doi: 10.1136/jmg.2009.072785
2010 47: 476-485J Med Genet
Bart L Loeys, Harry C Dietz, Alan C Braverman, et al.
syndrome
The revised Ghent nosology for the Marfan
http://jmg.bmj.com/content/47/7/476.full.html
Updated information and services can be found at:
These include:
References
http://jmg.bmj.com/content/47/7/476.full.html#related-urls
Article cited in:
http://jmg.bmj.com/content/47/7/476.full.html#ref-list-1
This article cites 73 articles, 16 of which can be accessed free at:
service
Email alerting
box at the top right corner of the online article.
Receive free email alerts when new articles cite this article. Sign up in the
Notes
http://jmg.bmj.com/cgi/reprintform
To order reprints of this article go to:
http://jmg.bmj.com/subscriptions
go to: Journal of Medical GeneticsTo subscribe to
group.bmj.com on September 15, 2010 - Published by jmg.bmj.comDownloaded from
The revised Ghent nosology for the Marfan syndrome
Bart L Loeys,
1
Harry C Dietz,
2
Alan C Braverman,
3
Bert L Callewaert,
1
Julie De Backer,
1
Richard B Devereux,
4
Yvonne Hilhorst-Hofstee,
5
Guillaume Jondeau,
6
Laurence Faivre,
7
Dianna M Milewicz,
8
Reed E Pyeritz,
9
Paul D Sponseller,
10
Paul Wordsworth,
11
Anne M De Paepe
1
ABSTRACT
The diagnosis of Marfan syndrome (MFS) relies on
defined clinical criteria (Ghent nosology), outlined by
international expert opinion to facilitate accurate
recognition of this genetic aneurysm syndrome and to
improve patient management and counselling. These
Ghent criteria, comprising a set of major and minor
manifestations in different body systems, have proven to
work well since with improving molecular techniques,
confirmation of the diagnosis is possible in over 95% of
patients. However, concerns with the current nosology
are that some of the diagnostic criteria have not been
sufficiently validated, are not applicable in children or
necessitate expensive and specialised investigations.
The recognition of variable clinical expression and the
recently extended differential diagnosis further
confound accurate diagnostic decision making.
Moreover, the diagnosis of MFSdwhether or not
established correctlydcan be stigmatising, hamper
career aspirations, restrict life insurance opportunities,
and cause psychosocial burden. An international expert
panel has established a revised Ghent nosology, which
puts more weight on the cardiovascular manifestations
and in which aortic root aneurysm and ectopia lentis are
the cardinal clinical features. In the absence of any family
history, the presence of these two manifestations is
sufficient for the unequivocal diagnosis of MFS. In
absence of either of these two, the presence of
a bonafide FBN1 mutation or a combination of systemic
manifestations is required. For the latter a new scoring
system has been designed. In this revised nosology,
FBN1 testing, although not mandatory, has greater
weight in the diagnostic assessment. Special
considerations are given to the diagnosis of MFS in
children and alternative diagnoses in adults. We
anticipate that these new guidelines may delay
a definitive diagnosis of MFS but will decrease the risk of
premature or misdiagnosis and facilitate worldwide
discussion of risk and follow-up/management guidelines.
INTRODUCTION
Since Antoine-Bernard Marfan described the 5-year-
old Gabrielle with skeletal manifestations of the
disease that now bears his name,
1
important
progress has been made in the delineation of the
Marfan syndrome (MFS) and recognition of asso-
ciated risks. The main features of this autosomal
dominant disorder include disproportionate long
bone overgrowth, ectopia lentis and aortic root
aneurysm. In 1955, Victor McKusick first estab-
lished a classification of connective tissue disorders,
which resulted in the publication of his monograph
‘Heritable connective tissue disorders’.
23
In 1986,
an international panel of experts defined a set of
clinical criteria (Berlin nosology) for the diagnosis
of MFS
4
with the aim of facilitating accurate
communication about the condition between
healthcare providers, researchers and patients. It
was felt that this would improve proper patient
management and effective patient counselling.
Following the identification
of FBN1 (encoding
fibrillin-1) as the causal gene for MFS,
5
it was
recognised that the Berlin criteria falsely allowed
a diagnosis of MFS in individuals with a positive
family history of MFS, who had only non-specific
connective tissue findings themselves and who did
not carry the mutation present in more typically
affected family members. New diagnostic criteria
were therefore put forth in 1996, referred to as the
Ghent nosology.
6
These Ghent criteria were more
stringent than the Berlin criteria, mitigating over-
diagnosis of MFS and providing better guidelines to
differentiate MFS from related, ‘overlapping’
conditions such as the MASS phenotype (myopia,
mitral valve prolapse, borderline and non-progres-
sive aortic root dilatation, skeletal findings and
striae) and mitral valve prolapse syndrome (MVPS).
Since physicians associate the diagnosis of
‘Mar
fan syndrome’, above all else, with risk for
aortic aneurysm/dissection, it can be detrimental to
diagnose MFS in patients without tangible evidence
of such risk. Avoidable consequences associated
with misdiagnosis of MFS include: restriction of
career aspirations or access to insurance benefits;
additional financial burden associated with
frequent medical care; anxiety or situational
depression; unfounded marital or reproductive
decisions; loss of health benefits or psychosocial
stigmatisation associated with exercise restriction,
a particularly important issue during childhood.
The challenge is to balance such concerns with the
paramount need to maintain good health through
proper counselling and application of sound antic-
ipatory medical practices. Towards this objective, it
is also important to avoid the diagnosis of MFS
when clinical or molecular observations could
reveal alternative (and often more severe) diagnoses
that mandate specialised counselling or manage-
ment protocols.
The Ghent nosology employs a set of ‘major’ and
‘minor’ manifestations in numerous tissues
including the skeletal, ocular, cardiovascular, and
pulmonary systems and the dura, skin and integu-
ment.
6
Major manifestations include ectopia lentis,
aortic root dilatation/dissection, dural ectasia or
a combination of $4 out of eight major skeletal
features. The diagnosis of MFS in an index patient
1
Center for Medical Genetics,
Ghent University Hospital,
Ghent, Belgium
2
McKusick-Nathans Institute for
Genetic Medicine, Johns
Hopkins University and Howard
Hughes Medical Institute,
Baltimore, USA
3
Department of Cardiology,
Washington University School of
Medicine, Saint-Louis, USA
4
Weill Cornell Medical College,
New York, USA
5
Center for Human and Clinical
Genetics, Leiden University
Medical Center, Leiden, the
Netherlands
6
Centre de Re
´
fe
´
rence pour le
Syndrome de Marfan et
apparante
´
s, Hopital Bichat,
Paris, France
7
Center for Genetics, Children’s
Hospital, Dijon, France
8
Department of Medical
Genetics, University of Texas
Medical School, Houston, USA
9
Department of Medical
Genetics, University of
Pennsylvania, Philadelphia, USA
10
Department of Orthopedics,
Johns Hopkins University,
Baltimore, USA
11
Clinical Rheumatology,
Nuffield Orthopeadic Center,
Oxford, UK
Correspondence to
Professor Bart Loeys, Center for
Medical Genetics, Ghent
University Hospital, Building
OK5, De Pintelaan 185, 9000
Gent, Belgium;
bart.loeys@ugent.be
BLL and HCD contributed
equally to the manuscript.
Received 26 August 2009
Revised 16 December 2009
Accepted 17 December 2009
476 J Med Genet 2010;47:476e485. doi:10.1136/jmg.2009.072785
Original article
group.bmj.com on September 15, 2010 - Published by jmg.bmj.comDownloaded from
requires major involvement of at least two organ systems with
minor involvement of a third organ system. In the presence of an
FBN1 mutation known to cause MFS or a first degree relative
who was unequivocally diagnosed based upon Ghent nosology,
the presence of one major and one minor manifestation in
different organ systems is sufficient to make the diagnosis.
Current status of the Ghent nosology
The Ghent criteria have found worldwide application in helping
physicians to diagnose MFS appropriately. New molecular
techniques allow the detection of FBN1 mutations in up to 97%
of Marfan patients who fulfil the Ghent criteria.
7 8
This suggests
that the cur rent Ghent criteria have excellent speci ficity to
identify patients with FBN1 mutations. Consideration of
sensitivity is highly complex due to varying definitions of the
‘target’ population and competing clinical priorities. For
example, the current criteria have been criticised for taking
insufficient account of the age dependent nature of some clinical
manifestations (making the diagnosis in children more difficult)
9
and for including some rather non-specificphysicalmanifesta-
tions or poorly validated diagnostic thresholds. Although the
assignment of major and minor criteria within the Ghent
nosology has contributed to its utility, several of those criteria are
not intuitive when considered from the perspective of the
differential diagnosis or patient management. Consideration of
the d iagnosis of familial ectopia lentis is particularly illustrative
of the prevailing issues. This diagnostic category has been
widely applied for individuals and famil ies that show lens
dislocation and skeletal features of MFS but do not show aortic
enlargement or dissection. FBN1 mutations are seen in familial
ectopia lentis and are not easily distinguished from those
causing MFS on the basis of character or location within the
genedsuggesting either occult phenotypeegenotype correla-
tions or the influence of modifiers.
The Ghent nosology clearly attempted to accommodate the
fact
that some people with ectopia lentis, skeletal findings and
even FBN1 mutation have less cardiovascular risk (ie, risk to the
aortic root) than seen in classic MFS, by allowing the diagnosis
of familial ectopia lentis in the absence of a second major
Marfan manifestation. However, inadequate data were avail-
able to evaluate the critical issue of whether cardiovascular risk
could be p redicted by the presence of non-cardiac features, such
as dural ect asia or major versus mi nor skeletal involvement. At
the other extreme, is it justified not to dia gnose M FS in
someone with typical lens dislocation and aortic root enlarge-
ment simply because they lack minor skeletal or skin findings?
To address some of these issues, an international panel (see
acknowledgement) of experts in the diagnosis and manage-
ment of MFS was convened in Brussels, Belgium by the
National Marfan Foundation (USA) and charged with consid-
ering modifications to the Ghent criteria. Other factors under
consideration included the specialised nature, availability and
cost of diagnostic tests for selected manifestations (eg, dural
ectasia), the need to define certain diagnostic categories better
(eg, familial ectopia lentis, MASS phenotype
10
and MVPS), to
define features that should trigger alternative diagnoses a nd
a desire to complement diagnostic criteria with follow-up, and
management guidelines for various patient groups including
childrenwhodonotyetfulfil the diagnostic criteria but may do
so i n the fut ure.
Proposal for new nosology
This proposal for a revised nosology (box 1) was based on critical
review of clinical characteristics in large published patient
cohorts,
7 81112
and expert opinions of the panel members with
extensive experience in applying the current criteria, the differ-
ential diagnosis of MFS, and the strengths and limitations of
molecular genetic testing. Several guiding principles were
followed: maximal use of evidence based decision making;
attention to practical (patient centric) implications; a focus on
features and criteria that distinguish MFS from other disorders;
and definition of purposeful thresholds for diagnosis. As a result,
five major changes in the diagnostic guidelines are proposed.
First, more weight is given to two cardinal features of MFS,
aortic
root aneurysm/dissection and ectopia lentis. In the
absence of findings that are not expected in MFS, the combi-
nation of ectopia lentis and aortic root enlargement/dissection
should be sufficient to make the diagnosis. All other cardiovas-
cular and ocular manifestations of MFS and findings in other
organ systems, such as the skeleton, dura, skin and lungs,
contribute to a ‘systemic score’ (box 2) that guides diagnosis
when aortic disease is present but ectopia lentis is not.
Second, a more prominent role is assigned to molecular
genetic testing of FBN1 and other relevant genes (eg, TGFBR1
and 2), as well as other genes indicated in table 1. In practice,
this does not make FBN1 testing a formal requirement (which
imposes financial burden in some countries, and does not yet
have 100% sensitivity and specificity), but allows its appropriate
use when available.
Box 1 Revised Ghent criteria for diagnosis of Marfan
syndrome and related conditions
In the absence of family history:
(1) Ao (Z $2) AND EL¼MFS*
(2) Ao (Z $2) AND FBN1¼MFS
(3) Ao (Z $2) AND Syst ($7pts)¼MFS*
(4) EL AND FBN1 with known Ao¼MFS
EL with or without Syst AND with an FBN1 not known with Ao or
no FBN1¼ELS
Ao (Z < 2) AND Syst ($5 with at least one skeletal feature)
without EL¼MASS
MVP AND Ao (Z <2) AND Syst (<5) without EL¼MVPS
In the presence of family history:
(5) EL AND FH of MFS (as defined above)¼MFS
(6) Syst ($7 pts) AND FH of MFS (as defined above)¼MFS*
(7) Ao (Z$2 above 20 years old, $3 below 20 years) +FH of
MFS (as defined above)¼MFS*
* Caveat: without discriminating features of SGS, LDS or vEDS
(as defined in table 1) AND after TGFBR1/2, collagen biochem-
istry, COL3A1 testing if indicated. Other conditions/genes will
emerge with time.
Ao, aortic diameter at the sinuses of Valsalva above indicated
Z-score or aortic root dissection; EL, ectopia lentis; ELS, ectopia
lentis syndrome; FBN1, fibrillin-1 mutation (as defined in box 3);
FBN1 not known with Ao, FBN1 mutation that has not previously
been associated aortic root aneurysm/dissection; FBN1 with
known Ao, FBN1 mutation that has been identified in an individual
with aortic aneurysm; MASS, myopia, mitral valve prolapse,
borderline (Z<2) aortic root dilatation, striae, skeletal findings
phenotype; MFS, Marfan syndrome; MVPS, mitral valve prolapse
syndrome; Syst, systemic score (see box 2); and Z, Z-score.
J Med Genet 2010;47:476e485. doi:10.1136/jmg.2009.072785 477
Original article
group.bmj.com on September 15, 2010 - Published by jmg.bmj.comDownloaded from
Third, some of the less specific manifestations of MFS were
either removed or made less in fluential in the diagnostic evalu-
ation of patients. This avoids the use of obligate thresholds that
lack clear validation or general availability.
Fourth, the new criteria formalise the concept that additional
diagnostic considerations and testing are required if a patient has
sufficient findings to satisfy the criteria for MFS but also shows
unexpected findings, particularly if they segregate with disease
in the family or if they are suggestive of a specific alternative
diagnosis. Particular emphasis is placed on SphrintzeneGoldberg
syndrome (SGS), LoeyseDietz syndrome (LDS), and the
vascular form of Ehlerse Danlos syndrome (vEDS). SGS and LDS
have substantial overlap with MFS, including the potential for
similar involvement of the skeleton, aortic root, skin and dura
(table 1). Occasionally, vEDS shows overlap in the vascular
system, dura, skin and skeleton. It is essential to consider
discriminating features (table 1) because each of these conditions
has a unique risk profile and management protocol.
Finally, this nosology should help to allay concerns regarding
delayed or ambiguous diagnoses by providing context specific
recommendations for patient counselling and follow-up.
In the revised nosology, new diagnostic criteria have been
defined for a sporadic patient and for an index patient with
a positive family history (box 1). In the absence of a conclusive
family history of MFS, the diagnosis can be established in four
distinct scenarios:
1. The presence of aortic root dilatation (Z-score $2
when
standardised to age and body size) or dissection
13
and ectopia
lentis allows the unequivocal diagnosis of MFS, irrespective
of the presence or absence of systemic features except where
these are indicative of SGS, LDS or vEDS (table 1).
2. The presence of aortic root dilatation (Z$2) or dissection and
the identification of a bona fide FBN1 mutation (box 3) is
sufficient to establish the diagnosis even when ectopia lentis
is absent. An overview of criteria that enhance confidence in
the pathogenetic potential for MFS of particular FBN1
mutations is provided in box 3. These include missense
mutations that substitute or create cysteine residues, alter
one of the conserved residues important for calcium binding
in epidermal growth factor-like (EGF) domains, create
a premature termination codon (nonsense mutations),
delete or insert coding sequence, or disrupt the consensus
sequence for pre-mRNA splicing. Evidence for pathogenicity
of other types of missense mutations would include its
absence in at least 400 ethnically matched control chromo-
somes and co-segregation with disease in the family, or de
novo occurrence in a sporadic case (with confirmation of
paternity). Definitive evidence of linkage to a predisposing
FBN1 haplotype can substitute for an FBN1 mutation for
diagnostic purposes, but this linkage analysis requires at least
six informative meioses in the patient’s family to confirm the
MFS associated FBN1 allele. The absence of a mutation in the
FBN1 gene despite complete screening is possible in MFS.
3. Where aortic root dilatation (Z $2) or dissection is present
but ectopia lentis is absent and the FBN1 status is either
unknown or negative, an MFS diagnosis is confirmed by the
presence of sufficient systemic findings ($7 points, according
to a new scoring system) (box 2). However, features
suggestive of SGS, LDS or vEDS must be excluded and
appropriate alternative genetic testing (TGFBR1/2, collagen
biochemistry, COL3A1, and other relevant genetic testing
when indicated and available upon the discovery of other
genes) should be performed.
4. In the presence of ectopia lentis but absence of aortic root
dilatation/dissection, the identification of an FBN1 mutation
previously associated with aortic disease is required before
Box 2 Scoring of systemic features
<
Wrist AND thumb sign e 3 (wrist OR thumb sign e 1)
<
Pectus carinatum deformity e 2 (pectus excavatum or chest
asymmetry e 1)
<
Hindfoot deformity e 2 (plain pes planus e 1)
<
Pneumothorax e 2
<
Dural ectasia e 2
<
Protrusio acetabuli e 2
<
Reduced US/LS AND increased arm/height AND no severe
scoliosis e 1
<
Scoliosis or thoracolumbar kyphosis e 1
<
Reduced elbow extension e 1
<
Facial features (3/5) e 1 (dolichocephaly, enophthalmos,
downslanting palpebral fissures, malar hypoplasia, retrogna-
thia)
<
Skin striae e 1
<
Myopia > 3 diopters - 1
<
Mitral valve prolapse (all types) e 1
Maximum total: 20 points; score $7
indicates systemic
involvement; US/LS, upper segment/lower segment ratio.
Table 1 Features of differential diagnosis
Differential diagnosis Gene Discriminating features
LoeyseDietz syndrome (LDS) TGFBR1/2 Bifid uvula/cleft palate, arterial tortuosity, hypertelorism, diffuse
aortic and arterial aneurysms, craniosynostosis, clubfoot,
cervical spine instability, thin and velvety skin, easy bruising
ShprintzeneGoldberg syndrome (SGS) FBN1 and other Craniosynostosis, mental retardation
Congenital contractural arachnodactyly (CCA) FBN2 Crumpled ears, contractures
WeilleMarchesani syndrome (WMS) FBN1 and ADAMTS10 Microspherophakia, brachydactyly, joint stiffness
Ectopia lentis syndrome (ELS) FBN1
LTBP2
ADAMTSL4
Lack of aortic root dilatation
Homocystinuria CBS Thrombosis, mental retardation
Familial thoracic aortic aneurysm syndrome (FTAA) TGFBR1/2, ACTA2 Lack of Marfanoid skeletal features, levido reticularis, iris
flocculi
FTAA with bicupid aortic valve (BAV)
FTAA with patent ductus arteriosus (PDA) MYH11
Arterial tortuosity syndrome (ATS) SLC2A10 Generalised arterial tortuosity, arterial stenosis, facial
dysmorphism
EhlerseDanlos syndromes (vascular, valvular, kyphoscoliotic
type)
COL3A1, COL1A2, PLOD1 Middle sized artery aneurysm, severe valvular insufficiency,
translucent skin, dystrophic scars, facial characteristics
478 J Med Genet 2010;47:476e485. doi:10.1136/jmg.2009.072785
Original article
group.bmj.com on September 15, 2010 - Published by jmg.bmj.comDownloaded from
making the diagnosis of MFS. If the FBN1 mutation is not
unequivocally associated with cardiovascular disease in either
a related or unrelated proband, the patient should be classifi ed
as ‘ectopia lentis syndrome’ (see differential diagnosis).
In an individual with a positive family history of MFS (where
a family member has been independently diagnosed using the
above criteria), the diagnosis can be established in the presence
of ectopia lentis, or a systemic score $7 points or aortic root
dilatation with Z $2 in adults ($20 years old) or Z $3in
individuals <20 years old.
Special consideration should be given to young individuals
(<20 years old). In sporadic cases, these children may not fitin
one of the four proposed scenarios. If insufficient systemic
features (<7) and/or borderline aortic root measurements (Z <3)
are present (without FBN1 mutation), we suggest to use the
term ‘non-specific connective tissue disorder’ until follow-up
echocardiographic evaluation shows aortic root dilation (Z $3).
If an FBN1 mutation is identified in sporadic or familial cases but
aortic root measurements are still below Z¼3, we propose to use
the term ‘potential MFS’ until the aorta reaches threshold.
Neonatal MFS is not considered as a separate category, but
rather represents the severe end of the MFS spectrum.
In adults (>20 years), we define three main categories of
alternative diagnoses: ectopia lentis syndrome (ELS), MASS
phenotype (myopia, mitral valve prolapse, borderline (Z<2)
aortic root enlargement, skin and skeletal findings), and mitral
valve prolapse syndrome (MVPS) (see differential diagnosis).
Finally, we recognise that some patients will remain difficult
to classify due to overlap of phenotypes from different entities,
the evolving nature of these connective tissue diseases, absence
of mutation after screening of the appropriate genes, or diver-
gence between the phenotype and the genotype. However, these
patients should be uncommon and will hopefully benefit from
better definition of still unrecognised phenotypes in the future.
ORGAN SYSTEM SPECIFIC CONSIDERATIONS
Cardiovascular criteria
A key diagnostic criterion in the new nosology is aortic root
aneurysm or dissection. Aortic root aneurysm is defined as
enlargement of the aortic root at the level of the sinuses of
Valsalva. Aortic root measurements should be done parallel to
the plane of the aortic valve and perpendicular to the axis of
blood flow. The largest correctly measured root diameter
obtained from at least three transthoracic images should be
corrected for age and body size and interpreted as a Z-score.
There are var ying practices regarding whether root measure-
ments should be done in systole or diastole and whether the
thickness of one aortic wall should be included (ie, the leading
edge to leading edge method). The method employed must
match that used to generate the normative data for Z-scores to
be valid. For echocardiographic measurements made from inner
wall to inner wall during systole in individuals #25 years,
a convenient Z-score calculator can be found at http://www.
marfan.org. For echocardiographic measurements made from
leading edge to leading edge in diastole in all age groups, refer-
ence graphs and Z-score equations are available
13
. If trans-
thoracic echocardiographic evaluations do not allow precise
visualisation of the proximal aorta, transoesophageal echocar-
diography or CT or MRI imaging should be applied, with special
attention to using double-oblique images to obtain correct
diameter measurements and use of the same nomograms.
14
Mitral valve prolapse is also a common finding in MFS and is
included as a feature in the systemic score. Mitral valve prolapse
should be defined by echocardiography as protrusion of one or
both of the mitral valve leaflets across the plane of the mitral
annulus during systole. This is best detected in parasternal long
axis or apical long axis three-chamber or two-chamber views.
There are no special criteria for diagnosing MVP in MFS and
standard practices should be applied.
15
Pulmonary artery (PA) dilation (eg, main PA diameter
>23 mm in adults)
16
is often seen in MFS, but it is not speci fic
to this diagnosis. In addition, complications of pulmonary artery
disease occur rarely. PA dilation was not therefore included in
the systemic score because further research is needed regarding
thresholds and the diagnostic utility of this finding.
Patients with MFS can develop aortic enlargement or dissection
at
segments distant from the aortic root. The frequency of this
finding (particularly at the proximal descending thoracic aorta and
in the abdomen) appears to be increasing with the prolonged
survival due to improved management of disease at the aortic root.
While descending aortic aneurysm or dissection in the absence of
aortic root enlargement can occur in Mar fan syndrome,
17 18
this is
rare and given the low specificity of this finding for MFS, this
finding is not included in the diagnostic criteria. Intermittent
imaging of the descending thoracic aorta is indicated in adult
patients where there is a clinical suspicion of Marfan syndrome in
the absence of aortic root enlargement. Widespread vascular
disease is more common with other conditions in the differential
diagnosis, such as vascular EDS and LDS. For example, systemic
vascular imaging (head to pelvis) is recommended if there is
a suspicion of LDS because of the high frequency of tortuosity,
aneurysms and dissections throughout the vascular tree.
Ocular criteria
The most prominent ocular features of MFS are myopia and
ectopia lentis. The diagnosis of ectopia lentis is based on slit-
lamp examination after maximal dilatation of the pupil. Ectopia
lentis reflects failure of supporting structures called ciliary
zonules. Dislocation of the lens in MFS is most typically upward
and temporal, but deviation in any direction may occur. If lens
subluxation is deemed equivocal or minimal, manifesting only as
a scalloped or ruf fled lens margin at extremes of gaze, the eye
exam should be repeated later before a definitive diagnosis of
ectopia lentis can be made (such findings can occur outside the
Box 3 Criteria for causal FBN1 mutation
<
Mutation previously shown to segregate in Marfan family
<
De novo (with proven paternity and absence of disease in
parents) mutation (one of the five following categories)
<
Nonsense mutation
<
Inframe and out of frame deletion/insertion
<
Splice site mutations affecting canonical splice sequence or
shown to alter splicing on mRNA/cDNA level
<
Missense affecting/creating cysteine residues
<
Missense affecting conserved residues of the EGF consensus
sequence ((D/N)X(D/N)(E/Q)Xm(D/N)Xn(Y/F) with m and n
representing variable number of residues; D aspartic acid, N
asparagine, E glutamic acid, Q glutamine, Y tyrosine, F
phenylalanine)
<
Other missense mutations: segregation in family if possible +
absence in 400 ethnically matched control chromosomes, if
no family history absence in 400 ethnically matched control
chromosomes
<
Linkage of haplotype for n$6 meioses to the FBN1 locus
J Med Genet 2010;47:476e485. doi:10.1136/jmg.2009.072785 479
Original article
group.bmj.com on September 15, 2010 - Published by jmg.bmj.comDownloaded from
