Download UK Genetic Testing Network Marfan syndrome testing guideline

UK Genetic Testing Network
Marfan syndrome testing guideline workshop
5th September 2012, 10.30-3.15pm
Royal College of Physicians, London
Meeting report
Executive summary
The UK Genetic Testing Network (UKGTN) invited clinical geneticists, cardiologists with
a specialist interest in Marfan syndrome, molecular scientists, genetic counsellors and
representatives from a patient group (Marfan Association UK) to a workshop to discuss and
develop a consensus clinical diagnostic pathway for suspected Marfan syndrome and related
aortopathies and testing criteria for molecular genetic testing for Marfan syndrome. This
workshop was held in response to the need for formal testing criteria for Marfan syndrome
in order to incorporate the recent revisions in the clinical diagnostic criteria brought about by
the 2010 Ghent nosology.
The 2010 Ghent criteria places greater emphasis on the two cardinal features of Marfan
syndrome: ectopia lentis and aortic root aneurysm/dissection. Diagnosis is simplified, the
role of genetic testing has been clarified, and differential diagnosis is improved over the
previous Ghent criteria. Additional testing and/or follow-up is now formally included in the
criteria with a ‘potential Marfan syndrome’ label applicable to patients under the age of 20
years.
The importance of making a diagnosis and offering an equitable service is vital to patients.
An accurate diagnosis facilitates comprehensive genetic advice for the affected individual
and at risk family members. Importantly, it enables appropriate treatment and targeted
testing to be implemented for patients within a clinical pathway. Marfan Association UK, a
patient advocacy group for Marfan syndrome and overlapping disorders, also highlighted
the importance of educating GPs of the revised diagnostic criteria for Marfan syndrome as it
is normally the GPs who are the first point of contact for patients.
Consensus testing criteria for Marfan syndrome and the clinical diagnostic pathway for
suspected Marfan syndrome were agreed at the meeting.
Recommendations
• The testing criteria for Marfan syndrome should be considered for approval by the
UKGTN and implemented as soon as possible within the NHS.
• The clinical diagnostic pathway for suspected Marfan syndrome should be considered
for approval by the UKGTN and provided as guidance on the UKGTN website.
• It is recommended that a new panel test incorporating all the known genes for inherited
conditions with aortic involvement (so called “aortopathies”) should be developed for
NHS evaluation and clinical use.
UK Genetic Testing Network Marfan syndrome testing guideline workshop
5th September 2012 | Royal College of Physicians, London
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UK Genetic Testing Network Marfan syndrome testing guideline workshop
5th September 2012 | Royal College of Physicians, London
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REVISED GHENT CRITERIA (Loeys 2010)
* Loeys BL et al. The revised Ghent nosology for the Marfan syndrome. Journal of Medical Genetics
2010; 47: 476-485. Doi:10.1136/jmg.2009.072785
Table 1. Calculation of the Systemic Score
Feature
Value
Wrist AND thumb sign
3
Wrist OR thumb sign
1
Pectus carinatum deformity
2
Pectus excavatum or chest asymmetry
1
Hindfoot deformity
2
Plain flat foot (pes planus)
1
Pneumothorax
2
Dural ectasia
2
Protrusio acetabulae
2
Reduced upper segment / lower segment AND increased arm span/height ratios
1
Scoliosis or thoracolumbar kyphosis
1
Reduced elbow extension
1
3 of 5 facial features
1
Skin striae
1
Myopia
1
Mitral valve prolapse
1
Maximum total: 20 points
Score ≥ 7 indicates systemic involvement
US/LS= upper segment/lower segment ratio
Aortic root enlargement (Z-score ≥2.0 in those age ≥20 years or ≥3.0 in those age <20 years). Aortic size
must be standardised to age and body size for accurate interpretation. A Z-score ≥2.0 infers a value at or
above the 95th percentile, while a Z-score ≥3.0 infers a value at or above the 99th percentile.
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Introduction
Marfan syndrome is an inherited connective tissue disorder which is inherited in an autosomal
dominant manner. The disorder is caused by mutations in the Fibrillin 1 gene (FBN1). The
syndrome has a prevalence of around 1 in 5,000 individuals1 and has a high degree of
clinical variability. The main features involve the ocular, cardiovascular and skeletal systems
although the skin, lungs and dura may also be involved. Ocular involvement often presents
as myopia and ectopia lentis (displacement of the lens from the centre of the pupil) is also
a common presentation. Marfan syndrome patients are also at risk of retinal detachment,
glaucoma, and early cataract formation. Cardiovascular features often involve the dilatation
or dissection of the aorta and it is the cardiovascular features of Marfan syndrome that
account for much of the morbidity and early mortality. Skeletal features are characterised
by bone overgrowth and joint laxity with arms and legs being disproportionately long for
the size of the body. Several other conditions have also been recognised which present
overlapping clinical features with Marfan syndrome including ocular (e.g. ectopia lentis
syndrome), cardiovascular (e.g. bicuspid aortic valve) and skeletal features (ShprintzenGoldberg syndrome).
The clinical diagnosis of Marfan syndrome is complicated by this heterogeneity and in 1996
the Ghent criteria were developed to facilitate diagnosis. The 1996 criteria employed a set
of ‘major’ and ‘minor’ criteria with diagnosis in an index case requiring two major and at
least one minor criteria to be fulfilled. The major criteria included ectopia lentis, aortic root
dilatation/dissection, dural ectasia or a combination of more than four out of eight major
skeletal features. If the case has a mutation in the FBN1 gene known to cause Marfan
syndrome or has a first-degree relative that has been diagnosed with Marfan syndrome,
then the presence of one major and one minor criteria were enough to diagnose Marfan
syndrome. Although mutations in FBN1 are identifiable in the vast majority of patients
diagnosed using the 1996 criteria, concerns over the sensitivity of the criteria were raised;
for example not enough account being taken of the age-dependent nature of some of the
clinical features which makes diagnosis in children very difficult.
Concerns with the validity of some of the diagnostic criteria coupled with problems in
diagnosing children and greater understanding of the variable clinical expression and
differential diagnoses of conditions with overlapping features led to revised 2010 Ghent
criteria2. The new criteria places more weight on the two main features of Marfan syndrome,
aortic root aneurysm/dissection and ectopia lentis. Diagnosis can be made with the presence
of these two features. Other clinical features contribute towards a ‘systemic’ score which
when combined to give a score of greater than or equal to seven can guide diagnosis in the
absence of the two main features. A more prominent role was also given to genetic testing
so that the absence of one of the two main features plus the presence of a known causal
mutation in FBN1 would be sufficient for a diagnosis to be made. Less specific clinical
features, for example dural ectasia, were either removed or made less influential in the new
criteria. The new criteria also formalised the need for additional diagnostic considerations,
tests, or follow-up in patients that either did not fulfil the criteria for diagnosis but showed
other unexpected findings and the use of ‘potential Marfan syndrome’ in patients under the
age of 20 to take into account that the phenotype may develop with age.
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Many genes are known to be involved in the aetiology of inherited aortopathies. A number
of laboratories provide genetic testing for these genes for example, TGFBR1 and TGFBR2
genes, as well as FBN1. The recent revisions in the clinical diagnosis of Marfan syndrome
introduced by the 2010 Ghent criteria provide an opportunity to develop testing criteria for
Marfan syndrome and to develop the clinical diagnostic pathway for suspected Marfan
syndrome patients. This will facilitate and optimise targeted testing of FBN1 to allow the
right test to be conducted for the right patient at the right time.
The UK Genetic Testing Network (UKGTN) invited clinical geneticists, cardiologists with
a specialist interest in Marfan syndrome, molecular scientists, genetic counsellors and
representatives from a patient group (Marfan Association UK) to a workshop to discuss
and develop a consensus clinical diagnostic pathway for suspected Marfan syndrome and
related aortopathies and testing criteria for molecular genetic testing for Marfan syndrome.
The objectives for the workshop were:
• To develop and publish consensus testing criteria for Marfan syndrome using the 2010
Ghent criteria
• To develop and publish a consensus clinical diagnostic pathway for suspected Marfan
syndrome patients which captures the changes in the diagnostic criteria following
acceptance of the 2010 Ghent criteria
• To make available a report of the workshop and the agreed clinical diagnostic pathway
and testing criteria for Marfan syndrome
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Summary of Presentations
1. Genetic testing in Marfan syndrome and related aortopathies
Leema Robert (Guy’s and St Thomas Hospital, UK)
Presentation
With a lack of consensus testing criteria in the UK, Guy’s and St Thomas Hospital has been
using its own diagnostic pathway for the last 10 years. The 1996 Ghent criteria are well
established and are used in the clinical diagnosis of Marfan syndrome. These criteria are
generally agreed to be very good, with a FBN1 mutation pick up rate of 97%, but are limited in
that they include some non-specific findings, make no allowance for age-dependent features,
are not helpful for considering differential diagnosis or planning further management, and
result in difficulty in deciding whether there is cardiovascular risk in those families with just
musculoskeletal features and/or ectopic lentis. However, most departments now use the
revised Ghent criteria (2010 version) which are clearer, have a more precise definition of the
clinical subgroups, and provide better advice for follow-up and management when applied to
children with suspected Marfan syndrome. The new scoring system gives greater weight to
more specific symptoms such as a positive family history of Marfan syndrome, ectopia lentis,
and dilated aortic root. It is generally agreed that these new criteria are an improvement on
the old 1996 criteria.
Thoracic aortic aneurysm is a major health problem with potentially devastating consequences.
The incidence rate of the aortopathies is roughly 10.4 per 100,000 person-years and in 20%
of cases a positive family history is seen. The causes of aortopathies can be thought of
as non-genetic and genetic, with genetic causes further sub-categorised into syndromic
(for example Marfan syndrome) and non-syndromic (such as bicuspid aortic valve with
aneurysms of the ascending aorta or tetralogy of Fallot). The research into genetic causes of
aortopathies continues with several genotype-phenotype associations discovered in the last
few years including further discoveries of phenotypic clinical variation within single families.
This highlights the need to remain abreast of the evolving literature as it has allowed the team
at Guy’s to make several diagnoses following the recognition of a similar clinical phenotype
in patients seen at Guy’s and the ordering of appropriate testing for positive confirmation.
The importance of clear and precise clinical phenotyping cannot be over stated regardless
of whether it is done by the cardiologist or the clinical geneticist. It is also becoming apparent
that there is significant overlap of the clinical phenotypes in aortopathies and panel testing
using next generation sequencing maybe the way forward.
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2. Marfan syndrome in Scotland
John Dean (Aberdeen Royal Infirmary, Scotland)
Presentation
In Scotland there are four clinical genetics centres and although there is no formal Marfan
syndrome network, there is a managed clinical network for familial arrhythmias. Scotland has
had its own guideline since 2000, which made use of the Ghent 1996 criteria. The Scottish
guideline states that all suspected Marfan syndrome patients should have an echocardiogram
to measure the diameter of the Sinus of Valsalva relative to age and body surface area. Other
investigations such as X-ray for protrusion or magnetic resonance imaging for dural ectasia
are undertaken if the patient would fulfil the diagnostic criteria if the result was positive. The
Ghent 1996 nosology was adapted to make clinical use easier: for example, myopia was
also allowed to count as ocular involvement. Genetic testing is undertaken if a positive test
would make the Marfan syndrome diagnosis. Electronic records are created and used in the
clinics and these are designed as care pathways for patients with Marfan syndrome thereby
allowing automated calculation of the Ghent criteria scores. The current electronic records
include both the 1996 criteria and the revised 2010 criteria. The algorithm for the 1996
scoring system was easy to create but the 2010 scoring algorithm was more complex and
was difficult to implement because there are ‘gaps’ in the 2010 nosology into which some
patients fall. Both the original criteria and the revised criteria have problems with regard
to making a diagnosis in children but this is a problem with the natural history of Marfan
syndrome as some phenotypes do not manifest in young children.
In a review, both the 1996 and 2010 nosologies were compared in 40 index cases. 34 of
these patients fulfilled the criteria for both nosologies with FBN1 mutation testing positive in
24 of 31 patients. By investigating the cases classified differently by the two nosologies, it
was concluded that the 2010 revision makes it easier to diagnose Marfan syndrome when
there is only information about the eyes and aorta but the 1996 criteria are more sensitive
and detect some FBN1 positive cases that were missed by the 2010 revision. In conclusion,
genetic testing should be routine in suspected cases but in cases referred because of family
history of Marfan syndrome, caution should be exercised if the index case has not been
tested. Genetic testing should include FBN1, TGFBR1 and TGFBR2, and additional tests
should be considered if negative or other clinical features are involved.
3a.Cardiologist perspective
Christoph Kiesewetter (Guy’s and St Thomas’ Foundation Trust, UK)
Presentation
In the adult cardiac clinic, the early identification and establishment of a diagnosis is critical
as it allows early prophylactic surgery that prevents aortic dissection and rupture, greatly
improving health outcomes. Finding the molecular mechanism behind Marfan syndrome and
related aortopathies improves diagnostic testing. The use of a multidisciplinary team during
diagnosis of a patient helps to produce a correct diagnosis. The current approach involves
the correct phenotyping of the various clinical manifestations using the revised 2010 criteria
whereby greater diagnostic weight is given to the two cardinal features of Marfan syndrome
- aortic root aneurysm/dissection and ectopia lentis - and also to molecular genetic testing.
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Clinical phenotyping is a key component of diagnosis in suspected Marfan syndrome patients
and their relatives and should include a multidisciplinary team including professionals with
specific training and experience in Marfan syndrome and related aortopathies. The accuracy
of the diagnosis is key and all investigations require a rigorous approach. One of the key
investigations using transthoracic echocardiography is that of determining the diameter and
searching for the dissection of the aortic root and all other parts of the aorta. Magnetic
resonance imaging (or computed tomography angiography) is often necessary to complete
this assessment. Careful evaluation of imaging results is required with respect to not only
the size and location of the abnormal aortic root but also the shape. The key message is
careful clinical phenotyping and considered evaluation using a multidisciplinary team with
appropriate expertise and experience of Marfan syndrome and related aortopathies.
3b.Marfan syndrome and related aortopathies – perspective from paediatric cardiac
clinic
Juan Pablo Kaski (Great Ormond Street Hospital and University College London, UK)
Presentation
The aortopathy clinic is part of the Inherited Cardiovascular Diseases Unit at Great Ormond
Street Hospital. Many of the tests conducted in adults are also conducted in children,
including electrocardiography, echocardiography and cardiovascular MRI. In this clinic,
three broad groups of patients are seen: 1) those with known aortopathy syndromes; 2)
first-degree relatives of known cases (attending for screening); and 3) children referred for
investigation for possible Marfan syndrome or related disorders. The known aortopathy
syndrome group include patients with clinical diagnoses of Marfan syndrome, Loeys-Dietz,
and Ehlers-Danlos (type IV). The value of genetic testing in this group includes confirming
molecular diagnosis, potentially providing prognostic information, guiding surveillance
and management with respect to the timing of interventions and the type or necessity of
pharmacological therapy. Confirmed diagnosis in this first group can also lead to cascade
screening in family members (the second group). Genetic testing in this second group of
patients, if positive, allows confirmation of the diagnosis and appropriate surveillance and
management. If predictive genetic testing is negative, the ‘patient’ can be given the ‘all-clear’
and discharged from the clinic. The third group of patients – those with possible Marfan
syndrome – have not fulfilled the Ghent criteria which, in the paediatric population, may be
due to the age-dependent nature of penetrance for clinical features or because the condition
exhibits incomplete expression and may have overlapping phenotypes with other related
conditions. Many of these patients therefore get a ‘non-specific connective tissue disorder’
diagnosis, and require ongoing follow-up. Genetic testing in this group of patients may
provide a specific diagnosis which can then guide surveillance and management. This third
group is also interesting for research purposes as they are the group of patients that may
lead to new gene discovery. As alluded to in other presentations, the phenotyping of children
is paramount and should be used as the basis on which to conduct further investigations.
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4. Marfan syndrome and related aortopathies: developing consensus guidelines
Bart Loeys (Antwerp University Hospital, Belgium)
Presentation
There is ongoing debate as to whether the identification of any gene mutation in FBN1 should
equate to a diagnosis of Marfan syndrome. However, different mutations result in many
different syndromes with significant differences in the clinical phenotype when compared to
Marfan syndrome (for example acromicric/geleophysic dysplasia which presents as short
stature and joint stiffness). Great care should be taken when thinking about making all FBN1
mutations equate to Marfan syndrome. In classical Marfan syndrome patients using the
original 1996 Ghent criteria, traditional sequencing techniques are able to identify a mutation
in FBN1 in around 90% of patients. The mutations in the other 10% could be due to deletions
or duplications, mutations within the promoter or 3’ UTR regions, or may not be detected
due to the limitations of the technology currently being used. It is also possible that the
causal mutation may be in other known or unknown genes (locus heterogeneity). But none
of these reasons have currently been demonstrated to account for the 5-10% of unidentified
mutations and further research into new areas is ongoing.
The 1996 Ghent criteria have been used worldwide and have been found to be helpful in
making the diagnosis of Marfan syndrome and both sensitive and specific in identifying
FBN1 mutation carriers. However, in the absence of aortic dilatation, the diagnosis of
Marfan syndrome in patients was found to be stigmatising, hampered career aspirations,
and restricted insurance opportunities and lifestyle choices. Some of the minor diagnostic
criteria used were not very specific to Marfan syndrome and had not been clinically validated.
The criteria were also difficult to apply to children although this is due to the nature of the
condition and so remains in the revised criteria. An evidence-based approach was used
to update the criteria with greater emphasis placed on whether genetic testing impacts on
clinical management and also in distinguishing between Marfan syndrome and the related
disorders with improved differential diagnostics. The major and minor criteria from the 1996
were abandoned and replaced by a greater focus on the two cardinal features of aortic root
dilatation/dissection and ectopia lentis. There is less emphasis now on the less specific
clinical presentations of Marfan syndrome. The addition of better differential diagnosis and
the addition of follow-up and surveillance of ambiguous diagnoses have led to criteria which
is easier to apply. The concordance between the old and new criteria is very high with
discordance between the two main clinical criteria resulting in fewer diagnoses without
vascular disease and the earlier diagnosis of young children. However, the systemic score
aspect of the new criteria will require prospective evaluation.
The clinical utility card for FBN1 mutation screening was published in the European Journal of
Human Genetics in 2010. It queries the usefulness of FBN1 testing when a clinical diagnosis
of Marfan syndrome has been made. Appropriate treatment should be started regardless
of FBN1 mutation status if a clinical diagnosis has been made as there is no evidence
that outcomes differ based on FBN1 mutation status. However, there is no consensus at a
European level with regards to the timing for the initiation of aortic treatment. FBN1 mutation
testing seems useful when patients do not fulfil Ghent criteria but they do have suggestive
cardiovascular features, are sporadic young cases, or the testing is taking place in familial
members of a positive case. This would allow confirmation of Marfan syndrome before all
clinical features have presented themselves. Testing criteria do not exist at a European
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level and countries such as Belgium and the Netherlands are moving towards using a panel
of genes rather than testing in a sequential manner. This is partly driven by cheaper costs
but also because there is significant overlap between the clinical phenotypes which make
clinical diagnosis difficult especially in young children.
5. The patient perspective
Diane and Robin Rust (Marfan Association UK)
Presentation
The incidence of Marfan syndrome is estimated to be 1 in 3,300 which suggests that there
are approximately 19,000 patients in the UK based on 2011 population figures. Although
uncertainty exists regarding the actual number of patients in the UK, all patients still need
clinical services and resources. The General Practitioner (GP) is a very important person to
the patient and is a focal point for the patient to return to. GPs should be included as referrers
for testing along with cardiology and genetic services. Patients sometimes feel that they can
get locked into certain specialities due to the multidisciplinary nature of the condition and not
all genetic centres deal appropriately with the family members who may also be at risk. This
is not a universal problem though. Patients should be kept fully informed of tests, results and
their consequences along with appropriate counselling, although it is acknowledged that
this can be difficult. All diagnosed patients should also be referred to the Marfan Association
UK although whether they follow this up is their choice. Inconclusive results can be both
devastating and very difficult for a patient to understand and ongoing support is still required.
Family cascade testing should be conducted when Marfan syndrome is diagnosed in an
index case. Children will also benefit from genetic testing in order to confirm a suspected
diagnosis.
All involved in the care of Marfan syndrome patients should communicate with one another
in order to establish good continuity of care for the patient. A lead care coordinator should
be designated and the patient’s own GP should be kept informed. Cardiac and pulmonary
rehabilitation is not conducted in a timely manner following surgery and this places stress on
both the patient and their families. Patients should be seen by all specialities involved ideally
in a ‘one-stop shop’ facility in order to not only minimise disruption to the patient but also to
aid the diagnostic process and speed up the onset of treatment. Working in this manner in
a clinic at Frimley Park Hospital made making a diagnosis easier. It was acknowledged that
sometimes holding these types of clinics results in them being held less frequently but the
Marfan Association UK would strongly recommend that the frequency of Marfan syndrome
clinics should not be reduced. The Marfan Association UK is also worried that the removal of
the ‘tall and thin’ phenotype from the revised Ghent criteria would mean that GPs may miss
this often obvious clinical presentation of Marfan syndrome and thus hinder the progress
made to date. GPs should be educated to help them identify Marfan syndrome and should
be kept informed of new developments as they are the first contact for patients.
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6. Impact of emerging technology platforms
Edward Blair (Oxford University Hospital NHS Trust, UK)
Presentation
Hypertrophic Cardiomyopathy (HCM) can be used as an example condition to assess the
impact of emerging technology on genetic testing. HCM is similar to Marfan syndrome and
related disorders in terms of the clinical and genetic heterogeneity. For HCM, the clinical
utility of genetic testing is not always solely about making a diagnosis. Marfan syndrome can
often be diagnosed without the need for genetic testing. Utility has been shown in cascade
testing in family members. It has been shown to be cost-effective, identifies those ‘at-risk’
and also very importantly, allows the discharge of those ‘not at-risk’. Marfan syndrome has
stronger evidence for prognostic indications than HCM and thus there is greater potential use
of the information from genetic testing. The challenge lies with the clinical heterogeneity, the
genetic heterogeneity, and the interpretation of results which make up clinical sensitivity.
With HCM, research advances have increased the number of genes associated with HCM,
the cost of testing and turn-around time has reduced, and the knowledge-base has increased
leading to improved interpretation of results. All these factors have improved clinical sensitivity
(9-11% with the 13 gene vs 4 gene panel) with 13 genes currently being tested although a
28 gene cardiac panel is being developed. Trends over the last 10 years for HCM genetic
testing show the number of referrals has gone up. Improvements in testing platforms along
with reduced costs will continue to expand the knowledge-base in Marfan syndrome if used.
Allied to clear and comprehensive clinical phenotyping, a panel test approach would be the
best manner in which to proceed with genetic testing in the Marfan syndrome clinic setting
rather than a sequential gene-by-gene approach. However, it should be noted that the
analysis of results is complex and will remain so as our knowledge continues to expand.
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Discussions
The testing criteria for patients with Marfan syndrome and the clinical diagnostic pathway
for suspected Marfan syndrome patients were discussed and all agreed that they should
be simple to understand and implement. The importance of clear clinical assessment using
the 2010 Ghent criteria cannot be over emphasised. It was agreed that patients would
be referred for genetic testing by either the consultant clinical geneticist or the consultant
cardiologist. It was also agreed that patients should be referred for FBN1 genetic testing with
one of the following: aortic root dilatation/dissection; ectopia lentis; a positive family history
of Marfan syndrome; or a systemic score of greater than or equal to 7 (Annex 1). If the FBN1
test is positive then the patient should continue with the standard care pathway for Marfan
syndrome. If the test is negative then the patient should be referred to a specialist service for
assessment where genetic testing for Marfan syndrome and the related aortopathies should
be considered as appropriate (Annex 2).
There is now an opportunity to significantly improve the clinical diagnostic pathway for
suspected Marfan syndrome patients through the development of a test panel which will test
known genes for inherited syndromes with aortic involvement. This is possible because of the
development of next generation sequencing. The expected benefits of such a new genetic
test includes greater efficiency of genetic testing compared to the current sequential testing
approach and improved diagnosis rate. It is also envisaged that there will be a considerable
reduction in the time to diagnosis for patients. NHS laboratories should be encouraged to
collaborate in identifying which laboratory will lead in the development of such a test.
Recommendations
• The testing criteria for Marfan syndrome should be considered for approval by the
UKGTN and implemented as soon as possible within the NHS.
• The clinical diagnostic pathway for suspected Marfan syndrome should be considered
for approval by the UKGTN and provided as guidance on the UKGTN website.
• It is recommended that a new panel test incorporating all the known genes for inherited
conditions with aortic involvement (so called “aortopathies”) should be developed for
NHS evaluation and clinical use.
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Authors
Gurdeep S Sagoo, PHG Foundation
Shehla Mohammed, UKGTN
Mark Kroese, UKGTN and PHG Foundation
The Foundation for Genomics and Population Health (PHG Foundation)
was commissioned by the UKGTN to write this report.
The PHG Foundation is the working name of the Foundation for Genomics and Population Health,
a charitable company registered in England and Wales, charity No. 1118664 company No. 5823194
References
1. Orphanet. Prevalence of rare diseases, Orphanet Report Series, May 2012, Number
1: Listed in alphabetical order of disease or group of diseases available at http://www.
orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_
list.pdf accessed on 24/09/2012.
2. Loeys BL, et al. The revised Ghent nosology for the Marfan syndrome. Journal of
Medical Genetics 2010; 47: 476-485. Doi:10.1136/jmg.2009.072785
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Annex 1: Agreed consensus testing criteria
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REVISED GHENT CRITERIA (Loeys 2010)
* Loeys BL et al. The revised Ghent nosology for the Marfan syndrome. Journal of Medical Genetics
2010; 47: 476-485. Doi:10.1136/jmg.2009.072785
Table 1. Calculation of the Systemic Score
Feature
Value
Wrist AND thumb sign
3
Wrist OR thumb sign
1
Pectus carinatum deformity
2
Pectus excavatum or chest asymmetry
1
Hindfoot deformity
2
Plain flat foot (pes planus)
1
Pneumothorax
2
Dural ectasia
2
Protrusio acetabulae
2
Reduced upper segment / lower segment AND increased arm span/height ratios
1
Scoliosis or thoracolumbar kyphosis
1
Reduced elbow extension
1
3 of 5 facial features
1
Skin striae
1
Myopia
1
Mitral valve prolapse
1
Maximum total: 20 points
Score ≥ 7 indicates systemic involvement
US/LS= upper segment/lower segment ratio
Aortic root enlargement (Z-score ≥2.0 in those age ≥20 years or ≥3.0 in those age <20 years). Aortic size
must be standardised to age and body size for accurate interpretation. A Z-score ≥2.0 infers a value at or
above the 95th percentile, while a Z-score ≥3.0 infers a value at or above the 99th percentile.
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Annex 2: Agreed consensus clinical pathway for
suspected Marfan syndrome
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Annex 3: Marfan Association UK briefing paper
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Annex 4: Meeting programme
MARFAN’S SYNDROME AND RELATED AORTOPATHIES: DEVELOPING
CONSENSUS TESTING GUIDELINES
Held on 5th September 2012 at the Council Chamber, Royal College of Physicians,
London
Chaired by Rosalind Skinner
10.00
Registration and Coffee
10.30
Introduction and welcome
Rosalind Skinner
10.40 Background and scope of workshop
Shehla Mohammed
Current practice:
10.45
Clinical and testing pathway
Leema Roberts
11.00
The Scottish experience
John Dean
11.30
Perspective from the cardiac clinic
Adult clinic
Christoph Kiesewetter
Paediatric clinic
Juan Kaski
11.45
European perspective
Bart Loeys
12.00
Patient perspective
Diane and Robin Rust
12.15
Lunch
13.00
Impact of emerging technology platforms
13.15
Development of recommendations on consensus referral and testing
guidelines
15.00
Summary and closing remarks
Edward Blair
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Annex 5: Meeting attendees
Name
Job Title
Organisation
Edward Blair
Consultant Clinical Geneticist and Clinical
Lead
Oxford University Hospital NHS Trust
Paul Brennan
Clinical Director, Northern Genetics Service
Newcastle Hospitals NHS Foundation
Trust
Glen Brice
Genetics Counsellor
St George’s Clinical Genetics, London
Sally Cottrell
Clinical Scientist (Molecular Genetics)
St George’s Hospital, London
John Dean
Clinical Geneticist
NHS Grampian, Aberdeen
Perry Elliott
Professor of Cardiovascular Medicine
University College London
Lucy Jenkins
Head of Molecular Genetics
Great Ormond Street Hospital
Juan Kaski
Paediatric Cardiologist in Inherited Cardiac
Disease
Great Ormond Street Hospital
Christoph Kiesewetter
Consultant ACHD Cardiologist
Guy’s and St Thomas Hospital
Mark Kroese
Public Health Advisor, UKGTN
Anna Lehmann
Genetic Counsellor
Guy’s and St Thomas Hospital
Bart Loeys
Clinical Geneticist
Antwerp University Hospital
Sarju Mehta
Clinical Geneticist
Addenbrookes Hospital, Cambridge
Shehla Mohammed
Clinical Advisor, UKGTN
Nicole Motton
Clinical Scientist
West Midlands Regional Genetics Lab
Leema Robert
Consultant Clinical Geneticist
Guy’s and St Thomas Hospital
Diane Rust
Chairman/Support Coordinator
Marfan Association UK
Robin Rust
Patient Support and D/B Management
Marfan Association UK
Anand Saggar
Consultant in Clinical Genetics
St George’s Hospital, London
Gurdeep Sagoo
Epidemiologist
PHG Foundation
Saba Sharif
Consultant Clinical Geneticist
West Midlands Regional Genetic
Service
Rosalind Skinner
Chair, UKGTN
Su Stenhouse
Scientific Advisor, UKGTN
Fiona Stewart
Chair, UKGTN Genetic Test and Evaluation
Working Group
Jacquie Westwood
Director, UKGTN
UK Genetic Testing Network Marfan syndrome testing guideline workshop
5th September 2012 | Royal College of Physicians, London
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