Part 1: Commentary
Mary has been confirmed as being homozygous for
the Fibrillin gene (FBN1) for Marfan's Syndrome which is typically inherited in
a autosomal dominant pattern. She has demonstrated complex response to multiple
medications and has multiple clinical conditions that are not explained by the
disease variant or by 1 year of traditional diagnostic testing. Mary and her
family have several options: a) to participat in a clinical trial offering full
exome analysis to her and her parents at no cost, b) seek full gemone analysis
through their insurance carrier which may take 4-6 months, c) pay out of pocket
for full genome analysis (can run between $5-10 K), or d) use
direct-to-consumer services and perform independent analysis of raw
results.
Marfan's syndrome is autosomal dominant where approximately 75% of individuals with Marfan syndrome
have an affected parent and approximately 25% of probands with Marfan
syndrome have a de novo mutation. There are 68 allelic variants that are
responsible for a wide array of phenotypical features associated with Marfan's.
For example, CYS1409SER is responsible for a mild variant where clinical
features are not apparent and diagnosis was only made by genetic testing.
However, the more typical variant is ARG1137PRO, in which the classic
severe features are noted such as aortic root dilatation. The primitive genetic
tests only searched for known defects and if not found, the patients were
deemed clear of the disease. However, with advancements in genetic testing, we
now know that variants are also responsible for clinical disease. Even tho the
typically the same variants are passed on from generation to generation, there
can be other defects that occur de novo and can cause other symptoms. So in
Mary's case, it is appropriate to proceed with a diagnostic full genome
sequence analysis.
Out of her options, the most
valid one appears to be participating in a clinical trial for testing. Not only
will the hefty costs of the test be eliminated for her and her family, there
may be a possible treatment they could offer if a known variant is found on her
analysis. She would have access to health care professionals that are involved
with genetic tests and possibly be the best people to interpret her analysis.
It is also feasible to go through her insurance company, however, if
waiting 4-6 months would be detrimental to her life span and obtaining life
saving medications, it may not be worth the wait.
The American College of
Medicine Genetics released several statements on direct-to-consumer testing
which I agree with. ( ACMG statement on direct-to-consumer testing and ACMG
statement on direct-to-consumer testing in the USA.) Consumers who
are searching for answers to their medical conditions, are vulnerable to being
misled by the results of unproven and invalid genetic tests. Guidance from a
health care professional can help guide the consumers in the appropriate
direction for their test results. The consumer may be concerned about only one
or two results that they know about and are interested in, however, if other
results are found that can affect their health and the health of their family
members in a different way, this should be addressed by a health care
professional and not left to the companies performing the tests. Also, genetic
tests provide only one piece of information about a person's health -- other
issues such as environmental factors, life style choices, family history, and
reproduction history, may also need to be addressed in order to obtain maximal
benefit in their treatment plan. These factors cannot be addressed by at -home
kits or the testing companies.
With regards to incidental
findings, their provider should address, inform and discuss these
findings with the patient. The patient has a right to know the results of any
test that is performed on them, especially since they have provided consent for
testing with the anticipation that they will find some answers. Even though we
may pick up incidental findings that are not deemed to have clinical
significance (yet), the patients should be informed of this and continued to be
monitored if necessary. It is absolutely pertinent to discuss any results that
have known treatment or prevention strategies that could possibly save the
patient's or her family's life.
Part 2:
Using OMIM for FBN1, and .0001 MARFAN SYNDROME, SEVERE CLASSIC, the rs ID is
|
| rs137854456. Below is the identification of rs137854456 within the sequence: |
The beginning position of the variant site appears to be at 48487365.
 |
| Beginning position of variant site |
My variant appears to be on exon 28 as depicted below.
The VCF formatted data is noted below:
CHROM POS ID REF ALT QUAL FILTER INFO FORMAT CB00001
15 48487365 rs137854456 G C 25 PASS NS=1;DP=35;AF=0.5;DB GT:GQ 1│1:52
