Results of fibrillin-1 gene analysis in children from

inbred families with lens subluxation

Arif O. Khan, MD,a Hanno J. Bolz, MD,b,c and Carsten Bergmann, MDb,d

BACKGROUND Autosomal dominant mutation of the FBN1 gene (fibrillin-1) results in a spectrum of dis-
ease (type 1 fibrillopathies) ranging from Marfan syndrome with lens subluxation and car-
diovascular complications to milder connective tissues phenotypes. The likelihood of
FBN1 mutation in children referred to ophthalmologists because of lens subluxation is un-
clear. We report the results of routine FBN1 sequencing for children from inbred families
referred with nontraumatic lens subluxation without cataract or vitreoretinal degeneration.
METHODS Medical records of such patients from 2009 to 2012 were retrospectively reviewed.
RESULTS Eight identified probands (3-11 years old; 4 boys) from consanguineous and/or endoga-
mous Saudi Arabian families all harbored FBN1 mutation—7 autosomal dominant and 1
autosomal recessive (homozygous). Four mutations were novel. One child had a family
history for lens subluxation. Seven had facial and/or skeletal features suggestive of type 1
fibrillinopathy. The parents of the autosomal recessive case were confirmed to be hetero-
zygous carriers without lens subluxation or other clinical signs of type 1 fibrillinopathy.
CONCLUSIONS Autosomal dominant type 1 fibrillinopathy was the major cause for lens subluxation in this
cohort despite the fact that families were inbred and thus at higher risk for recessive disease.
This highlights the frequency of new mutations in the gene and has important implications
for genetic counseling and systemic assessment. The autosomal recessive case represents
the fourth such case reported to date. Her heterozygous parents were unaffected carriers,
suggesting that some FBN1 mutations can act as hypomorphic alleles rather than exhibit-
ing the dominant negative effect typically attributed to FBN1 mutations. ( J AAPOS
2014;18:134-139)

E
ctopia lentis is a general term that refers to a dis-
placed crystalline lens. Lens subluxation specif-
ically refers to a crystalline lens that is off center
superiorly or inferiorly and/or laterally but remains behind
the iris. A lens that is completed displaced into the anterior
chamber or vitreous cavity is considered luxated. If the lens
remains normally positioned behind the pupil but with
weakness of the supporting zonules for 360 degrees and
resultant anterior–posterior deepening, spherophakia de-
velops. The major causes of ectopia lentis are gene muta-
tions and trauma.
Fibrillin-1 is an important component of the lens zon-
ules and is encoded by the gene fibrillin-1 (Mendelian In-
heritance in Man [MIM] *134797; FBN1). Autosomal
Author affiliations: aDivision of Pediatric Ophthalmology, King Khaled Eye Specialist
Hospital, Riyadh, Saudi Arabia; bCenter of Human Genetics, Bioscientia, Ingelheim,
Germany; cInstitute of Human Genetics, University of Cologne, Cologne, Germany;
d
Department of Nephrology & Center for Clinical Research, University Hospital Freiburg,
Germany
Submitted June 18, 2013.
Revision accepted November 28, 2013.
Correspondence: Arif O. Khan, MD, Division of Pediatric Ophthalmology, King Khaled
Eye Specialist Hospital, Riyadh 11462, Saudi Arabia (email: arif.khan@mssm.edu).
Copyright Ó 2014 by the American Association for Pediatric Ophthalmology and
Strabismus.
1091-8531/$36.00
http://dx.doi.org/10.1016/j.jaapos.2013.11.012
dominant mutation in FBN1 is an important genetic cause
of crystalline lens subluxation as well as a spectrum of over-
lapping extraocular findings primarily involving the skel-
etal and cardiovascular systems; these phenotypes can be
considered type 1 fibrillinopathies.1-3 Approximately
1,500 FBN1 mutations have been reported to date, most
of which are missense, are associated with Marfan
syndrome, are considered to have a dominant-negative ef-
fect (ie, a deleterious effect on the normal allele’s function),
and are private mutations unique to individual families
(Human Genome Mutation Database Professional
2012.4, http://www.hgmd.cf.ac.uk/). Marfan syndrome is
a type 1 fibrillinopathy characterized by a myopathic facies
and tall thin body habitus and defined by international
criteria,4,5 the most important of which clinically are
ectopia lentis and progressive aortic root dilatation.
Because the latter is life-threatening if not addressed early,
ophthalmologists who manage lens subluxation in children
should recognize those with underlying type 1 fibrillinop-
athy and refer such children for appropriate systemic eval-
uation. Those children with underlying type 1
fibrillinopathy who have lens subluxation and a Marfanoid
habitus or a family history for type 1 fibrillinopathy are
obvious FBN1 mutation suspects. However, some affected
children may not develop a Marfanoid body habitus until
after several years of age or never do,6-8 and in the

134 Journal of AAPOS

Volume 18 Number 2 / April 2014
absence of family history for the disease the likelihood of
FBN1 mutation in a child referred for apparently isolated
lens subluxation is unclear.
We report the results of FBN1 sequencing in a cohort of
children referred for management of lens subluxation on
the Arabian Peninsula, where homozygous autosomal
recessive causes for lens subluxation may be more common
than autosomal dominant causes because consanguineous
and/or endogamous marriage is customary.9
Subjects and Methods
The Institutional Review Board of the King Khaled Eye
Specialist Hospital granted approval for this retrospective case
series. The medical records of Saudi Arabian children referred
to a pediatric ophthalmologist for nontraumatic lens subluxation
were reviewed from 2009 to 2012. Children with cataract, vitre-
oretinal degeneration, complete lens luxation, or obviously ab-
sent or broken zonules were excluded because these findings
suggest specific genetic diagnoses (as detailed in the Discussion).
Keratometry was performed when patients cooperated. In addi-
tion to complete ophthalmological examination that included
cycloplegic refraction (cyclopentolate 1%), general physical
assessment with attention to clinical features commonly associ-
ated with Marfan syndrome (facial features, body habitus, chest
integrity, presence/absence of scoliosis, relative finger length)
was performed.
Regardless of the results of general physical assessment, as a
routine all children who met the above referral criteria underwent
FBN1 sequencing after informed consent. Venous blood samples
(5-10 cc) were collected and DNA extracted. Mutation analysis of
the entire FBN1 coding region (exons 1-65) and adjacent intronic
boundaries was performed by Sanger sequencing (primers used
for PCR and direct sequencing are available on request). The re-
sulting sequence data was compared with the reference sequence
ENSG00000166147. Bioinformatic analysis was performed using
different in silico algorithms10-12 and SeqPilot software (JSI
medical systems, Kippenheim, Germany). Parents of children
found to harbor a FBN1 mutation underwent ophthalmic
screening (visual acuity testing, slit-lamp examination) and gen-
eral physical assessment with attention to clinical features
commonly associated with Marfan syndrome as noted above.
Results
A total of 8 children (3-11 years old; 4 boys and 4 girls) were
identified. All were from consanguineous and/or endoga-
mous families; only 1 had a family history that included
additional relatives being affected by childhood lens sub-
luxation. Two children had a presumptive clinical suspi-
cion for Marfan syndrome raised by a pediatrician before
referral. Seven had facial and/or skeletal features suggestive
of type 1 fibrillinopathy noted by the pediatric ophthalmol-
ogist. Clinical findings are summarized in Table 1. For
each family a FBN1 mutation was found; 4 were
previously reported3,13-16 and 4 were novel to this study
(cases 1, 4, 6, 8; Table 1).
Journal of AAPOS
Khan, Bolz, and Bergmann 135
Of the 8 children, 7 harbored a heterozygous autosomal
dominant mutation. The eighth child harbored a homozy-
gous autosomal recessive mutation. This child (case 8) had
a novel mutation (c.7258A.C; p.Asn2420His) that
substitutes a highly conserved amino acid and is predicted
to be pathogenic by the bioinformatics programs SIFT,10
PolyPhen2,11 and MutationTaster.12 Other than lens
subluxation and facial features suggestive of type 1 fibrillin-
opathy (Figures 1 and 2), she had no other clinical
abnormalities and was developmentally normal for a 3-
year-old girl. Her parents, confirmed as heterozygous
carriers for the mutation, had no ectopia lentis or facial/
skeletal features to suggest type 1 fibrillinopathy.4
Discussion
Despite the fact that homozygous autosomal recessive ge-
netic eye diseases are more common in this population, pri-
vate autosomal dominant FBN1 mutation was the
predominant cause for pediatric lens subluxation without
cataract or vitreoretinal degeneration in this case series,
which highlights the relative frequency of new mutation
in the gene and its specificity for the phenotype. Facial
and/or skeletal features suggestive of type 1 fibrillinopathy
were present in 7 of the 8 children. In the case of the
affected girl harboring a homozygous autosomal recessive
FBN1 mutation, the findings in her family are probably
related to a reduction of protein product rather than the
dominant negative effect typically attributed to FBN1 mu-
tation.
FBN1 is a 65-exon gene that encodes fibrillin-1, a
cysteine-rich secreted extracellular matrix glycoprotein
that is the major component of connective tissue microfi-
brils—both the type containing an elastin core (known as
elastic fibers and found throughout the body) and the
type without an elastin core (found in selected structures,
such as the ciliary zonules of the eye).17 Cysteine residues
are important in forming disulphide bonds and thus the
protein’s normal three-dimensional folding. In addition
to its structural role, fibrillin-1 interacts with growth fac-
tors. For example, it sequesters and thus inhibits trans-
forming growth factor beta, the overexpression of which
leads to extraocular connective tissue manifestations such
as seen in Marfan syndrome.18
Fibrillin-1 is mainly comprised of 47 domains homolo-
gous to the precursor of human epithelial growth factor
(EGF), 43 of which contain a calcium-binding consensus
sequence. Interspersed among these EGF domains are 8
transforming growth factor beta 1 binding protein like
domains (TGFBR1s). In addition, fibrillin-1 has 2 hybrid
domains that combine features of both EGF and TGFBR1
domains, a unique amino-terminal stretch of basic resi-
dues, a proline-rich domain, and a carboxy-terminal re-
gion. Criteria for what constitutes a causal FBN1
mutation in a clinically affected individual include missense
variants that substitute or create cysteine residues, missense
variants that alter one of the conserved residues important
136 Khan, Bolz, and Bergmann Volume 18 Number 2 / April 2014

Table 1A. Summary of ophthalmic findings

ID Age (sex) Eye BCVA HCD K1 K2 Lens subluxation RNS
1 11(F) R 20/25 12.3 39.8 39.4 N/A 15
L 20/25 12.1 40.8 38.4 N/A 15
2 7 (M) R 20/50 N/A 39.06 41.67 superonasal 17 15.00  080
L 20/30 N/A 39.29 41.41 superonasal 10 12.00  070
3 6 (F) R 20/40 12.7 38 37.4 inferonasal 112.5 12.00  070
L 20/40 12 35.9 32 superonasal 16.5
4 5 (M) R 20/25 11.11 39.7 41.7 superonasal 11
L 20/25 11.77 38.7 42.5 superonasal 11
5 4 (F) R 20/50 N/A N/A N/A superotemporal 16
L 20/70 N/A N/A N/A superotemporal 16.75
6 4 (M) R 20/50 N/A N/A N/A superior 9.5 15.75  090
L 20/50 N/A N/A N/A superior 7.5 15.75  090
7 4 (M) R CSM N/A 39.25 41.25 superotemporal 11
L CSM N/A 39 41.25 superotemporal 11
8 3 (F) R CSM 11 N/A N/A inferior 13
L CSM 11 N/A N/A inferior 14
BCVA, best-corrected visual acuity; CSM, central, steady, maintained fixation; HCD, horizontal corneal diameter, mm; K1, K2, keratometry; RNS,
clearest retinoscopy refraction; N/A, information not documented.

Table 1B. Summary of nonophthalmic findings and mutations

ID General Additional findings FBN1 mutation Mutation reference
1 F cardiac valvular disease c.693C.A; p.Cys231X (heterozygous) Current study
2 F, C, E lid ptosis; cardiac valvular disease c.3464-1G.A; IVS27-1G.A (heterozygous) 13 (MFS)
3 E scoliosis c.2722T.C; p.Cys908Arg (heterozygous) 3 (MFS)
4 F, C, E ——— c.216712T.C; IVS1712T.C (heterozygous) Current study
5 none familial EL only c.2051G.A; p.Cys684Tyr (heterozygous) 14 (MFS)
6 F clindactyly c.8010C.G; p.Typ2670X (heterozygous) Current study
7 F low-set ears c.4588C.T (p.Arg1530Cys) (heterozygous) 15,16 (EL)
8 F ——— c.7258A.C (p.Asn2420His) (homozygous) Current study
C, pectus excavatum; E, long, thin extremities; EL, ectopia lentis; F, myopathic facies; MFS, Marfan syndrome.

for calcium binding in EGF domains, nonsense mutations,
in-frame and out-of-frame deletions/insertions, and splice
site mutations shown to alter splicing on mRNA/cDNA
level.5 Phenotype-genotype correlation for FBN1 muta-
tions is limited and variable expressivity is common; lens
subluxation is the most consistent feature, particularly in
mutations that affect a cysteine residue.3,7,19
Although isolated ectopia lentis has been described as an
FBN1-related phenotype, the diagnosis of isolated FBN1-
related ectopia lentis should be made with caution and not
at all in children. Careful assessment of adults with FBN1-
related ectopia lentis virtually always reveals other manifes-
tations of Marfan syndrome, whether or not they meet
criteria for the formal diagnosis; however, in children ex-
traocular manifestations of Marfan syndrome from FBN1
mutation may not yet be evident.6,7,19 In one study of 8
children with apparently isolated ectopia lentis found to
harbor underlying FBN1 mutation, cardiovascular
imaging performed solely based on the mutation results
revealed 7 of the 8 had evidence of aortic root dilation.8
Thus any child with apparently isolated ectopia lentis
found to have underlying FBN1 mutation should be re-
garded as potential Marfan syndrome (“Marfan syndrome
suspect”) rather than isolated ectopia lentis and must be
followed accordingly for the possibility of progressive
aortic root dilation.5 All families in this cohort were
referred for cardiovascular evaluation and follow-up,
including the older affected family members of case 5
(who thus far have no extraocular manifestations).
Whereas the diagnosis of isolated ectopia lentis should
not be made in a child with FBN1 mutation, pediatric iso-
lated ectopia lentis can be caused by autosomal recessive
mutation in ADAMTSL4 (MIM *610113; a disintegrin-
like and metalloproteinase with thrombospondin type 1
like 4), which encodes a fibrillin-1-binding protein that fa-
cilitates microfibril assembly. The 15 different
ADAMTSL4 mutations documented to underlie isolated
ectopia lentis cases and isolated ectopia lentis et pupillae
are mostly from Europe,20,21 one of which is a founder
20 base-pair deletion.22 To date, in the Middle East region
autosomal recessive ADAMTSL4 mutations have only
been documented in 1 Jordanian and 1 Turkish family.23,24
One child in our cohort with lens subluxation had molec-
ularly proven biallelic disease (homozygous autosomal
recessive FBN1 mutation) and her parents were confirmed
to be heterozygous for the mutation but unaffected and
thus carriers. This unusual finding supports the hypothesis
that some FBN1 mutations can behave as hypomorphic al-
leles (where lack of normal protein leads to disease) rather
than the more commonly cited mechanism of a dominant

Journal of AAPOS
Volume 18 Number 2 / April 2014
FIG 1. Patient 7. The facial photograph of this child with lens sublux-
ation shows features consistent with type 1 fibrillinopathy such as
myopathic facies and an appearance older than her actual age
(3 years).
FIG 2. Patient 4. A slit-beam photograph in the left eye of this child
with lens subluxation but no cataract or vitreoretinal degeneration
shows zonules are intact. Zonules are present for 360 degrees (but
may not be clear in the photograph).
negative effect (where the mutated protein interferes with
normal protein function).25-27 Homozygous autosomal
recessive FBN1 mutations have been reported previously
in 3 families.25-27 As was the case for the current family,
the affected homozygous children had lens subluxation but
their heterozygous parents did not; however, some
heterozygous individuals from these families were found
to have type 1 fibrillinopathy rather than simply being
Journal of AAPOS
Khan, Bolz, and Bergmann 137
unaffected carriers.25-27 The first report was of 2 cousins
from a consanguineous Turkish family with Marfan
syndrome and homozygous c.1453C.T FBN1 mutation
(p.Arg485Cys).25 The heterozygous parents did not have
ectopia lentis, did not fulfill Ghent criteria for Marfan syn-
drome, and were thus carriers. The mutation, located close
to the final cysteine residue in a calcium-binding EGF
domain, was predicted to disrupt the domain’s structure.
The second report described 3 relatives from a Turkish fam-
ily with homozygous c.7454A.T mutations (p.As-
p2458Val).26 The mutation, located in the first aspartic
acid of a calcium-binding EGF domain, was predicted to
act as a hypomorphic allele. Although none of the confirmed
heterozygous individuals had ectopia lentis, 1 did fulfill
Ghent criteria for the diagnosis of Marfan syndrome after
careful examination. The third report was a Mexican Amer-
ican woman with homozygous c.7726C.T mutation
(p.Arg2576Cys), which substituted a seventh cysteine in an
EGF domain.27 Her mother was confirmed to be heterozy-
gous for the mutation but was described as lacking examina-
tion findings of Marfan syndrome and was thus considered a
carrier; the father had died from a cardiac event and was thus
unavailable for examination. The woman gave birth to a son
who was apparently affected by autosomal dominant type 1
fibrillinopathy but mutation testing was not performed.27 In
addition to these 3 families with homozygous autosomal
recessive FBN1 mutations, 3 families with compound het-
erozygous autosomal recessive FBN1 mutations have also
been reported.28,29 All compound heterozygous children
had ectopia lentis with Marfan syndrome, and 1 child had
a neonatal lethal form.28 Heterozygotes ranged from having
clear Marfan syndrome to mild type 1 fibrillinopathy.28,29 A
true heterozygous carrier state for FBN1 mutation is rare
and perhaps only detected when an inbred family has
children affected by homozygous autosomal recessive
disease.
The fact that FBN1 mutation was found in all of our
cases highlights the specificity of the ophthalmic pheno-
type studied in this cohort—lens subluxation with intact
zonules without cataract or vitreoretinal degeneration.
Although it was not a selection criteria for inclusion, all
children in our series who had keratometry readings had
relatively flat keratometry (Table 1), also a known feature
of type 1 fibrillinopathy.30,31
Phenotypes of ectopia lentis with ocular and/or extraoc-
ular presenting features that suggest specific genetic en-
tities were not part of this study. ADAMTSL4-related
isolated lens subluxation tends to manifest at an earlier
age than that of FBN1-related lens subluxation and can
include ectopia pupillae20,21; from prior reports it is not
clear whether zonules are stretched or fragmented and
whether the crystalline lens tends to be subluxated or
luxated. Homocystinuria from cystathionine beta-
synthase deficiency (MIM 236200) characteristically pre-
sents to ophthalmologists with broken rather than
stretched zonules and a tendency for crystalline lens luxa-
tion, often into the anterior chamber.32 Autosomal
138 Khan, Bolz, and Bergmann
recessive mutations in LTBP2 (MIM *602091; latent trans-
forming growth factor-beta binding protein 2) also result
in fragmented zonules and thus a tendency for crystalline
lens luxatation (also anteriorly in the authors’ experience),
often in the context of primary megalocornea and with a
tendency for secondary lens-related glaucoma.33 Knobloch
syndrome (MIM 267750), classically defined as occipital
defect with retinal detachment and caused by an autosomal
recessive mutation in COL18A1 (MIM *120328; collagen
XVIII alpha-1), has been recently shown to be diagnosable
from the ocular phenotype alone, which includes temporal
ectopia lentis in the setting of characteristic vitreoretinal
degeneration.34 Weill-Marchesani syndrome (MIM
277600) and Weill-Marchesani like syndrome (MIM
613195) are caused by autosomal recessive mutations in
ADAMTS10 (MIM *608990; a disintegrin-like and metal-
loproteinase with thrombospondin type 1 motif 10) and
ADAMTS17 (MIM *607511; a disintegrin-like and metal-
loproteinase with thrombospondin type 1 motif 17),
respectively, and both typically include spherophakia
with a tendency for secondary glaucoma.35,36 Cohen
syndrome (MIM #216550), caused by autosomal recessive
mutations in COH1 (MIM *607817), is characterized by
mental delay, a specific facies, truncal obesity, and
pigmentary retinopathy but also can include progressive
spherophakia with anterior chamber shallowing.37 Rarely,
ectopia lentis has been documented as part the aniridia
phenotype (MIM #106210) from autosomal dominant mu-
tations in PAX6 (MIM *607108),38 as part of type 2 colla-
genopathies such as Stickler syndrome (MIM 1120140),39
and as part of a recently described unique phenotype that
resembles Knobloch syndrome and is from an autosomal
recessive mutation in VSX2 (MIM *142993).40 One
distinct but to date idiopathic ectopia lentis phenotype
that is most likely autosomal recessive is the syndrome of
ectopia lentis, spontaneous filtering blebs, and craniofacial
dysmorphism (MIM %601552) that has been documented
in 2 different Lebanese Druze families41,42 and an orphan
of unknown ethnicity also identified in Lebanon.43
Although with careful examination these different genetic
causes of ectopia lentis can often be distinguished from
one other, phenotypic overlap can occur as the involved
genes interact with each other in the extracellular matrix.
For example, in a few rare families, FBN1 mutation44,45
and LTBP2 mutation46 have been implicated in phenotypes
of Weill-Marchesani syndrome and Weill-Marchesani like
syndrome.
In conclusion, autosomal dominant FBN1 mutation was
the major cause for lens subluxation without cataract or vit-
reoretinal degeneration in these referred children from
inbred families rather than autosomal recessive disease.
This has important implications for genetic counseling of
affected children from not only consanguineous but also
from nonconsanguineous families. Most of these children
did have discernible extraocular signs of type 1 fibrillinop-
athy at the time of referral. One case had underlying homo-
zygous autosomal recessive FBN1 mutation and the
Volume 18 Number 2 / April 2014
unaffected parents were confirmed to be heterozygous car-
riers, which suggests that some FBN1 mutations can
behave as hypomorphic alleles rather than exhibiting the
more commonly attributed mechanism of a dominant-
negative effect.
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