Ophthalmic Genetics

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A family harboring homozygous FZD4 deletion

supports the existence of recessive FZD4-related
familial exudative vitreoretinopathy

Arif O. Khan, Steffen Lenzner & Hanno J. Bolz

To cite this article: Arif O. Khan, Steffen Lenzner & Hanno J. Bolz (2017) A family harboring
homozygous FZD4 deletion supports the existence of recessive FZD4-related familial exudative
vitreoretinopathy, Ophthalmic Genetics, 38:4, 380-382, DOI: 10.1080/13816810.2016.1217551

To link to this article: https://doi.org/10.1080/13816810.2016.1217551

Published online: 26 Sep 2016.

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OPHTHALMIC GENETICS
2017, VOL. 38, NO. 4, 380–382
http://dx.doi.org/10.1080/13816810.2016.1217551

CASE REPORT

A family harboring homozygous FZD4 deletion supports the existence of recessive

FZD4-related familial exudative vitreoretinopathy
Arif O. Khana, Steffen Lenznerb, and Hanno J. Bolzb,c
a
Eye Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates; bCenter for Human Genetics, Bioscientia, Ingelheim, Germany;
c
Institute of Human Genetics, University of Cologne, Cologne, Germany

ABSTRACT ARTICLE HISTORY

Purpose: To document recessive FZD4-related familial exudative vitreoretinopathy. Received 4 June 2016
Methods: Retrospective case series. Accepted 22 July 2016
Results: Two brothers, the only two males among five siblings, had bilateral infantile retinal detachments KEYWORDS
and were referred for genetic counseling. Next-generation sequencing uncovered a homozygous FZD4 Familial exudative
frameshift deletion in both affected brothers (c.40_49delCCCGGGGGCG; p.Pro14Serfs*44). None of the vitreoretinopathy; FZD4;
other immediate family members had clinical evidence for retinal disease, including the three family retina
members who underwent confirmatory genetic testing and were found to be heterozygous for the
mutation (both parents and one sister).
Conclusions: The findings in this family support the concept that some mutated FZD4 alleles can be
associated with recessive rather than dominant disease.

Introduction older brother had by history the same presentation with no history
of ocular surgery or trauma and at the time of examination
Familial exudative vitreoretinopathy (FEVR) is a disease of retinal
showed bilateral phthisis. Both parents and all three sisters under-
vascular developmental that primarily affects the peripheral retina
went clinical ophthalmic examination with attention to the retinal
and shows marked variable expressivity.1 Clinical features range
periphery and no abnormalities were noted.
from mild to severe and can include retinal vessel dragging, folds,
Venous blood was taken from the proband for DNA extraction
dysplasia, and exudation that is pre-, intra-, or sub-retinal. When
and sequencing. Sanger sequencing of exons 2 and 3 of NDP
retinal detachment occurs, it can be from traction, exudation, tear,
(NM_000266.3) was performed but did not reveal mutations.
a combination of these factors, or, in severe cases, dysplasia (con-
Subsequently, we conducted next-generation sequencing (NGS)
genital non-attachment). FEVR is classically autosomal dominant
of a panel of the 10 genes known to be related to retinal dysplasia
and is genetically heterogeneous, associated with heterozygous
by the end of 2013 (COL11A1, COL18A1, COL2A1, COL9A1,
mutations in frizzled-4 (FZD4), low-density lipoprotein recep-
FZD4, KCNJ13, LRP5, RS1, TSPAN12, ZNF408) using pre-
tor-related protein 5 (LRP5), tetraspanin-12 (TSPAN12), zinc fin-
viously-described methods.6 Briefly, the 251 coding exons of the
ger protein 408 (ZNF408),2 and, most recently, kinesin family
genes were enriched using Roche/Nimblegen sequence capture
member 11 (KIF11).3,4 FEVR can also be X-linked, from hemi-
technology and sequenced on an Illumina HiSeq 1500 system.
zygous mutations in norrin (NDP).2 Recessive FEVR, first
The high-coverage NGS data obtained with our approach were
described for LRP5, is less common and has been recognized for
also analyzed for copy number variations to rule out large dele-
multiple families with bi-allelic mutations in LRP5 or TSPAN12.2
tions or duplications.6 Bioinformatic programs were used for
There has been only one patient reported with recessive FEVR
evaluation of variants’ pathogenicity as previously described.6,7
from FZD4 mutations, a single Japanese girl.5 In this report we
Confirmation of the only identified mutation (in FZD4) and
describe two Arab siblings with FZD4-related recessive FEVR and
segregation analyses were carried out by PCR-amplification of
thus support the concept that some mutated FZD4 alleles can be
the corresponding exon, followed by Sanger sequencing. FZD4
associated with recessive rather than dominant disease.
sequence data (NM_012193.3) revealed a homozygous frameshift
deletion in both affected brothers (c.40_49delCCCGGGGGCG; p.
Case series Pro14Serfs*44) (Figure 1). Of the four family members available
for carrier testing, both parents and one sister were heterozygous
Two brothers, the only two males among five siblings, had bilat-
for the mutation. Fluorescein angiography was attempted to assess
eral infantile retinal detachments and were referred for genetic
the retinal periphery in those heterozygous for the mutation but
counseling. The proband, an otherwise healthy full-term baby boy
because the sister vomited during infusion the family declined
noted to have bilateral leukocoria and poor vision soon after birth,
completion of this testing.
was confirmed to have bilateral funnel retinal detachments. His

CONTACT Arif O. Khan, MD arif.khan@mssm.edu Eye Institute, Cleveland Clinic Abu Dhabi, PO Box 112412, Abu Dhabi, UAE.
Color versions of one or more figures in the article can be found online at http://www.tandfonline.com/iopg.
© 2017 Taylor & Francis
 OPHTHALMIC GENETICS 381

Figure 1. (A) Pedigree of the consanguineous Arabian FEVR family. (B) Upper panel: Schematic representation of mapped sequencing reads visualized with the Integrative
Genomics Viewer (IGV) for the homozygous frameshift deletion c.40_49delCCCGGGGGCG (p.Pro14Serfs*44) of patient II:4. The middle panel represents the electropher-
ogram from Sanger sequencing of the respective FZD4 region in patient II:4, compared to the sequence of a wildtype individual (healthy sister II:3; lower panel).

Discussion
In this family, a severe FEVR phenotype segregated with a bi-
allelic deletion in FZD4. Heterozygotes were asymptomatic and
without retinal findings; however, because fluorescein angiogra-
phy was not performed the presence of a subtle phenotype cannot
be ruled out. NGS excluded mutations in other genes associated
with FEVR. This report, the first to describe familial recessive
FZD4-related FEVR, confirms that some mutated FZD4 alleles
can cause recessive rather than dominant disease. FZD4 functions
in the Norrin/Frizzled4 signaling pathway, a variant of Wnt
signaling that has a central role in retinal vascular development.
At least three other genes associated with FEVR also function in
this pathway (NDP, LRP5, TSPAN12).
Interestingly, the FEVR deletion that segregated as a recessive
disease-causing allele in this family was previously reported as a
cause for dominant FEVR in an outbred Chinese family.8 In that
family, two heterozygous individuals were described as having
mild peripheral findings that were discernible only by fluores-
cence angiography. The third heterozygous individual was
described as having severe disease. While variable expressivity is
well-recognized for FEVR, such a severe discrepancy in phenotype
of the third heterozygous individual of that family from the other
two heterozygotes of that family (and the three heterozygotes
from the current family) is unusual. It would have been interesting
to sequence other genes related to FEVR in that third heterozy-
gous individual to assess the possibility of multiple FEVR-related
gene mutations underlying the severe difference in phenotype.
This concept of mutations in more than one gene associated with
FEVR has been raised before.9,10 It seems appropriate to do NGS
of FEVR genes when there is marked variable expressivity for
apparently dominant disease.
Declaration of interest
The authors report no conflicts of interest. The authors alone are
responsible for the content and writing of this article.
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