoprotein fibrillin-1—an important component of the extracellular matrix (ECM). Fibrillin-1 is particularly important for the proper formation of elastic fibers, such as those that constitute the walls of large blood vessels, ligaments, and regions of the eye. It also sequesters transforming growth factor beta (TGF-β), a growth factor responsible for cell proliferation and differentiation. Low fibrillin-1 levels can lead to elevated TGF-β, which leads to the degradation of the ECM.
The most recognizable symptom of Marfan syndrome is the characteristic body morphology: disproportionately long, slender limbs and digits, above average height, stooped shoulders, scoliosis, and either a protruding or sunken appearing chest. In addition, many of these individuals have abnormally flexible joints and early-onset arthritis. These individuals are also predisposed to a number of conditions involving the heart and major blood vessels including poor circulation and various heart murmurs. The most serious of these is a situation known as ‘aortic dissection,’ wherein blood under high pressure forces its way between layers of the wall of the aorta. If untreated, this can lead to massive hemorrhage and death within minutes. Figure 1 shows the incidence of common symptoms of Marfan syndrome among patients with the same mutation.
Figure 1 Relative incidence of common symptoms in Marfan syndrome
A patient has come to see you complaining of arthritis. You find that he has a heart murmur and weak circulation to his extremities. You also notice that he is 6’7” tall with extremely long fingers. You suspect Marfan syndrome and record a thorough family history from the patient. Figure 2 shows the pedigree of this patient’s family with respect to symptoms of Marfan syndrome.
Figure 2 Patient’s family history and pedigree with respect to symptoms of Marfan syndrome
1 = Your patient
1a = Son; 6’7” tall; treated for scoliosis from young age
1b = Normal-appearing daughter; average height
2,3 = Normal-appearing brother and sister; average heights
4 = Tall sister; arthritis from age 26
5 = Father; 6’7” tall; died of aortic dissection
6 = Aunt; normal limb length; hyper flexible; lost eyesight at age 40
7 = Normal-appearing uncle; average height
8 = Uncle with long fingers; average height; circulation issues
* = Mother’s side of the family all appear normal; average heights
Data adapted from: Stheneur, C., Tubach, F., Jouneaux, M., Roy, C., Benoist, G., Chevallier, B., Boileau, C., Jondeau, G. (2014). Study of phenotype evolution during childhood in Marfan syndrome to improve clinical recognition. Genetics in Medicine, 16(3), 246-250.
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[question] => Based on Figure 2, what is the most likely mode of inheritance for Marfan syndrome?
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[answer] => 2
[description] => Reason for Correct Answer:
Males and females are affected equally.
Marfan syndrome appears in every generation, without gaps.
Only the offspring of affected individuals exhibit the phenotype.
Approximately 50% of the offspring of affected individuals exhibit the phenotype.
The most likely mode of inheritance for Marfan syndrome is autosomal dominant.
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[each_answer] => A. Autosomal recessive
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[each_answer] => B. Autosomal dominant
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[each_answer] => C. X-linked recessive
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[each_answer] => D. X-linked dominant
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[quiz_unique_key] => 1403770772
[question] => In terms of Mendelian genetics, what might explain why the range of symptoms observed in this patient’s family members and among other people with Marfan syndrome?
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[answer] => 2
[description] => Reason for Correct Answer:
In the context of a single family, family members likely share the same underlying genetic mutation in the FBN1 gene. Therefore, within this family, the range of symptoms is NOT likely due to different FBN1 mutations with different effects, although this may affect the variable expressivity of Marfan syndrome.
Co-dominance is where two alleles are each expressed fully (for example in blood type), and incomplete dominance is where two alleles are both expressed in a less than complete fashion resulting in a ‘third’ phenotype (for example, an allele for a white flower and an allele for a red flower producing a pink flower).
However, there is nothing in the passage to indicate that there are multiple alleles that exhibit codominance or incomplete dominance.
The variable range of symptoms among people with Marfan syndrome (variable expressivity) describes how the expression of a genotype or disease is different in different individuals because of other environmental or genetic factors. These can include:
Figure 1
Figure 2- Genetic Modifiers: Other genetic factors, known as genetic modifiers, may interact with the FBN1 gene and influence the expressivity of Marfan syndrome.
- Environmental Factors: Environmental factors, such as diet, physical activity, and overall health, can also play a role in shaping the expression of Marfan syndrome. For example, factors like blood pressure control and cardiovascular health may influence the progression of aortic complications.
- Epigenetic Factors: Epigenetic modifications, which affect how genes are regulated without changing the underlying DNA sequence, can contribute to variable expressivity. Epigenetic changes can influence the extent to which the FBN1 gene is turned on or off in different tissues and individuals.
- Individual Genetic Background: Each person has a unique genetic background, and the combination of genetic variants across the entire genome can contribute to the variability in symptom expression.
A. Different mutations in the FBN1 gene can lead to varying degrees of impact on the structure and function of fibrillin-1.
) [1] => Array ( [each_answer] =>B. Other genetic factors, known as genetic modifiers, may interact with the FBN1 gene and influence the expressivity of Marfan syndrome.
) [2] => Array ( [each_answer] =>C. Incomplete dominance is at play, leading to a mix of symptoms in affected individuals
) [3] => Array ( [each_answer] =>D. The symptoms in family members are random and unrelated to genetic factors.
) ) ) [2] => Array ( [quiz_unique_key] => 1403770772 [question] =>What is the likelihood that this patient’s daughter is a carrier for Marfan syndrome?
[value] => Array ( [answer] => 4 [description] =>Reason for Correct Answer:
The inheritance pattern of Marfan syndrome is autosomal dominant. When a dominant allele is present, it will always be expressed over a recessive allele.
All individuals with the FBN1 gene mutation of Marfan syndrome will exhibit symptoms of Marfan syndrome.
The patient’s daughter does not have any symptoms of Marfan syndrome, so she must not have the FBN1 gene mutation.
There is a 0% chance that the patient’s daughter is a carrier for Marfan syndrome.
A. 100%
) [1] => Array ( [each_answer] =>B. 50%
) [2] => Array ( [each_answer] =>C. 25%
) [3] => Array ( [each_answer] =>D. 0%
) ) ) [3] => Array ( [quiz_unique_key] => 1403770772 [question] =>Based on the information in the passage, what is the most plausible explanation for why the risk of aortic dissection increased in patients with Marfan syndrome?
[value] => Array ( [answer] => 3 [description] =>Reason for Correct Answer:
The passage states that TGF-β causes cell proliferation, so reduced TGF-β would not cause this.
The passage states that fibrillin is essential for the proper formation of elastic fibers. Elastic fibers are an important part of arterial walls, and are a major component in maintaining vascular tone and arterial blood pressure.
An aortic dissection is described as blood forcing its way between layers of the arterial wall.
The risk of aortic dissection in patients with Marfan syndrome is increased because defective elastic fibers in Marfan patients produces poorly formed arterial walls with compromised structural integrity – i.e. with reduced elasticity that reduces the ability of the vessel walls to deform in response to changes in pressure and return to their original shape.
A. Reduced TGF-β leads to excess cell proliferation in the aortic cell wall, resulting in increased rigidity.
) [1] => Array ( [each_answer] =>B. The increased height and limb length in Marfan patients increases the pressure within the aorta due to the increased peripheral blood vessel length.
) [2] => Array ( [each_answer] =>C. Reduced elasticity reduces the ability of the vessel walls to deform in response to changes in pressure and return to their original shape.
) [3] => Array ( [each_answer] =>D. The physical strain of rapid vertical growth in Marfan patients induces a tear in the aorta due to a constant stretching force on the vessel.
) ) ) [4] => Array ( [quiz_unique_key] => 1403770772 [question] =>For an individual who is homozygous for the FBN1 mutation, and assuming no sporadic mutations, what is the probability of each of their parents having Marfan syndrome?
[value] => Array ( [answer] => 1 [description] =>Reason for Correct Answer:
A child receives one allele for a given gene from each parent.
For an individual who is homozygous for the mutate allele, each parent must have passed the mutant FBN1 gene to that individual.
The mutated FBN1 allele in Marfan syndrome is a dominant allele. The passage states that all individuals with this mutation will express some form of Marfan syndrome.
Each parent therefore has a 100% chance of having Marfan syndrome.
A. Each parent has a 100% chance of having Marfan syndrome.
) [1] => Array ( [each_answer] =>B. Each parent has a 50% chance of having Marfan syndrome.
) [2] => Array ( [each_answer] =>C. Each parent has a .02% (1/5000) chance of having Marfan syndrome.
) [3] => Array ( [each_answer] =>D. It cannot be determined without more information.
) ) ) [5] => Array ( [quiz_unique_key] => 1403770772 [question] =>In addition to variable expressivity, the data in Table 1 best exhibits what genetic phenomena?
[value] => Array ( [answer] => 2 [description] =>Reason for Correct Answer:
Polygeny refers to the situation in which a trait is influenced by multiple genes. Human traits such as height, skin color, and intelligence often exhibit polygenic inheritance. This is similar to epistasis, which occurs when the expression of one gene affects the expression of another gene.
The data shown in Figure 1 do not involve the influence of multiple genes and therefore do not indicate effects of polygeny.
Incomplete penetrance occurs when an allele causes the disease in less than 100% of cases. Although Figure 1 shows that not everyone with the disease has every symptom or sign, it does NOT indicate that anyone has the gene and does not have the disease. In addition, it does not indicate the proportion of people with the gene that have the disease in general.
Genetic imprinting involves the selective expression of either the maternal or paternal allele of a gene, leading to different phenotypic outcomes depending on the parent of origin. The expression of imprinted genes can be “turned off” or “turned on” based on the parental origin of the allele. There is nothing in Figure 1 to indicate genes being turned on or off in the mother or father.
The data in Figure 1 exhibits both variable expressivity and pleiotropy, which contribute to the diverse range of clinical manifestations observed in affected individuals.
Variable expressivity refers to the range of severity and specific features of a genetic disorder that can vary among individuals who carry the same disease-causing mutation. In Marfan syndrome, individuals with the same FBN1 gene mutation may display a spectrum of clinical manifestations with varying degrees of severity. For example, one individual may have pronounced skeletal features, while another may primarily exhibit cardiovascular complications.
Pleiotropy is the phenomenon where a single gene has multiple effects on the phenotype of an organism. In Marfan syndrome, the FBN1 gene mutation leads to the production of abnormal fibrillin-1, a protein involved in the formation of elastic fibers in connective tissue. The pleiotropic effects of the FBN1 mutation are evident in the various systems and tissues affected by Marfan syndrome. These include the skeletal system (e.g., tall stature, long limbs), cardiovascular system (e.g., aortic aneurysms, aortic dissection), and ocular system (e.g., lens dislocation, myopia).
A. Incomplete penetrance
) [1] => Array ( [each_answer] =>B. Pleiotropy
) [2] => Array ( [each_answer] =>C. Genetic imprinting
) [3] => Array ( [each_answer] =>D. Polygeny
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