Marfan's Syndrome: Overview, Pathophysiology, and Genetic Testing

This article provides an overview of Marfan's Syndrome, a rare hereditary disorder affecting connective tissues. It discusses the pathophysiology of the disease, genotypic and phenotypic analysis, and the importance of genetic testing. The article also explores the impact of heredity on the risk of developing Marfan's Syndrome, as well as the risks, barriers, and ethical considerations associated with testing. Overall, it provides a comprehensive understanding of the disease and its implications.

Running head: MARFAN’S SYNDROME
Topic: MARFAN’S SYNDROME
Name of the Student
Name of the University:
Author’s Notes:

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Marfan’s syndrome is a kind of rare hereditary disorder. Cohort studies conducted on
this disease claims that the birth incidence for such disorders in 23.3 per 100,000 individuals
especially 1 patient per 4268 people (Chiu et al.,2014). According to Cook et al (2016),
cardiovascular abnormalities are the main reasons behind the increased rates of morbidity a
as well as mortality in the syndrome along with other clinically related diseases. Moreover
there is pathogenic contribution of the deregulated growth factor which eventually affects the
signaling process and impairs it. The following essay highlights the overview of the diseases,
pathophysiology of the Marfan’s syndrome, genotypic, phenotypic analysis of the disease
along with various risks and barriers associated on the personal environmental backdrop
along with their effect on the social cultural society.
Overview of the disease:
Marfan’s syndrome is a type of genetic disorder affecting the connective tissues of the
body. The connective tissue plays an important role in holding of cells tissues and organs of
the body together simultaneously helping in the proper development and growth of the body.
Almost 1 out of 50000 people suffer from Marfan’s syndrome which is inclusive of men as
well as women irrespective of races and ethnicity. About 3 out of 4 people suffer from
Marfan’s syndrome through the genetic mutation from their parents. However spontaneous
mutations occur in some people where they are the first people to inherit the disease.
Genetically there is a 50 % chance of a person with Marfan’s syndrome passing the genetic
mutation to their progeny. People with Marfan’s syndrome develop serious conditions
involving aortic enlargement. Children suffering from Marfan’s syndrome are young and do
not usually develop symptoms like aortic enlargement or other signs of the disease till they
are adults (The Marfan Foundation, 2019).

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Pathophysiology involved with the disorder:
Marfan’s syndrome is a connective tissue disorder which is an inherited in an
autosomal dominant manner. Marfan’s syndrome is mainly caused by gene mutations
especially the FFBN1 gene. The gene is important for Fibrilin1 which is a glycoprotein.
Fibrilin -1 is the main constituent inclusive of the micro fibrils constituting the extracellular
matrix.
According to Dietz et al., (2016), Marfan’s syndrome is caused by the heterozygous
mutations in the gene FBN1 which encode extracellular matrix protein Fibrillin 1. Missense
mutations are common which have very high frequency of substitutions which either lead to
the destruction or creation of cysteine residues present in repetitive growth factor like growth
transforming factor TGBβ. FBN1 mutations involves insertions as well as deletions inclusive
of altered spliced events which alter the coding sequence but maintain the open reading
frames which helps in the creation of termination codon. The phenotypic- genotypic
correlations in Marfan’s syndrome include allelic heterogeneity along with the fact that most
of the phenotypes often show genetic variation and potentially influence the genetic as well
as environmental modifiers of the disease. Reductions as well as abnormalities in the gene
causes weakness in tissue, increased signaling of the growth beta factor. Loss of interactions
of the cell matrix, and ultimately to various phenotypic manifaifestations of the Marfan’s
syndrome. The most important clinical manifestations of Marfan’s syndrome is
cardiovascular involvement (Takeda et al ,2016).
Punett square, pedigree analysis and examination of the genotype and phenotype

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M m
Punette squares are useful in determination of genotypes through proper crossing or
breeding experiments. From the evaluation of the Punett Square for Marfan’s syndrome, the
genotypes of the parents have been considered with the alleles M and m. The combination of
the alleles have been represented through Punette Square and it can be seen that almost 50 %
of chances of disease transmission is there. Among the possible genotypes of the off-springs,
one of them is a carrier and the other is not a carrier. Overall the result of getting the disease
from the parents is 50-50.
m
m
?
Mm mm
Mm Mm

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This is the proband pedigree with Marfan’s Syndrome. +/- is a representation of the
heterozygous type while -/- is the wild type. The circles and squares are represented by the
females and males. The filled symbols are a representation of the symptoms affected with
Marfan’s syndrome as shown by the arrow. From the evaluation of the pedigree charts, it can
be found that most of the patients with Marfan’s syndrome often develop cardiovascular
diseases. Moreover it has affected only males of the family. This disease can be either an X
linked or Y-linked disorder. The son of the second generations are tall swanky with extended
arms and fingers. Thus, a pedigree chart is important for the analysis of human inherited
diseases and from this chart the inheritance of the allele for Marfan’s syndrome is evident. It
is a autosomal dominant disease as the disease can occur due to presence of genes in one of
the parent which is a characteristic of the dominant type. Moreover, it is autosomal as it is
inherited from a non sex- chromosome.
Discussion of 2 research studies explored in the diseases which influences the person’s
risk of development of the diseases
Various genotype phenotype relations can be evaluated for the correlation of Marfan’s
syndrome with cardiovascular involvement. Early observations by Aoyoma et al.,(2016) have
shown that mutations often lead to deposition of the fibrillin 1 protein in very less amounts.
Moreover the low levels of protein have been associated with various shortened event free
survivals along with various cardiovascular complications. Furthermore, through previous
studies on this syndrome have found that patients having premature terminations codon have
worse prognosis and increased chances of aortic surgery, aortic complications and mortality
rates. Similarly, the author have found that there is a relation of truncation mutations in
Marfan’s syndrome with mutation carriers (Wang et al.,2018). Alberts et al., (2014) have
observed that data on DNA analysis of 184 patients suffering from Marfan’s syndrome have

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carried FBN1 mutations which influences the phenotype. The relationship between the
genotypes and the phenotypes in LV dilatation have been occurring due to non-sense
mutations. Moreover, haplo-sufficiency is often believed to the main reason leading to the
disease.
Impact of heredity on the risk of development of Marfan’s syndrome
Marfan’s syndrome is an autosomal dominant disease as discussed above. However, a
minimum of 25 % of the disease syndrome occurs due to new mutations in the FBN1 gene.
Thus it often occurs in people where there has been no history of the disorder in the family.
Mechanism by which the gene cause an increased risk of development of the diseases are:
Mutations in the FBN1 gene especially on chromosome 15 causes the specific
disorder which eventually weakens the ligaments, tendons and connective tissues. FBN 1 is
mainly located at the chromosome 15q consisting of 65 exons and encoding 2871 structural
proteins like fibrilin 1 which is further a 360 kDa glycoprotein having 47 epidermal growth
factors. According to the mutations of the Universal Mutation Database, almost 3000
mutations including 1745 mutations have been documented. Moreover, a missense mutation
in Exon 14 of FBN1 have occurred where substitution of the cysteine has been changed by
glycine ultimately leading to non consanguineous family for generations (Wang et al.,2015).
Thus these specific changes in the genes have continued for generations which
increases the risks for the development of the Marfan’s syndrome for continuing generations.

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Risks and barriers involved with testing which affects personal, environmental and
financial factors
The costs of genetic testing are huge varying upon the nature as well as complexity of
the tests. Moreover the costs increase when multiple tests are required for obtaining a proper
and meaningful interpretation of the test. Although health insurance policies mean to cover
most of the expenses but most of the times increased costs are not covered completely under
the health insurances .Moreover for appealing to governmental health policies, state privacy
protection laws are important for consideration. Without the affirmation from the
governmental organizations, insurance companies cannot give health insurances. Thus it can
be seen the increased cost of the diagnosis of genetic hereditary disorders like Marfan’s
syndrome that there are various financial barriers and risks which are very important for
consideration of the stability of the present condition (ghr.nlm.nih.gov, 2019).
There are further barriers to the tests for diagnosis of the disease which can affect the
individual personally. For an instance for carrying out eye tests glaucoma have to be checked
where the pressure of the eyeball of should be maintained and can affect the individual while
testing. Moreover, the risks are enhanced for old people with heart diseases. Regular
echocardiograms done for the diagnosis should be done carefully and is hectic for the older
citizens. Physical risks are often very negligible as they require small amounts of blood
samples. However the same procedures are risky for pregnant women as there is an increased
risk of losing the pregnancy as the tests required sample of the amniotic fluid as well as tissue
sample from the fetus (ghr.nlm.nih.gov, 2019).
The prevalence of methods like genetic testing has specific environmental exposures.
It affects the gene-gene and gene environment interactions among a huge
population .Moreover, there is increased chances of single nucleotide polymorphisms (SNPs)

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which affect the genetic constitution of the environment. Moreover, premature transferals of
genetic testing procedures into practice affects the balance in the environment.
Impact on legal, ethical, socioeconomic factors
Various ethical issues are involved in the testing procedures of Marfan’s syndrome.
Availability of the informative test in the workplace helps workers to perform while being
informed and well known about the kind of jobs taken by them. Genetic testing procedures
create hazardous environment. The safety of the worker regarding procedures like genetic
testing is of primary importance. For an instance, in the US a specific Chemical company
have been closed due to the failure to include a specific employee in proper cytogenetic
testing programs which have led to the development of leukemia. Thus consideration of
ethical issues are important for carrying out the disorders (Gendiseases and the disagonis
procedures with their healthcare professionals.etic screening and occupational and
environmental exposures, 2019).
There are various legal considerations which has to be kept in mind while carrying out
diagnosis based tests for Marfan’s syndrome and related hereditary disorders. Firstly,
communication of the test results is important for discussing with patients in a proper
understandable as well as compassionate manner. Results should only be released to those
individuals only with consent of the patient. Patients should be careful while considering
direct to consumer genetic testing procedures who are encouraged for discussing the results
of the tests with their respective healthcare professionals. Health providers should confirm
the confidentiality of the information of the patients. They should not inform other members
of the family without the prior permission of the patients. Healthcare professionals should not
discuss test results with the members of the family.

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As far the social effects of the Marfan’s syndrome is considered, people suffering
from genetic disorders often face emotional as well as social issues. Changes in outlook and
lifestyles are affected. Restriction of activities for Marfan’s syndrome often has a negative
impact on the social effect of the person. Such people often feel angry and afraid than other
normal people. They are often stressed about their hereditary characteristics and suffer from
anxiety regarding the passing of the diseases to their progeny (The Marfan foundation,2019).
Genetic testing and impact on the disease
Genetic testing is actually defined as the study of a person’s DNA for identification of
genetic differences as well as susceptibility to various diseases and abnormalities. Genetic
testing in Marfan’s syndrome helps in confirming as well as ruling out the diagnosis
procedure as required. Moreover it facilitates discussion involving pre implantation genetic
diagnoses and prenatal diagnosis as well. Whenever diagnosis cannot be used for the
determination through clinical evaluation, genetic testing may be helpful in those cases.
However there are several limitations regarding genetic testing. Only a particular
population are required for more than usual testing procedures for identification of the
alterations. Mutations in FBN1 syndrome might cause other conditions apart from Marfan’s
syndrome. Most of the times it is difficult for prediction of the condition for expecting the
mutation. Moreover, family members having same mutations can show a wide variety of
regarding the timing of its onset and the severity of various complications. Another limitation
of genetic testing procedures for Marfan’s syndrome is the increase in costs for the
procedure. Moreover the increased costs cannot be covered by health insurance companies
most of the times (Marfan.org, 2019).

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Genetic testing has a positive impact in the diagnosis of the disease. The clinical
management of various diseases including the Marfan’s syndrome have been improve due to
the specific incorporation of genetic testing procedures. Moreover prognosis of the patient
can be estimated easily due to the determination of specific genetic risks. Thus preventive
measures can be adapted and the therapeutic procedure can be incorporated successfully.
Thus the Marfan diseases and its clinical diagnosis often acts as an example of the clinical
benefit of genetics (Zighansin et aal.,2015).
From the following factors it can be concluded that there are various factors to be
considered while suffering from the disease. Marfan’s syndrome is a rare autosomal
dominant hereditary disorder where half of the progeny is affected and the rest half are
carriers. This disease occurs due to the missense mutation in the FB1 gene which shows
phenotypic characteristics like extended arms, feet, legs and fingers. One of the most
important disorders related with the development of the disease is cardiovascular diseases.
Diagnostic procedures mainly used for the diseases are echocardiograms and genetic testing
methods. However genetic testing methods include cultural and ethical barriers. Moreover
there are several legal consideration to be made during genetic testing procedures. The
mechanism by which the genes influence the heredity of the diseases is mainly mutations in
the specific chromosome especially chromosome 15 q. The patient suffers in terms of social
impact the disorder has, especially the impact of the community and the environment. Taking
all the factors into consideration the Marfan’s syndrome is a rare category of inherited
disorders which need to take care of carefully keeping in mind the social cultural and
environmental factors for the establishment of a healthy community and for enhancing the
mental health of the patients in future.

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