Content uploaded by Larry A Dedionisio
Author content
All content in this area was uploaded by Larry A Dedionisio on Feb 16, 2019
Content may be subject to copyright.
Eye
https://doi.org/10.1038/s41433-019-0346-x
REVIEW ARTICLE
Evaluation of TGFBI corneal dystrophy and molecular
diagnostic testing
Connie Chao-Shern 1,2 ●Lawrence A. DeDionisio 2●Jun-Heok Jang2●Clara C. Chan3●Vance Thompson4●
Kathleen Christie1●M. Andrew Nesbit1●C. B. Tara McMullen1
Received: 27 April 2018 / Revised: 10 December 2018 / Accepted: 29 December 2018
© The Author(s) 2019. This article is published with open access
Abstract
To date, 70 different TGFBI mutations that cause epithelial-stromal corneal dystrophies have been described. At present one
commercially available test examines for the five most common of these mutations: R124H, R124C, R124L, R555W, and
R555Q. To expand the capability of identifying the causative mutation in the remaining cases, 57 mutations would need to be
added. The aim of this study was to obtain a better understanding of the worldwide distribution and population differences of
TGFBI mutations and to assess which mutations could be included or excluded from any potential assay. A total of 184
published papers in Human Gene Mutation Database (HGMD) and PubMed from 34 countries worldwide reporting over 1600
corneal dystrophy cases were reviewed. Global data from 600,000 samples using the commercially available test were
analyzed. Case studies by University College of London (UCL), Moorfield’s Corneal Dystrophy Study data and 19 samples
from patients with clinical abnormality or uncertainty for which the current test detected no mutation were used to predict an
achievable detection rate. Data from the literature search showed no difference in the spectrum and frequency of each
mutation in different populations or geographical locations. According to our analysis, an increase to the worldwide detection
rate in all populations from 75 to 90% could be achieved by the addition of six mutations—H626R, A546D, H572R, G623D,
R124S, and M502V—to the currently available test and that may be beneficial for LASIK pre-screening worldwide.
Introduction
The cornea is an avascular transparent tissue at the front
of the eye that begins the process of focusing light onto
the retina and accounts for around two-thirds of the eye’s
optical power. A number of heritable conditions affect
corneal clarity, and they are categorized by the affected
corneal layer as posterior, stromal or superficial [1].
Autosomal dominant (AD), X-linked recessive (XR), and
autosomal recessive (AR) inheritance patterns have all
been observed, and in many cases, the disease locus has
been mapped and the causative gene has been identified.
The most studied corneal dystrophies are those caused by
AD missense mutations in the transforming growth factor
beta-induced gene (TGFBI) located on chromosome
5q31.1, which encodes an extracellular matrix protein
thought to play pivotal roles in physiologic and pathologic
responses by mediating cell adhesion, migration, pro-
liferation and differentiation [2]. To date, 70 TGFBI
mutations are reported in the Human Gene Mutation
Database (HGMD) to cause a spectrum of different
epithelial-stromal corneal dystrophies with corneal
The author is willing to share the interactive map (Fig. 1) upon request.
Please send request to chao_shern-c@ulster.ac.uk. In addition, the
author wishes to be the central repository of newly discovered TGFBI
mutations. Please contact the author for data entry to the map. The
report person will be credited for providing the information.
*M. Andrew Nesbit
a.nesbit@ulster.ac.uk
1Biomedical Sciences Research Institute, University of Ulster,
Coleraine, Northern Ireland, UK
2Avellino Lab USA, Inc., Menlo Park, CA, USA
3Department of Ophthalmology, University of Toronto,
Toronto, Canada
4Vance Thompson Vision, Sioux Falls, SD, USA
Supplementary information The online version of this article (https://
doi.org/10.1038/s41433-019-0346-x) contains supplementary
material, which is available to authorized users.
1234567890();,:
1234567890();,:
amyloid and non-amyloid deposits, including granular
corneal dystrophy type 1 (GCD1) and type 2 (GCD2,
previously designated as Avellino Corneal Dystrophy
[3]), epithelial basement membrane dystrophy (EBMD),
lattice corneal dystrophy (LCD), Reis-Bücklers corneal
dystrophy (RBCD) and Thiel-Behnke corneal dystrophy
(TBCD) [4,5]. Different TGFBI mutations can cause
specific corneal dystrophies, and a genotype-phenotype
correlation has been demonstrated at two mutation hot-
spots, R124 and R555 [5].
Laser in situ keratomileusis (LASIK) is a surgical
procedure that provides vision correction for myopia
(nearsightedness), hyperopia (farsightedness), and astig-
matism. A thin flap in the corneal epithelium and anterior
stroma is cut and folded, and the exposed stromal layer is
reshaped by laser to change its corneal focusing power.
Photorefractive keratectomy (PRK) and phototherapeutic
keratectomy(PTK)surgeryaffectvisioncorrectionor
treat various ocular disorders by removing superficial
opacities and surface irregularities from the cornea. These
surface corneal surgeries induce a wound in the stromal
layer, which causes the expression of TGFBI to be upre-
gulated, resulting in corneal amyloid deposition within the
corneas of individuals who carry the TGFBI mutations
leading to pathology associated with corneal dystrophy
[6]. It is known that GCD1, LCD1, RBCD, and TBCD
have early childhood onsets. However, GCD2 carries a
different presentation. The initial age of onset is depen-
dent on whether the patient is heterozygous or homo-
zygous for the mutation [7]. Homozygous patients are
diagnosed as early as 3 years, while heterozygous have a
delayedpresentation.Giventhedelayinpresentationof
heterozygote, some of these patients have undergone laser
vision correction. Unfortunately, many reports have
demonstrated the exacerbation of GCD2 after treatment
with PRK, LASIK, and PTK. Consequently, LASIK is
contraindicated in GCD2 [7]. Therefore, it is our opinion
that genetic screening for these late onset, heterozygous
mutations should be performed before refractive surgeries
[6–11]. A commercially available genetic test has been
developed that can detect within the TGFBI gene the five
most common mutations which are linked to the five more
common types of corneal dystrophy.
●R124H for granular corneal dystrophy type 2
●R124C for lattice corneal dystrophy type 1
●R124L for Reis-Buckler corneal dystrophy
●R555W for granular corneal dystrophy type 1
●R555Q for Thiel-Behnke corneal dystrophy
This five-mutation genetic test was originally designed
for the Korean and Japanese population, where a majority of
the TGFBI corneal dystrophy cases are diagnosed as GCD2
caused by the R124H mutation [12]. Within Korea and
Japan, the test is used primarily as a screening tool prior to
refractive surgery. However, in the US and Europe, the test
is used both to screen refractive surgery candidates and as a
confirmatory test for clinical diagnosis of corneal dystrophy
disease. The purpose of this study is to review the pre-
valence of different TGFBI mutations in various popula-
tions and geographic locations to determine whether the
available genetic test, as currently constituted, is optimal for
use in different populations worldwide.
Materials and methods
Worldwide literature search
A worldwide literature search was performed using the
articles curated in the HGMD database (QIAGEN, Hilden,
Germany) via a paid academic research version, last
accessed on 23 February 2018 and articles in PubMed (US
National Library of Medicine, National Institutes of
Health). Reviewed herein are 184 articles with over 1600
reported individual patient cases (Supplementary Material).
An interactive world map based on the data within the lit-
erature and developed with a Google Maps application was
created and used to plot the reported mutation information,
ethnicities, and case numbers (a copy of the link is available
upon request).
Global available genetic test data analysis
The available genetic test (Avellino Labs USA, Menlo Park,
CA) was utilized to test over 600,000 patient samples
worldwide (Korea, Japan, China, USA, and Europe). In
short, epithelial cells were collected from subjects’buccal
mucosa with Copan buccal swabs (Copan Italia, Brescia,
and Italy), which were subsequently inserted into a pro-
tective outer tube. DNA extractions were carried out either
with the DNA Extract All Reagents Kit or the ChargeS-
witch gDNA Normalized Buccal Cell Kit (Thermo Fisher
Scientific, Waltham, MA, USA). DNA amplification was
produced by TaqMan GTXpress Master Mix or TaqPath
ProAMp Multiplex Master Mix (Thermo Fisher Scientific,
Waltham, MA, USA). Custom TaqMan®Assay Design
Tool (ThermoFisher Scientific, Waltham, MA, USA) was
used to design PCR primers and probes for each mutation,
and the Custom TaqMan®Assays were manufactured by
Thermo Fisher Scientific (Waltham, MA, USA). Genotyp-
ing data was collected with a 7500 FAST Real-Time PCR
System (Thermo Fisher Scientific, Waltham, MA, USA).
Short oligos containing wild-type and mutant sequences
were utilized as control materials (ThermoFisher Scientific,
Waltham, MA, USA).
C. Chao-Shern et al.
Assessment of an expanded panel with six
additional mutations
Six mutations were identified from the literature search as a
group of mutations with the next highest number of reported
cases that may be included in an expanded testing panel.
Primer and probe sets were designed using Thermo Fisher’s
Custom TaqMan®Assay Design Tool (Thermo Fisher
Scientific, Waltham, MA, USA). Genetic testing was con-
ducted on epithelial cells collected from the inner cheeks
with an iSWAB collection kit (Mawi DNA Technologies,
Hayward, CA, USA). Genomic DNA was extracted with a
QIAGEN QIAamp®DNA blood mini kit (Hilden, Ger-
many), and whole exome sequencing (WES) was carried
out with the ACE platform™(Personalis Inc., Menlo Park,
CA, USA).
Informed consent was obtained from the subjects and
WES was performed on two related patients with lattice-like
corneal erosions before this study was initiated. Three epi-
thelial erosion in the lattice-like change in the center of the
right eye of the 27-year-old male proband where a tree
branch injury took place four years prior. The proband’s
mother was subsequently examined and observed lattice-
like lines on both LASIK flaps where she had bilateral
LASIK surgeries 14 years previously. To determine whe-
ther there was a genetic component of the symptoms,
samples were sent to us for genetic study. Real-time PCR
test was designed according to the WES results for the
mutation detected from both the proband and his mother.
Same test designing method was used for the other five
mutations. Then PCR tests were performed on the two
related patients and other 17 nonrelated patients with clin-
ical abnormality or uncertainty for which the available
genetic test detected no mutation. The expanded eleven
mutation panel (Table 1) was used to assess the detection
rate that would have been achieved with the cohort TGFBI
dystrophy patients in the study conducted in 2016 by Uni-
versity College London, Moorfield Eye Hospital [5].
Results
Worldwide literature search
The HGMD database was interrogated and 70 different
TGFBI mutations were found. The HGMD database was
used to identify the papers in which these mutations were
described in order to build up a picture of a worldwide
distribution (Fig. 1a, b). Each flag in the world map contains
a summary of the mutations reported in a specific region or
a country. The summary includes ethnicities, mutations and
the total number of cases reported for each mutation
(Fig. 1a). The mutations are spread with no significant
differences in distribution in specific populations or geo-
graphical regions. Very few cases were reported from South
America, and there were no case reports from Africa or
Russia. The map can be used to extract country-specific
information e.g., London indicated by a red arrow in
Fig. 1b.
Globally, 75% of the TGFBI mutations reported in the
over 1600 cases consisted of one of the five mutations
currently detected by the available genetic test. While
reports of novel TGFBI mutations are likely to be published,
the most common TGFBI mutations, found at codons R124
and R555, are conversely under-reported. Therefore, it is
difficult to obtain an accurate estimation of the true
worldwide detection rate of TGFBI dystrophies within the
literature.
Based on the ranking of the highest reported case num-
bers from our study, the effect on TGFBI mutation detection
rates by adding six mutations to the available genetic test
panel was evaluated. The reported number of cases for each
of the five most common mutations and the six additional
mutations proposed for the expanded test are shown in
Table 1. It is noteworthy that the H626R is the fourth most
prevalent mutation after R124L. This finding supports the
inclusion of this mutation in an expanded panel for the
diagnosis of TGFBI corneal dystrophy. Although only four
cases of TGFBI corneal dystrophy associated with M502V
have been reported within the literature (Supplementary
Material), we discovered a heterozygous mutation for
M502V in one sample. Patients with H626R and G623D
TGFBI mutations (included in the six-additional mutation
panel) demonstrated onset in the 4th decade or later and
Table 1 This table ranks the five most common mutations within
reported cases (Supplementary Material) from highest to lowest. In
addition, it lists the case numbers from high to low for the six
additional mutations
Mutations Reported
case numbers
Five most common mutations In the current genetic test panel
R124C Lattice Corneal Dystrophy type 1 372
R555W Granular Corneal Dystrophy type 1 338
R124H Granular Corneal Dystrophy type 2 325
R124L Reis-Buckler corneal dystrophy 110
R555Q Thiel-Behnke corneal dystrophy 75
Six additional mutations In the expended test panel
H626R Lattice Corneal Dystrophy subtype I/IIIA 117
A546D Variant Lattice Corneal Dystrophy 48
H572R Lattice Corneal Dystrophy subtype 1 34
G623D Variant Reis-Buckler Corneal Dystrophy 26
R124S Subtype Granular Corneal Dystrophy type 1 18
M502V Variant Corneal Dystrophy and Variant
Thiel-Behnke Corneal Dystrophy
4
Evaluation of TGFBI corneal dystrophy and molecular diagnostic testing
Fig. 1 aWorld map of reported cases with various TGFBI mutations.
Each bubble placed over a region or country contains the reported case
information, such as ethnicities, mutations, and case numbers. The
map illustrates that TGFBI mutations cases are reported all over the
world, except for in regions with limited research capacity or language
difficulties for publication. Very few cases were reported from South
America, and no case. reports were identified from Africa or Russia.
bThe red bubble points at London, England as an example of the
information contained within the bubble. The legend on the left shows
the reported mutations, ethnicity and total case numbers for each
reported mutation
C. Chao-Shern et al.
patients with A546D and H572R mutations presented onset
during mid to late 20s, after the age at which refractive
surgery may be considered. Therefore, it was included in
the expanded panel.
From the cases reported in the literature, we calculated
that the addition of the six new mutations to the existing
panel will increase the worldwide detection rate from 75 to
90% (Fig. 2). The addition of the additional mutations to the
available genetic test would theoretically increase the
detection rate by 32% in South America and 30% in North
America. Europe and Asia, both with a 13% increase in
detection rates would also benefit from the proposed eleven
mutation panel (Fig. 2).
Global available genetic test data analysis
Since 2008, more than 600,000 samples worldwide were
tested by the available genetic test; most of the samples
were from Korea and Japan, where the test is used for pre-
refractive surgery screening. An analysis of the global
testing data demonstrated that the detection rate in Korea is
approximately 15 in 10,000 people, which closely matches
the reported prevalence of 1 in 870 people [11]. The
detection rate of TGFBI mutations in Japan (3 in 10,000)
was lower than that in Korea. In Korea, the test is admi-
nistered as a general screening for all refractive surgery
candidates, whereas in Japan, patients are first subjected to a
rigorous clinical examination and only those patients who
have no detected corneal abnormalities have samples sub-
mitted for the genetic test.
The clinics/hospitals in Korea and Japan use the genetic
test for screening purposes as it forms part of the practice
guidelines for refractive surgery. In the US, some clinics/
hospitals use the test for screening during the pre-operative
examination for vision corrective surgery, whereas others
use it as a confirmation for clinical diagnosis or to exclude
TGFBI mutations if the surgeon has any doubt about the
imperfections noted in the patient’s cornea. European clinics
utilize the test mostly for this type of clinical confirmation.
Assessment of an expanded panel with six
additional mutations
Few population studies like the 2016 UCL, Moorfield’s
Corneal Dystrophy Study [5] have conducted Sanger
sequencing on the entire TGFBI gene. This study provided
us with a set of data on which to evaluate the addition of six
new mutations sites to enhance the pick-up rate in a given
population. In brief, the study consisted of 91 unrelated
TGFBI corneal dystrophy cases in which 68 had a diagnosis
of epithelial-stromal TGFBI associated dystrophy (RBCD,
TBCD, LCD, and GCD) and 23 had a diagnosis of bilateral
EBMD [5]. For the UK population we utilized this study as
our reference, and we evaluated a set of six TGFBI muta-
tions to determine whether these mutations in combination
with the five mutations genetic test were appropriate. The
data showed that the detection rate in the UK cohort would
increase from 90 to 97% (Table 2). Other candidate muta-
tions may be considered, such as V625D and A620D from
Table 2, in order to increase the detection rate to almost
100%. This finding demonstrates that the inclusion of six
additional mutations to the available genetic test, while
improving the pick-up rate, will still miss some important
mutations found in the UK population.
We found that 16 of the 19 samples with clinical indi-
cations that tested negative with the original genetic test
were still negative (84.2% of the total), while three tested
positive (15.7% of the total) with the expanded panel. The
WES results of a mother and son pair with a clinical
diagnosis of late-onset of LCD were positive for a hetero-
zygous TGFBI H626R mutation. Parallel real-time PCR
testing showed the same heterozygous H626R mutation.
The third sample was discovered to be heterozygous for
M502V. The result was confirmed with Sanger sequencing
Subsequent patient history revealed that the patient had very
small corneal scarring on the left cornea. There was no
family history of corneal dystrophy or opacity.
In accordance with evidence in the literature, we estimate
that adding six mutations to the available genetic test would
increase the detection rate by 15%. This coincides with the
15.7% percent increase in detection for our sample cohort (3
of 19 samples).
Discussion
The reported prevalence of TGFBI corneal dystrophies in
Asia is one in 870 in Korea [13] and one in 416 in China
Fig. 2 Comparison by geographic region. The original genetic test
with five mutations, the six additional mutations and the proposed
expanded 11 mutation panel were modeled in over 1600 reported
cases. The detection rate of the available genetic test with five muta-
tions was very close between Europe and Asia
Evaluation of TGFBI corneal dystrophy and molecular diagnostic testing
[14]. Asia has a high myopia rate, and a study conducted by
Holden et al. predicted that by 2050, the Asian-Pacific
population will have the highest myopia prevalence rate
among all populations at 66.4% compared to the global
prevalence of 49.8% [12]. With the high prevalence of
myopia in these Asian populations, the use of LASIK vision
correction surgery is consistently increasing and is predicted
to continue to rise. With the known prevalence of TGFBI
mutations in the Asian population and the high myopia rate,
mutation testing is important in this region; subsequently,
the five-mutation genetic test was initially introduced in
Asian-Pacific populations.
Since the first description by Folberg et al. [15], in 1988
of TGFBI mutations as the cause of granular corneal dys-
trophy, our awareness and understanding of this disease has
increased steadily. The most common R124 and R555
mutations are well documented (Supplementary Material),
and additional mutations are being examined more closely
to understand the next tier of common variants. In this
study, we reviewed reports in the literature on various
TGFBI corneal dystrophies to understand the prevalence of
this disease. The worldwide prevalence of this disease is
unknown; however, the disease outcome is debilitating. The
ultimate treatment is corneal transplant, and the recurrent
nature of the disease often requires subsequent corneal
transplants, which is traumatic and costly to both the
patients and the medical system. The preventative actions
include avoid having refractive surgeries, or any eye sur-
geries that will injure the cornea. Special care should be
taken to prevent accidental cornea injuries such as
scratching or corneal trauma. Prevention and prescreening
with molecular diagnostic testing to detect mutations is key.
In accordance with evidence in the literature, we deter-
mined that detection rates will improve with the addition of
six mutations to the available genetic test. We did not dis-
cover geographic or population differences; therefore, the
newly proposed six additional mutations are appropriate for
worldwide use as an enhancement of the present genetic
test. The new mutations included in an expanded test panel
would considerably improve the mutation detection rate;
however, this expanded test will not be able to detect all of
the more than 60 TGFBI mutations. The law of diminishing
returns, where the return of benefits fails to increase sig-
nificantly with added cost must be considered, and other
detection strategies may need to be evaluated, such as
microarray hybridization or targeted resequencing to test
for up to 70 TGFBI mutations referenced here and
elsewhere [5].
The goal is to provide enhanced testing capability in the
prescreening test prior to refractive surgery. Another
objective is to close the gap between the detection rate
resulting from genetic testing and clinical diagnosis. The
testing of 19 samples for the presence of the six additional
mutations in the expanded panel proves that the expanded
genetic test will have increased detectability of TGFBI
mutations. There are ways to achieve a 100% detection rate
by using technologies such as WES. However, it is very
costly and time consuming to employ WES as a screening
tool. We must consider feasibility factors such as cost,
turnaround time and accuracy of the refractive screening
Table 2 Yellow highlighting
indicates the theoretical results
of the available genetic test
UCL/Moorfields % detection of 91 UK ethnically diverse cohort with 68 TGFBI CDs
Clinical diagnosis Case # Case % TGFBI mutation Mutation # Mutation % Comments
Lattice Corneal Dystrophy 24 35% R124C 19 28%
V625D 1 1% Asian
H626R 2 3%
A620D 1 1% Asian
G623D 1 1%
Granular Corneal Dystrophy 1 21 31% R555W 13 19%
Granular Corneal Dystrophy 2 R124H 8 12%
TB/RB CD 23 34% R555Q 20 29%
R124L 1 1%
G623D 2 3%
Total TGFBI CD 68 Universal test 61 90%
Additional 6
SNPs
57%
Total 11 SNPs 66 97%
This test would detect 90% of the 68 TGFBI CD cohort identified by the Moorfield’s Corneal Dystrophy
Study [5]. The green highlighting shows the six additional mutations identified through literature research.
They increase the detection rate by 7%, which brings the overall detection rate in the UK to 97%.
C. Chao-Shern et al.
test. Ultimately, an affordable targeted sequencing panel
containing all 70 TGFBI mutations as a second-tier testing
should be made available, which allows patients with very
rare mutations an opportunity to be tested. It is very con-
cerning that patients carrying the rarer mutations would go
through the refractive surgery without the means of being
tested [16–26].
Acknowledgements The authors are thankful for all the unconditional
support provided by Mr. Gene Lee and the Avellino USA lab staff.
Finally, to our ophthalmologists who contributed their time and effort
to provide valuable samples and clinical information and to the
patients, without whom we could not conduct this study.
Compliance with ethical standards
Conflict of interest TM is a consultant to Avellino Lab USA, Inc. and
a professor of Ulster University. MAN is a Senior Lecturer of Ulster
University. LDD and J-HJ are employees of Avellino Lab USA, Inc.
CCS is a PhD student of Ulster University and an employee of
Avellino Lab USA, Inc. The authors declare that they have no conflict
of interest. The authors alone are responsible for the content and
writing of this article.
Publisher’s note: Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
Open Access This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as
long as you give appropriate credit to the original author(s) and the
source, provide a link to the Creative Commons license, and indicate if
changes were made. The images or other third party material in this
article are included in the article’s Creative Commons license, unless
indicated otherwise in a credit line to the material. If material is not
included in the article’s Creative Commons license and your intended
use is not permitted by statutory regulation or exceeds the permitted
use, you will need to obtain permission directly from the copyright
holder. To view a copy of this license, visit http://creativecommons.
org/licenses/by/4.0/.
References
1. Klintworth GK. Corneal dystrophies. Orphanet J rare Dis.
2009;4:7.
2. Han KE, Choi SI, Maeng YS, Stulting RD, Ji YW, Kim EK.
Pathogenesis and treatments of TGFBI corneal dystrophies. Pro-
gress Retin eye Res. 2016;50:67–88.
3. Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas
NS, et al. Human gene mutation database (HGMD®): 2003
update. Human Mutat. 2003;21:577–81.
4. Korvatska E, Henry H, Mashima Y, Yamada M, Bachmann C,
Munier FL, et al. Amyloid and non-amyloid forms of 5q31-linked
corneal dystrophy resulting from kerato-epithelin mutations at
Arg-124 are associated with abnormal turnover of the protein. J
Biol Chem. 2000;275:11465–9.
5. Evans CJ, Davidson AE, Carnt N, López KE, Veli N, Thaung CM,
et al. Genotype-phenotype correlation for TGFBI corneal dystro-
phies identifies p.(G623D) as a novel cause of epithelial basement
membrane dystrophy TGFBI p.(G623D) Identified as Novel Cause
of EBMD. Invest Ophthalmol & Vis Sci. 2016;57:5407–14.
6. Dinh R, Rapuano CJ, Cohen EJ, Laibson PR. Recurrence of
corneal dystrophy after excimer laser phototherapeutic kera-
tectomy. Ophthalmology. 1999;106:1490–7.
7. Copeland R, Afshari N. Principles and Practice of Cornea. New
Delhi: Jaypee Brothers Medical Publishers. 2013.
8. Han KE, Chung WS, Choi SI, Kim BY, Kim EK. Clinical findings
and treatments of granular corneal dystrophy type 2 (avellino
corneal dystrophy): a review of the literature. Eye Contact lens.
2010;36:296–9.
9. Aldave AJ, et al. A clinical and histopathologic examination of
accelerated TGFBI p deposition after LASIK in combined
granular-lattice corneal dystrophy. Am J Ophthalmol.
2007;143:416–9. https://doi.org/10.1016/j.ajo.2006.11.056
10. Dogru M, Katakami C, Nishida T, Yamanaka A. Alteration of the
ocular surface with recurrence of granular/Avellino corneal dys-
trophy after phototherapeutic keratectomy: report of five cases and
literature review. Ophthalmology. 2001;108:810–7. https://doi.
org/10.1016/S0161-6420(00)00657-6
11. Ellies P, Bejjani RA, Bourges JL, Boelle PY, Renard G, Dighiero
PL. Phototherapeutic keratectomy for BIGH3-linked corneal
dystrophy recurring after penetrating keratoplasty. Ophthalmol-
ogy. 2003;110:1119–25.
12. Weiss JS, Møller HU, Lisch W, Kinoshita S, Aldave AJ, Belin
MW, et al. The IC3D classification of the corneal dystrophies.
Cornea. 2008;27(Suppl 2):S1.
13. Lee JH, Cristol SM, Kim WC, Chung ES, Tchah H, Kim MS,
et al. Prevalence of granular corneal dystrophy type 2 (Avellino
corneal dystrophy) in the Korean population. Ophthalmic Epide-
miol. 2010;17:160–5.
14. Song Y, Sun M, Wang N, Zhou X, Zhao J, Wang Q, et al.
Prevalence of transforming growth factor β–induced gene
corneal dystrophies in Chinese refractive surgery candidates. J
Cataract Refr Surg. 2017;43:1489–94.
15. Folberg R, Alfonso E, Croxatto JO, Driezen NG, Panjwani N,
Laibson PR, et al. Clinically atypical granular corneal dystrophy
with pathologic features of lattice-like amyloid deposits: a study
of three families. Ophthalmology. 1988;95:46–51.
16. Reinstein DZ, Archer TJ, Randleman JB. Mathematical model to
compare the relative tensile strength of the cornea after PRK,
LASIK, and small incision lenticule extraction. J Refract Surg.
2013;29:454–60.
17. Seven I, Vahdati A, Pedersen IB, Vestergaard A, Hjortdal J,
Roberts CJ, et al. Contralateral eye comparison of SMILE and
flap-based corneal refractive surgery: computational analysis of
biomechanical impact. J Refract Surg. 2017;33:444–53.
18. Gomes JA, Tan D, Rapuano CJ, Belin MW, Ambrósio R Jr, Guell
JL, et al. Global consensus on keratoconus and ectatic diseases.
Cornea. 2015;3:359–69.
19. Kim BY, Olzmann JA, Choi SI, Ahn SY, Cho HS, Suh H, et al.
Corneal dystrophy-associated R124H mutation disrupts TGFBI
interaction with Periostin and causes mislocalization to the lyso-
some. J Biol Chem. 2009;284:19580–91.
20. Munier FL, Frueh BE, Othenin-Girard P, Uffer S, Cousin P, Wang
MX, et al. BIGH3 mutation spectrum in corneal dystrophies.
Invest Ophthalmol Vis Sci. 2002;43:949–54.
21. Ramachandran S, Deshpande O, Roseman CC, Rosenberg NA,
Feldman MW, Cavalli-Sforza LL. Support from the relationship
of genetic and geographic distance in human populations for a
serial founder effect originating in Africa. Proc Natl Acad Sci
USA. 2005;102:15942–7.
22. Stewart HS, Ridgway AE, Dixon MJ, Bonshek R, Parveen R,
Black G. Heterogeneity in granular corneal dystrophy:
Identification of three causative mutations in the TGFBI (BIGH3)
gene--Lessons for corneal amyloidogenesis. Human Mutat.
1999;14:126.
Evaluation of TGFBI corneal dystrophy and molecular diagnostic testing
23. Maeng YS, Lee GH, Lee B, Choi SI, Kim TI, Kim EK. Role of
TGFBI p in wound healing and mucin expression in corneal
epithelial cells. Yonsei Med J. 2017;58:423–31. https://doi.org/10.
3349/ymj.2017.58.2.423
24. Holden BA, Fricke TR, Wilson DA, Jong M, Naidoo KS, San-
karidurg P, et al. Global prevalence of myopia and high myopia
and temporal trends from 2000 through 2050. Ophthalmology .
2016;123:1036–42.
25. Kattan JM, Serna-Ojeda JC, Sharma A, Kim EK, Ramirez-
Miranda A, Cruz-Aguilar M, et al. Vortex pattern of
corneal deposits in granular corneal dystrophy associated
with the p.(Arg555Trp) mutation in TGFBI. Cornea. 2017;36:
210–6.
26. Jupp, PE., and Kanti VM. Maximum likelihood estimators for the
matrix von Mises-Fisher and Bingham distributions. The Annals
of Statistics 7, no. 3 (1979):599–606.
C. Chao-Shern et al.
