PHENOTYPIC VARIABILITY OF
RECESSIVE RDH12-ASSOCIATED RETINAL
DYSTROPHY
XUAN ZOU, MD, PHD,* QING FU, MD,† SHA FANG, PHD,‡ HUI LI, MD,* ZHONGQI GE, PHD,§¶
LIZHU YANG, MD,* MINGCHU XU, PHD,§¶ ZIXI SUN, MD,* HUAJIN LI, MD, PHD,* YUMEI LI, PHD,†§
FANGTIAN DONG, MD,* RUI CHEN, PHD,§¶**†† RUIFANG SUI, MD, PHD*
Purpose: To characterize the phenotypic variability and report the genetic defects in
a cohort of Chinese patients with biallelic variants of the retinol dehydrogenase 12 (RDH12)
gene.
Methods: The study included 38 patients from 38 unrelated families with biallelic
pathogenic RDH12 variants. Systematic next-generation sequencing data analysis, Sanger
sequencing validation, and segregation analysis were used to identify the pathogenic mutations.
Detailed ophthalmic examinations, including electroretinogram, fundus photography,
fundus autofluorescence and optical coherence tomography, and statistical analysis
were performed to evaluate phenotype variability.
Results: Twenty-five different mutations of RDH12 were identified in the 38 families. Six
of these variants were novel. Val146Asp was observed at the highest frequency (23.7%),
and it was followed by Arg62Ter (14.5%) and Thr49Met (9.2%). Twenty-three probands
were diagnosed with early-onset severe retinal dystrophy, 6 with Leber congenital amaurosis,
7 with autosomal recessive retinitis pigmentosa, and 2 with cone-rod dystrophy. Selfreported
nyctalopia occurred in about a half of patients (55.3%) and was significantly more
common among older patients (P , 0.01). Nyctalopia was not significantly associated with
best-corrected visual acuity (P = 0.72), but older patients had significantly greater bestcorrected
visual acuity loss (P , 0.01). Only 15.8% of the patients had nystagmus, which
was significantly more likely to occur among 36.8% of the patients with hyperopia .3D
(P , 0.01) and/or in cases of reduced best-corrected visual acuity (P = 0.01), but was not
associated with age (P = 0.87).
Conclusion: Several high-frequency RDH12 variants were identified in patients with
inherited retinal dystrophies, most of which were missense mutations. Variable but characteristic
phenotypes of a progressive nature was observed. Overall, the findings indicated
that biallelic RDH12 mutations are a common cause of early-onset retinal dystrophy and
a rare cause of cone-rod dystrophy.
RETINA 00:1–13, 2018
Retinol dehydrogenase 12 (RDH12) is a member of
the short-chain dehydrogenase/reductase superfamily
of proteins, and it is specifically expressed in
photoreceptor cells.1 The RDH12 gene maps to chromosome
14q23,2 encodes a protein composed of 316
amino acids, and might play a pivotal role in the formation
of 11-cis retinal from 11-cis retinol during the
regeneration of visual pigments.3 It catalyzes the redox
reactions of both all-trans and cis retinoids in the presence
of NADP and NADPH as cofactors.3
RDH12 mutations have been identified in patients
diagnosed with severe early-onset retinal dystrophy,
including Leber congenital amaurosis (LCA) and
early-onset severe retinal dystrophy (EOSRD).4–7 Leber
congenital amaurosis and EOSRD usually lead to
legal blindness in young adulthood (18–25 years of
age). RDH12 mutations also cause adult-onset autosomal
recessive and dominant retinitis pigmentosa8,9 and
cone-rod dystrophy (CORD).10–12 Genotype–
phenotype association has been proposed in patients
with RDH12 mutations.1,4,6 Irrespective of the type of
RDH12 variant, these individuals shared common
clinical features, such as poor visual acuity early in
life, followed by progressive loss of visual function
and retinal degeneration. Marked pigmentary retinopathy
and pronounced maculopathy are evident as is the
1
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corresponding loss of fundus autofluorescence. Optical
coherence tomography (OCT) of these patients has
revealed marked retinal atrophy and excavation at the
macula.6,13 Most previous genetic studies on RDH12
retinopathy were performed in the Western population,
and only limited data from Chinese patients are
available.14,15 To fill in this gap, in this report, we
present a detailed analysis of the ocular phenotypes of
38 index patients from 38 unrelated families carrying
biallelic pathogenic mutations in RDH12. This represents
the largest sample of autosomal recessively inherited
RDH12 patients reported to date. We analyzed
all mutations and ocular phenotypes in this cohort of
patients, which included six patients with RDH12
mutations previously reported by our group.16
Methods
Recruitment of Subjects
All participants were identified at the Ophthalmic
Genetics Clinic at Peking Union Medical College
Hospital (PUMCH), Beijing, China. We identified
RDH12 mutations in 38 index patients from 38 unrelated
families from a large cohort of retinal dystrophy
cases, including 275 unrelated LCA/EOSRD, 386
unrelated autosomal recessive retinitis pigmentosa
(ARRP), and 92 unrelated CORD cases. The diagnostic
criteria used in our study were based on those previously
reported; LCA was defined as bilateral
congenital blindness with extinguished or markedly
diminished electroretinogram (ERG) responses before
the first 6 months of life, as well as the absence of
systemic abnormalities.17,18 Early-onset severe retinal
dystrophy was defined as being milder than LCA and
present after the first 6 months of life but before 10
years.18–20 Autosomal recessive retinitis pigmentosa
was defined as sequential degeneration of rod photoreceptors
and retinal pigment epithelium followed by
cones, which presents after childhood, and is transmitted
in an autosomal recessive pattern.21,22 Cone-rod
dystrophy is characterized by early loss of cone photoreceptors
and additional rod dysfunction in the course
of the disease.23 Written informed consent was obtained
from either the participating individuals or their
guardians. This study was approved by the Institutional
Review Board of PUMCH and adhered to the
tenets of the Declaration of Helsinki and the Guidance
on Sample Collection of Human Genetic Diseases by
the Ministry of Public Health of China.
Clinical Evaluation
The full medical and family history of each
participant was obtained. Each patient underwent
detailed ophthalmic examination as follows: bestcorrected
visual acuity (BCVA) by the Snellen visual
acuity test, slit-lamp biomicroscopy, dilated indirect
ophthalmoscopy, fundus photography (Topcon,
Tokyo, Japan), fundus autofluorescence
(Heidelberg Engineering, Germany), visual field
(VF) test (Haag-Streit, Koeniz, Switzerland), OCT
(Topcon, Tokyo, Japan or Heidelberg Engineering,
Germany), and ERG (RetiPort ERG system; Roland
Consult, Wiesbaden, Germany). The VF test was
performed using an Octopus 101 perimeter with the
tG2 program or LVC (central low vision test) program.
The spectral domain OCT device used had an axial
resolution of 5 mm and acquired 128 horizontal B-scan
images, each containing 512 A scans, in less than 3.3
seconds. It covers a 6 mm (horizontal) · 6 mm (vertical)
· 1.7 mm (axial) volume. Electroretinogram was
performed using corneal “ERGjet” contact lens electrodes.
The ERG protocol complied with the standards
of the International Society for Clinical Electrophysiology
of Vision (www.iscev.org). This standard speci-
fies six responses: 1) dark-adapted 0.01 ERG, 2)
dark-adapted 3.0 ERG, 3) dark-adapted 3.0 oscillatory
potentials, 4) dark-adapted 10.0 ERG, 5) light-adapted
3.0 ERG, and 6) light-adapted 30-Hz flicker ERG.
Genetic Analysis
Genomic DNA was isolated from peripheral leukocytes
using a QIAamp DNA Blood Midi Kit (Qiagen,
Hilden, Germany) according to the manufacturer’s
protocol. Systematic next-generation sequencing and
From the *Department of Ophthalmology, Peking Union Medical
College Hospital, Peking Union Medical College, Chinese Academy
of Medical Sciences, Beijing, China; †Department of Ophthalmology,
Huashan Hospital, Fudan University, Shanghai, China; ‡School
of Statistics, Capital University of Economics and Business, Beijing,
China; §Human Genome Sequencing Center, Baylor College of
Medicine, Houston, Texas; ¶Department of Molecular and Human
Genetics, Baylor College of Medicine, Houston, Texas; **Structural
and Computational Biology and Molecular Biophysics Program,
Baylor College of Medicine, Houston, Texas; and †† rogram in
Developmental Biology, Baylor College of Medicine, Houston,
Texas.
The Foundation Fighting Blindness, USA, CD-CL-0808-
0470-PUMCH and CD-CL-0214-0637-PUMCH; National Natural
Science Foundation of China, China, 81470669; Beijing
Natural Science Foundation, China, 7152116; The Chinese Ministry
of Science and Technology, China, 2010DFB33430;
CAMS Innovation Fund for Medical Sciences, China, CIFMS
2016-12M-1-002; National Eye Institute, USA, R01EY022356,
R01EY018571, vision core grant P30EY002520; The Retina
Research Foundation, the Foundation Fighting Blindness,
USA, BR-GE-0613-0618-BCM.
None of the authors has any financial/conflicting interests to
disclose.
Reprint requests: Ruifang Sui, MD, PhD, Department of
Ophthalmology, Peking Union Medical College Hospital, Peking
Union Medical College, Chinese Academy of Medical Sciences,
Beijing 100730, China; e-mail: hrfsui@163.com
2 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2018 VOLUME 00 NUMBER 00
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data analyses were performed using methods reported
previously.16 We developed a capture panel that enriches
the entire coding exons and splice sites of 226
known retinal disease genes and other candidate retinal
disease genes.24 Sanger sequencing validation and
segregation analysis were used to identify putative
pathogenic RDH12 variants.
Library Preparation and Targeted Sequencing
Precapture Illumina libraries were generated according
to the manufacturer’s standard protocol for genomic
DNA library preparation. Briefly, 1 mg of
genomic DNA was fragmented to lengths of 200 to
500 bp. The DNA fragments were end-repaired using
polynucleotide kinase and Klenow. The 5ʹ ends of the
DNA fragments were phosphorylated, and a single
adenine base was added to the 3ʹ ends using Klenow
exonuclease. Illumina Y-shaped index adaptors were
ligated to the ends, the DNA fragments were PCR
amplified for 8 cycles, and fragments of 300 to 500
bp were isolated by bead purification. The precapture
libraries were quantified using the PicoGreen fluorescence
assay, and their size distributions were examined
with the Agilent 2100 Bioanalyzer. Forty-eight
precapture libraries (50 ng/library) were pooled
together for a single capture reaction. NimbleGen
SeqCap EZ hybridization and wash kits were used to
capture enrichment according to the manufacturer’s
standard protocol. The captured libraries were
sequenced on the Illumina HiSeq 2000 as 100-bp
paired-end reads according to the manufacturer’s
protocols.
Bioinformatics Analysis of Sequencing Results
The raw reads were aligned to the human reference
genome using BWA and then stored as .bam files.25
GATK was used to refine the alignment.26 SNPs and
Indels were called using Atlas2.27 Variants were filtered
against dbSNP, the 1,000 genome, the Exome
Variant Server (http://evs.gs.washington.edu/EVS/),
and the Baylor internal database; the minor allele frequency
cutoff was 0.5%.28,29 The protein variants
were annotated using ANNOVAR.30 The pathogenicity
of missense variants was predicted using
dbNSFP.31
Sanger Validation and Segregation Test
The RDH12 mutation was amplified with polymerase
chain reaction primers that were previously reported.14
After purification, the amplicons were
sequenced using forward and reverse primers on an
ABI 3730 Genetic Analyzer (ABI, Foster City, CA).
The sequences were assembled and analyzed using the
Lasergene SeqMan software (DNASTAR, Madison,
WI). The results were compared with the RDH12 reference
sequence (NM_152443.2). DNA from all available
family members was Sanger sequenced to confirm
segregation.
Statistical Analysis
Most patients had BCVA worse than 20/200;
therefore, the equivalent logarithm of the minimum
angle of resolution visual acuity value was not
applicable for statistical analysis. Equivalent scores
were assigned to each level of visual acuity,32,33 as
depicted in Table 1. If the difference in the visual
acuity score between two eyes was $5, the patient
was regarded as having significantly asymmetrical
BCVA. Significant asymmetry in refractive error was
considered if the error was .3D between two eyes.
Statistical analysis was performed using R version
3.3.1. Spearman correlation coefficient was used to
analyze the bivariate relationship between age and
BCVA. Because the visual acuity score is an ordinal
variable, ordinal regression analysis using the logistic
function as the inverse link function was used to model
the relationship between BCVA and the other variables
we were interested in, such as diagnosis and
retinal features. The ages of the four groups classified
by retinal appearance were compared using analysis of
variance. To evaluate whether age was related to the
incidence of nyctalopia, nystagmus, or strabismus, we
used the two-sample Kolmogorov–Smirnov test to
compare the difference in age distributions in patients
with and without nyctalopia (nystagmus or strabismus).
Comparison of mean age between the nyctalopia
group and the nonnyctalopia group was made by the
unpaired t-test. Fisher’s exact test was used to examine
the significance of the association between the two
kinds of classification, such as if nyctalopia is related
with BCVA or retinal appearance; if nystagmus is
related with BCVA, refractive error, or retinal
appearance; and if strabismus is related with BCVA,
Table 1. Visual Acuity Score in Patients With Biallelic
RDH12 Variants
Snellen Acuity Visual Acuity Score No. of Eyes (%)
20/2020/40 13 8 (10.8)
20/5020/100 46 14 (18.9)
20/12520/250 79 28 (37.8)
20/40020/1,000 1012 8 (10.5)
20/2000, CF, HM 13, 14, 15 12 (16.2)
LP, NLP 16, 17 4 (5.4)
Total 117 74
CF, finger counting; HM, hand motion; LP, light perception;
NLP, no light perception.
RDH12 RETINOPATHY ZOU ET AL 3
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Table 2. RDH12 Variants Analysis
Proband Diagnosis Variant 1 Effect 1 Reference Variant 2 Effect 2 Reference
1 LCA c.193 C
.T p.Arg65Ter 7 c.437T
.A p.Val146Asp 16
2 LCA c.623T
.A p.Val208Glu 16 c.524C
.T p.Ser175Leu 34
3 LCA c.437T
.A p.Val146Asp 16 c.601delT p.Cys201Ala,
fsX77
16
4 LCA c.437T
.A p.Val146Asp 16 c.721_723delTCC p. Ser241del 16
5 LCA c.437T
.A p.Val146Asp 16 c.506G
.A p.Arg169Gln 13
6† LCA c.710T
.C p.Leu237Pro This study c.710T
.C p.Leu237Pro This study
7 EOSRD c.437T
.A p.Val146Asp 16 c.IVS2 as-1G
.A p.splice defect This study
8 EOSRD c.437T
.A p.Val146Asp 16 c.535C
.G p.His179Asp 15
9 EOSRD c.226G
.A p.Gly76Arg 35 c.226G
.C p.Gly76Arg 35
10*† EOSRD c.226G
.A p.Gly76Arg 35 c.226G
.A p.Gly76Arg 35
11 EOSRD c.184C
.T p.Arg62Ter 5 c.437T
.A p.Val146Asp 16
12† EOSRD c.535C
.G p.His179Asp 15 c.535C
.G p.His179Asp 15
13 EOSRD c.184C
.T p.Arg62Ter 5 c.377C
.T p.Ala126Val 36
14 EOSRD c.437T
.A p.Val146Asp 16 c.506G
.A p.Arg169Gln 13
15*† EOSRD c.184C
.T p.Arg62Ter 5 c.184C
.T p.Arg62Ter 5
16 EOSRD c.505C
.G p.Arg169Gly 16 c.883C
.T p. Arg295Ter 7
17† EOSRD c.437T
.A p.Val146Asp 16 c.437T
.A p.Val146Asp 16
18 EOSRD c.184C
.T p.Arg62Ter 5 c.437T
.A p.Val146Asp 16
19† EOSRD c.146 C
.T p.Thr49Met 1,5 c.146 C
.T p.Thr49Met 1,5
20† EOSRD c.146 C
.T p.Thr49Met 1,5 c.146 C
.T p.Thr49Met 1,5
21 EOSRD c.505C
.T p.Arg169Trp 13 c.468C
.G p.Tyr156Ter This study
22† EOSRD c.505C
.T p.Arg169Trp 13 c.505C
.T p.Arg169Trp 13
23 EOSRD c.437T
.A p.Val146Asp 16 c.535C
.G p.His179Asp 15
24 EOSRD c.146 C
.T p.Thr49Met 1,5 c.437T
.A p.Val146Asp 16
25 EOSRD c.184C
.T p.Arg62Ter 5 c.437T
.A p.Val146Asp 16
26 EOSRD c.184C
.T p.Arg62Ter 5 c.437T
.A p.Val146Asp 16
27*† EOSRD c.377C
.T p.Ala126Val 36 c.377C
.T p.Ala126Val 36
28 EOSRD c.184C
.T p.Arg62Ter 5 c.437T
.A p.Val146Asp 16
29 EOSRD c.146 C
.T p.Thr49Met 1,5 c.184C
.T p.Arg62Ter 5
30 ARRP c.146 C
.T p.Thr49Met 1,5 c.377C
.T p.Ala126Val 36
31 ARRP c.505C
.T p.Arg169Trp 13 c.226G
.A p.Gly76Arg 35
32 ARRP c.226G
.A p.Gly76Arg 35 c.464C
.T p.Thr155Ile 1,7
33 ARRP c.433G
.A p.Gly145Arg 7 c.738_746delGCTCTGGCG p.Leu247_Ar
g249del
This study
34 ARRP c.437T
.A p.Val146Asp 16 c.377C
.T p.Ala126Val 36
35*† ARRP c.343+1G
.A splice defect This study c.343+1G
.A splice defect This study
36† ARRP c.184C
.T p.Arg62Ter 5 c.184C
.T p.Arg62Ter 5
37 CORD c.178G
.A p.Ala60Thr This study c.437T
.A p.Val146Asp 16
38 CORD c.139G
.A p.Ala47Thr 7 c.178G
.A p.Ala60Thr This study
*The patient was born from consanguineous parents.
†The patient has homozygous mutations.
4 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2018 VOLUME 00 NUMBER 00
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Table 3. Clinical Characteristics of Patients With Biallelic RDH12 Variants
ID Sex Age (y) Onset Age (y) Dx No. Aff. NB BCVA (R) BCVA (L) RE (R/L) Ret Other ERG
1M 4
,1 LCA 1 Y NA NA NA 2 Strabismus NA
2 F 10
,1 LCA 1 N 20/400 20/200 +1.75/+1.75 2 Normal NR
3M 9
,1 LCA 1 N 20/250 20/1,000 +5.75/+3.75 1 Strabismus, Nystagmus NR
4 F 13
,1 LCA 1 N CF 20/500 +8.75/+6.75 2 Nystagmus NR
5M 4
,1 LCA 1 N 20/400 20/400 +2.0/+2.25 2 Strabismus NR
6 F 42
,1 LCA 1 N NLP NLP NA 1 Strabismus, IOL NA
7 F 24 5 EOSRD 1 N HM HM +6.50/+2.25 1 Nystagmus, NR
8 M 16 5 EOSRD 2 Y 20/200 20/100 NA 1 PSO, Nystagmus NR
9 F 28 3 EOSRD 1 Y 20/200 20/200 +4.00/+3.50 1 PSO, Strabismus, Nystagmus NA
10* M 28 6 EOSRD 2 Y 20/200 20/200 NA 1 Normal NA
11 F 35 3 EOSRD 1 Y 20/1,000 CF NA 1 PSO, Strabismus, Nystagmus NR
12 F 12 1 EOSRD 1 N 20/200 20/40 +3.00/+1.50 2 Strabismus NA
13 F 19 7 EOSRD 1 N 20/200 20/63 +3.00/+0.75 2 Normal Diminished
14 M 20 3 EOSRD 1 N 20/40 20/40 NA 2 PSO NR
15* M 24 4 EOSRD 1 N 20/100 20/63
20.75/
21.00 1 Normal NR
16 F 20 6 EOSRD 1 Y CF CF NA 1 Mild cataract NR
17 M 12 3 EOSRD 1 Y 20/2000 20/50 +4.25/+0.25 1 Normal NR
18 M 6 6 EOSRD 1 Y 20/40 20/40 +4.75/+4.75 2 Normal NR
19 M 40 4 EOSRD 2 N 20/125 20/200 NA 3 PSO Diminished
20 M 25 5 EOSRD 1 Y 20/125 20/200 NA 1 Normal NR
21 M 15 6 EOSRD 1 Y 20/80 20/80
21.00/
23.00 2 PSO NR
22 M 31 5 EOSRD 1 Y 20/250 20/250
23.75/+0.5 1 Normal NR
23 F 16 9 EOSRD 1 Y 20/125 20/63 NA 1 PSO NR
24 F 18 8 EOSRD 1 Y 20/125 20/200
20.25/+0.25 1 Strabismus NR
25 F 25 3 EOSRD 1 N HM HM NA 3 Strabismus, PSO NA
26 M 16 4 EOSRD 1 Y 20/63 20/63 +0.5/+1.0 1 PSO NR
27* M 20 6 EOSRD 1 Y 20/400 20/400 +0.5/+1.75 1 Normal NR
28 M 6 4 EOSRD 1 N 20/125 20/200 +2.0/+2.5 2 Normal NR
29 F 6 3 EOSRD 1 N 20/100 20/200 +5.0/+5.25 3 Normal NR
30 F 23 19 ARRP 2 N 20/100 20/63 NA 3 Normal Diminished
31 M 39 13 ARRP 1 Y 20/200 20/40 NA 3 Normal NR
32 F 53 13 ARRP 1 Y LP HM NA 2/1 (R/L) Strabismus NA
33 F 30 15 ARRP 1 Y 20/200 HM NA 3 PSO NR
34 F 30 13 ARRP 2 Y 20/200 20/200 NA 3 PSO NA
35* F 26 16 ARRP 1 Y 20/125 20/200 NA 1 Normal NA
36 F 48 16 ARRP 5 Y HM LP NA 1 PSO NR
37 M 26 6 CORD 1 N 20/50 20/250 NA 4 Normal Reduced C&R
38 F 3 3 CORD 1 N 20/40 20/40 +5.0/+5.0 4 Normal Reduced C&R
Retina: 1, Macular coloboma–like lesion (mostly petal-like) with dense bone spicule pigmentation; 2, wide-spread pigment changes, RPE atrophy, and “gold-foil reflection” maculopathy;
3, Heavy and confluent pigment proliferation involving the macular region; 4, Retinal posterior pole atrophy with relatively normal peripheral retina.
Affected members refer to the number of family member who has the similar symptoms like the probands and is suspected to have the same disease.
*The patient was born from consanguineous parents. Patients 11, 18, 25, 26, and 28 share the same biallelic variants. Patients 8 and 23, 19 and 20, and 5 and 14 shared the same
biallelic variants, respectively.
C&R, cone and rod; Dx, diagnosis; IOL, intraocular lens; L, left; N, No; NA, not available; NB, night blindness; No. Aff., number of affected members; NR, nonrecordable; PSO,
posterior subcapsular opacity; R, right; RE, refractive error; Ret, retina appearance type; RPE, retinal pigment epithelium; VF, visual field; Y, yes.
RDH12 RETINOPATHY ZOU ET AL 5
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refractive error, asymmetry in BCVA/refractive error,
or retinal appearance. A four-sample test for equality
of proportions and two-sample test for equality of proportions
were performed to compare the proportion of
nyctalopia patients in different groups classified according
to retinal appearance. The two-sample test
for equality of proportions was also used to compare
the proportion of patients with nystagmus in different
groups classified according to refractive error. For
populations with nonnormal distributions or unequal
variance of the visual acuity score, Wilcoxon ranksum
test was used to compare the difference in BCVA
between the nystagmus group and nonnystagmus
group. A P value of less than 0.05 was considered to
indicate statistical significance.
Results
Mutation Analysis
Either homozygous or compound heterozygous mutations
were detected in RDH12 in 38 patients from 38
families. Among the patients, six patients had been previously
reported by our team.16 Overall, 27 patients carried
compound heterozygous RDH12 mutations, and 11
carried homozygous mutations in RDH12. Twenty-five
disease-causing variants were identified, among which
19 alleles have been previously reported as pathogenic.1,5,7,13,15,16,34–36
Six novel RDH12 mutations in
seven patients were identified in this study. The novel
variants included two missense (c.178G.A p.Ala60Thr
and c.710T.C p.Leu237Pro), one nonsense
(c.468C.G, p.Tyr156Ter), one small deletion
(c.738_746delGCTCTGGCG, p.Leu247_Arg249del),
and two mutations affecting splicing (IVS2 as-1G.A
and c.343+1G.A). Hotspot mutations were identified,
including p.Val146Asp (c.437T.A), which was the
most frequent mutation in our series at an allelic frequency
of 23.7%. It was followed by c.184C.T p.
Arg62Ter (14.5%) and c.146 C.T p.Thr49Met
(9.2%). The three hotspot mutations account for 47.4%
of the mutations in all patients. The percentage of missense
mutations in the LCA, EOSRD, and ARRP groups
was 75.0%, 73.9%, and 64.3%, respectively; the percentage
of nonsense/frameshift mutations was 25.0%, 23.9%,
and 21.4%, respectively; and the percentage of splicing
mutations was 0%, 2.2%, and 14.3%, respectively. There
were five probands with EOSRD (ID 11, 18, 25, 26,
and 28), who shared the same biallelic mutations (c.
184 C.T p.Arg62Ter and c. 437T.A p.Val146Asp).
Moreover, three pairs of patients (Patients 8 and 23, 19
and 20, and 5 and 14) shared the same biallelic RDH12
mutations. Both patients with CORD carried a heterozygous
missense mutation (c.178G.A, p.Ala60Thr).
The results of the mutation analyses are summarized in
Table 2.
Fig. 1. Retinal phenotypes of RDH12-associated retinopathy. Patient 7 (EOSRD) showed macular atrophy with dense bone spicule pigmentation (A).
Optical coherence tomography imaging showed a scalloped macula and chorioretinal atrophy without normal lamination (B). Patient 1 (LCA) showed
macular atrophy and bone spicule or irregular pigmentation (C). Optical coherence tomography imaging showed an enlarged central fovea and retinal
atrophy without a normal laminar structure (D); Patient 31 (ARRP) showed heavy and confluent pigment proliferation involving the macula (E). Optical
coherence tomography imaging showed macular and chorioretinal atrophy (F).
6 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2018 VOLUME 00 NUMBER 00
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Clinical Assessment
Basic ocular data for RDH12-associated retinopathy.
The patient cohort included 18 male patients and 20
female patients. The age of the patients ranged from 3 to
53 years, and the median age was 20 years. Four patients
were born of consanguineous parents (ID 10, 15, 27, and
35). The patients exhibited various clinical phenotypes,
and most cases had severe early-onset retinal dystrophy
(Table 3). Among the 38 patients, 6 patients were diagnosed
with LCA, 23 with EOSRD, 7 with ARRP, and 2
with CORD. RDH12 mutations were the causative factor
in 5.0% of all patients seen at our center with a diagnosis
of LCA, EOSRD, ARRP, or CORD, 10.5% of the patients
with LCA/EOSRD, 1.8% of the patients with
ARRP, and 2.2% of the patients with CORD.
All the patients complained of poor vision since
childhood or a few months after birth; 31 patients
(81.6%) had symptoms before 10 years of age; and 29
patients (76.3%) complained of gradually worsening
visual function. Visual acuity varied considerably at
examination and ranged from no light perception to
20/40. The median visual acuity was 20/200, which
was observed in 24.3% of the patients. The visual
acuity score showed significant correlations with age
(r = 0.389, P , 0.01) according to Spearman’s correlation
coefficient. Older patients tended to have worse
BCVA. From the likelihood ratio tests of ordinal
regression models, we found that the diagnosis
(LCA, EOSRD, ARRP, or CORD) was significantly
correlated with the visual acuity score after adjusting
for the effect of age (P , 0.01). Ordinal regression
analysis with Akaike information criterion as the criterion
for variable selection showed that the final
model contained two variables—age (P , 0.01) and
LCA (P , 0.01)—which were obviously correlated
with the visual acuity score. The estimated coefficient
of LCA was positive (estimated coefficient of LCA =
3.733). This means that, after adjusting for age, there
was no difference in BCVA between the patients with
EOSRD, ARRP, and CORD; however, the BCVA in
the patients with LCA was significantly worse than
that in the other three groups.
Varying degrees of macular atrophy and/or pigmentation
deposits were prominent and persistent features
Fig. 2. Retinal appearance of
patients with CORD. The image
for Patient 37 showed posterior
pole atrophy with a relatively
normal peripheral retina (A).
Autofluorescence imaging
showed loss of fluorescence in
the posterior pole with an edge
of increased fluorescence (B).
Optical coherence tomography
imaging showed macular atrophy
with relatively normal lamination
and absence of the
ellipsoid zone (C). The image
for Patient 38 showed mild
macular atrophy that resembled
a bull’s eye (D). Auto-
fluorescence imaging showed
macular hypofluorescence with
an edge of increased fluorescence
(E). Optical coherence
tomography imaging showed
parafoveal atrophy with damage
to the ellipsoid zone (F).
RDH12 RETINOPATHY ZOU ET AL 7
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of RDH12 retinopathy. The pigmentation ranged from
no pigment and mild scattered bone spicule to confluent
pigment proliferation. Salt-and-pepper pigmentation
and whitish yellow pinpoint spots were
infrequent. Based on fundus appearance, the retinal
phenotypes were divided into four types. Type 1 was
characterized by macular coloboma (mostly petal-like)
with dense bone spicule pigmentation in the midperipheral
retina (Figure 1A). Nineteen patients (37 eyes,
48.7%), including 2 patients with LCA, 14 patients
with EOSRD, and 3 patients with ARRP, belonged
to this subtype. Optical coherence tomography showed
posterior staphyloma and chorioretinal atrophy without
normal lamination (Figure 1B). Type 2 was characterized
by macular discoloration and widespread
bone spicule and/or salt–pepper pigmentation (Figure
1C). Eleven probands (21 eyes, 27.6%) including 4
patients with LCA and 6 patients with EOSRD, and
one eye in a patient with ARRP had this fundus phenotype.
Optical coherence tomography imaging
showed retina thinning without the ellipsoid zone
(Figure 1D). Type 3 was characterized by heavy and
confluent pigment proliferation in the midperipheral
region involving the macular region (Figure 1E).
Seven probands (14 eyes, 18.4%), including 4 ARRP
and 3 EOSRD probands, displayed this appearance.
Type 4 was characterized by retinal posterior pole
atrophy with a relatively normal peripheral retina. Two
patients with CORD exhibited this fundus appearance,
which was different from that in patients with other
diagnoses. Optical coherence tomography imaging
revealed thinning of the retina with relatively normal
lamination and absence of the ellipsoid zone. Auto-
fluorescence imaging showed hypofluorescence in the
posterior pole with an edge of hyperfluorescence
(Figure 2). From likelihood ratio tests of ordinal
Table 4. Full-Field Electroretinogram of Patients With Recordable Results
ID Dx
S 0.01 b-wave
Amplitude (mv)
S 3.0 b-wave
Amplitude (mv)
OPs
Amplitude
(mv)
P 3.0 b-wave
Amplitude (mv)
30-Hz Flicker a1-b1
Amplitudes (mv)
OD OS OD OS OD OS OD OS OD OS Electrode
13 EOSRD 0 13 15 61 0 0 13 26 13 6 JET
19 EOSRD 51 73 134 175 0 0 28 40 24 36 JET
30 ARRP 29 52 190 212 0 0 31 39 24 30 JET
37 CORD 55 48 138 140 50 58 28 31 27 20 DTL
38 CORD 67 87 125 301 0 77 124 95 53 70 DTL
OP, oscillatory potential.
Fig. 3. Fundus appearance of
Patient 30 and her sister. At the
first visit, the fundus (A)
showed a macular epiretinal
membrane with neovascularization
(black circle),
and tortuous vascular and epiretinal
hemorrhage in the retinal
posterior pole (black arrow).
Four years later (B), the macular
epiretinal hemorrhage had
become denser (black arrow),
and the vascular abnormality
had progressed (red circle). C.
The fundus photograph of the
contralateral eye. Her sister had
a similar manifestation but
without macular hemorrhage or
vascular abnormality (D).
8 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2018 VOLUME 00 NUMBER 00
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regression models, we found that the retinal phenotype
(Type 1, 2, 3, or 4) was significantly correlated with
the visual acuity score (P = 0.02). According to ordinal
regression analysis with AIC as the criterion of variable
selection, the final model contained 2 variables—
Type 2 and Type 4—which were obviously correlated
with the visual acuity score. The estimated coefficients
of Type 2 and Type 4 were negative (estimated coef-
ficient of Type 2 = 20.953, estimated coefficient of
Type 4 = 22.692), and the estimated coefficients of
Type 1 and Type 3 were 0. This means that the BCVA
of Type 1 and 3 patients was the worst and was followed
by the BCVA of Type 2 patients, with Type 4
having the best BCVA. One-way analysis of variance
showed that the average age for Type 1 (25.1 ± 1.8)
and 3 (27.6 ± 2.9) are comparable (P = 0.95), and that
it is higher than that for Type 2 (12.9 ± 2.3) (P , 0.01
for all). Because only two patients had Type 4, statistical
analysis was not possible.
Twenty-one patients (55.3%) reported night blindness.
Night blindness was a self-reported complaint of
poorer vision in dim light than in daylight. In
particular, patients usually reported difficulty in walking
outside at night, having to turn on lights on cloudy
days, or fear of going outside after sunset. A twosample
Kolmogorov–Smirnov test showed that there
was a significant difference in age distribution between
the nyctalopia and nonnyctalopia patients (P = 0.04).
One-sided unpaired t-test showed that patients with
nyctalopia were significantly older than those without
nyctalopia (P = 0.01). Nyctalopia was not associated
with BCVA according to Fisher’s exact test (P = 0.72).
The four-sample test showed that the proportion of
patients with nyctalopia was significantly different
between the four retinal-type groups (P , 0.01).
Moreover, based on the results of pair-wise comparison
and the two-sample test, we concluded that there
were a higher number of nyctalopia patients in the
Type 1 group than in the other three groups.
Cycloplegic refraction was performed in 19 patients
(38 eyes) with LCA, EOSRD, or CORD and revealed
hyperopia ($3 D) in 14 eyes (8 patients, 36.8%), refractive
error between -3D and +3 D in 23 eyes (13 patients,
60.5%), and myopia (.23D) in one eye (1 patient,
2.6%). Furthermore, six patients (15.8%) presented with
nystagmus, 10 patients (26.3%) presented with strabismus,
and 12 patients (31.6%) presented with posterior
capsular opacities. One-sided Wilcoxon rank-sum test
concluded that patients with nystagmus had worse
BCVA than the patients who did not (P = 0.01). Fisher’s
exact tests showed that nystagmus was not associated
with retinal phenotype (P = 0.07). The three-sample test
showed that the proportion of patients with nystagmus
was significantly different between the three refraction
groups (P , 0.01). Moreover, pair-wise comparison and
the two-sample test showed that patients with hyperopia
(.3D) had a much higher incidence of nystagmus than
the other refraction groups (P , 0.01). Nystagmus or
strabismus was not associated with age according to the
two-sample Kolmogorov–Smirnov test (P = 0.87 and
0.64, respectively). Strabismus was not significantly
associated with BCVA (P = 0.09), asymmetry in visual
Fig. 4. Clinical features of Patient 8, his younger brother, and Patient 23. Patient 8 had macular atrophy with dense bone spicule pigmentation. Optical
coherence tomography imaging showed a scalloped macular and chorioretinal atrophy without normal lamination (A). His younger brother had similar
findings from fundus and OCT imaging (B). The fundus appearance of Patient 23 was similar to that of the brothers; however, her macular atrophy was
milder (C).
RDH12 RETINOPATHY ZOU ET AL 9
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acuity (P = 0.72), asymmetry in refractive error (P =
0.12), level/type of refractive error, or retinal-type (P =
0.43) by Fisher’s exact test (P = 1).
Four of the six patients with LCA underwent ERG
tests, all of whom exhibited flat ERG tracing that could
not be differentiated from the background, which was
also called a “nonrecordable pattern.” Patients with
EOSRD and ARRP showed severely diminished to
nonrecordable patterns in their rod and/or cone responses.
Patients with CORD showed mild to severely
impaired cone and rod responses (Table 4). Twelve of
the total patients underwent VF tests. Although the test
reliability was moderate due to poor vision and fixation
instability, the results still showed severely
impaired VF tendency, with only a central or paracentral
VF (,5°).
Longitudinal follow-up of patients. Five patients
were followed up for more than 3 years. Patient 4 was
followed up for eight years. Her visual acuity
decreased from finger counting (CF) (right eye), 20/
500 (left eye) to light perception (LP) (both eyes).
Bone spicule pigmentation and macular atrophy also
showed slow progression. Patient 30 was followed up
for four years. The patient is the only one who had
vascular abnormality (tortuous vascular, retinal neovascularization,
and hemorrhage) and retinal
membrane formation (Figure 3, A–C). During the
follow-up, visual acuity decreased from 20/100 (right
eye), 20/63 (left eye) to 20/200 (right eye), 20/125 (left
eye). The macular retinal hemorrhage became denser
(Figure 3B). Patient 30 had a sister with the same
mutations, who had similar manifestations but
without macular membrane or vascular abnormality
(Figure 3D). The other three patients (ID 7, 19, and
31) were followed up for 3 to 5 years. During this
period, their ERG, visual field, vision, and fundus
appearance remained stable.
Phenotype comparison between patients sharing the
same mutations. Variations were also observed in
patients from different families with the same diseaserelated
genetic defects and even those from the same
family. Patient 8 (age, 16 years) had a younger brother
(age, 14 years) with the same mutations. Compared to
the nonrecordable ERG in Patient 8, the scotopic 3.0
responses of the younger brother were still detectable
but with severely diminished amplitude and delayed
latency in both eyes. The visual acuity, fundus
appearance, and OCT findings in the two brothers
were similar. Patient 23 (age, 16 years) showed the
same mutations as Patient 8 and his brother. Her
fundus appearance was similar to that of the brothers;
however, her macular atrophy was milder (Figure 4).
Five patients (ID 11, 18, 25, 26, and 28) carried the
same heterozygous mutations (p.Arg62Ter, p.Val146Asp).
Their visual acuity varied from 20/40 (both
eyes) to hand motion (HM) (both eyes), and their fundus
appearance also varied dramatically (Figure 5).
Furthermore, one patient (ID 32) in our study had
different fundus appearances in her left and right eye.
Discussion
Mutations in RDH12 are associated with recessively
inherited retinal dystrophies,4–7 and they are the underlying
cause in 3% to 7% of retinal dystrophy cases1,7,13;
Fig. 5. Fundus appearance in patients carrying p.Arg62Ter and p.Val146Asp. A. (Patient 28, M, 6 years) and (B) (Patient 18, M, 6 years) showed
macular discoloration. Optical coherence tomography imaging showing that the macular structure was relatively preserved. Visual acuity was 20/125
(right eye), 20/200 (left eye), and 20/40 (both eyes), respectively. C. (Patient 26, M, 16 years) had macular atrophy revealing the major choroidal
vessels. Optical coherence tomography imaging showed a concave macula without retinal lamination. His visual acuity was 20/63 (both eyes). D.
(Patient 11, F, 35 years) had macular atrophy. Optical coherence tomography imaging showed significant loss of normal retinal lamination and thinning
of the retina. Her vision was 20/1,000 (right eye) and CF (left eye).
10 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2018 VOLUME 00 NUMBER 00
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this is consistent with the finding in our cohort (5%). In
our cohort, these mutations were found to be more frequent
in the patients with LCA/EOSRD (11%), but this
percentage is much higher than that in the western population
(,4%).4,37 The findings of this study and of
previous studies indicate that the clinical presentations
related to RDH12 mutations include LCA, EOSRD,
ARRP, ADRP,8 and CORD.12 Early-onset severe retinal
dystrophy was the most common clinical diagnosis of
RDH12-related recessive retinopathy in our cohort.
Compared to other phenotypes, LCA presents with very
early-onset and the worst visual function, and it therefore
represents the most severe phenotype of RDH12-related
recessive retinopathy.
We identified several frequently occurring mutations,
which indicated race-specific hot spots. The most
common allele was p.Val146Asp; it was followed by
p.Arg62Ter and p.Thr49Met. The three most frequent
mutations accounted for 50% of the cases in our cohort.
The most common RDH12 mutation was reported to be
p.Cys201Arg in patients of Indian descent13 and p.
Ala269AlafsX1 in patients of British Caucasian descendant.13
These findings indicate that the mutation spectrum
of RDH12 varies across different ethnic groups.
Screening the hot spots in a large cohort of patients could
be the first step in the identification of RDH12 mutations.
Most variants (71.6%) identified in this study were missense
mutations. In vitro studies have shown that missense
variants of the RDH12 gene exhibited diminished
and aberrant catalytic activity after they were assayed for
their ability to convert all-trans retinal to all-trans retinol.5,7
It is interesting that only the two patients with
CORD carried c.178G.A, p.Ala60Thr. It was reported
that different nucleotide replacement at the same position
(c.178 G.C, p.Ala60Pro) is related to cone dystrophy.38
Therefore, Ala60 may be liable to cone dysfunction.
Nonsense and frameshift mutations cause premature protein
termination and are probably pathogenic. Furthermore,
loss of function seems to result from decreased
protein stability as a consequence of significantly
reduced expression levels of the protein.7
Generally, RDH12 retinopathy is characterized by
impaired visual function in early life, which starts at 2
to 4 years. The condition worsens progressively, with
most patients having significant vision loss before 30
years5 and both rod and cone ERG being undetectable
in patients older than 20 years.6 This conclusion is supported
both by the cross-sectional data of our study, and
the evaluation of the influence of age on BCVA and
retina appearance. Severe visual impairment was noted
in our cohort, and most patients’ vision acuity was
around 20/200, regardless of the onset age and diagnosis.
Furthermore, vision problems often occurred before
school age, and vision loss gradually progressed. These
results are consistent with previous reports.5,39 Age
showed a significant correlation with BCVA, nyctalopia,
macular coloboma-like lesion, and the density of retinal
pigmentation. It is possible that macular atrophy becomes
prominent, retinal pigmentation accumulates,
and retinal function decreases with age, and that this
results in poorer BCVA and more severe night blindness,
all of which reflect the progressive nature of the disease.
The involvement of RDH12 in a dynamic process (the
regeneration of the retina) could explain the progressive
nature of the disease, which is in contrast with the congenital
severe stationary CORD form of LCA that is
ascribed to the GUCY2D, AIPL1, or RPGRIP1 genes.4
Night blindness was a predominant symptom in our
patients and in previous reports.40 Our findings indicated
that patients with Type 1 retina are more likely to present
with nyctalopia. Accordingly, it is postulated that the
dense retinal pigmentation in the peripheral area is a sign
of rod dysfunction and death. Some patients exhibited
complications such as nystagmus, strabismus, and/or
subcapsular cataract. Although both night blindness
and BCVA are related to increasing age, the correlation
between nyctalopia and BCVA was not statistically significant.
The possible explanation is that night blindness
and visual acuity are independent because nyctalopia
mainly reflects rods dysfunction; however, daytime
vision depends on cones. Nystagmus is associated with
severe visual impairment and hyperopia, and only
presents in patients with LCA and EOSRD. Congenital
blindness significantly affects the emmetropization process41
and will cause fixation instability as well. It occurs
less frequently than LCA, which is ascribed to the GUCY2D,
42 AIPL1,
43 or RPE6544 gene. Strabismus is generally
nonspecific in childhood retinal dystrophies,45 and
in our patients, strabismus was not associated with asymmetry
of refractive/visual acuity error, poor vision, or
hyperopia.
We have also highlighted the recognizable retinal
findings that are indicative of recessive RDH12 retinopathy.
For genotype–phenotype analysis, we classified
the retinal phenotypes into four types. Macular
coloboma–like lesion with dense retina pigmentation
is a common feature of these types. This lesion and
confluent pigmentation involving the macula tend to
cause severe vision problem that is related to age. The
patients with CORD had a characteristic retinal
appearance that was very different from that of the
other presentations. There were also infrequent findings
in several patients, such as vascular abnormality,
epiretinal membrane, retinal hemorrhage, and subretinal
yellowish dots. Given their low incidence, these
retinal phenotypes may not be specific to the identified
genetic defects. Moreover, even patients with the same
mutations presented with different retinal appearances.
RDH12 RETINOPATHY ZOU ET AL 11
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However, age showed a significant correlation with
macular coloboma–like lesion and denser retinal pigmentation.
A previous report has also recorded the
progressive formation of coloboma-like lesions.39 One
possible explanation is that the differences in retinal
findings reflect the different stages of the disease. It is
also possible that there exist unknown genetic modi-
fiers that alter the expression of the involved genes.
For example, in the case of complex alleles that
include a pathogenic mutation and a neutral or an
apparent polymorphism, the latter could modify the
function of the pathogenic mutant.7 Environmental
factors could also contribute to the phenotypic variability
of RDH12 retinopathy.
Some cases of LCA or EOSRD caused by mutations
in other genes may resemble RDH12 retinopathy. For
example, LCA patients with CRB1 or NMNAT1 mutations
may present obvious macular atrophy; however, in
the case of these other mutations, visual impairment occurs
earlier and the lesion does not resemble a petal. In
addition, there are significant differences in the OCT
findings. For example, patients with CRB1 mutations
usually have a thickened retina in the parafoveal area.46
However, the fundus of patients with CRX mutations is
similar to that of some patients with RDH12 retinopathy.
Moreover, CRX mutations can also be inherited as an
autosomal dominant trait, and marked macular atrophy is
present in most cases after age 6.47–49
The limitation of the study was that we did not use
a validated BCVA test to determine logarithm of the
minimum angle of resolution visual acuity in patients
with vision worse than 20/200, which was a substantial
proportion of our cohort. Use of CF, HM, and LP to
quantify vision in those patients is unreliable.
Conclusions
We present the detailed ocular phenotypes in 38
unrelated index patients, who were identified by
biallelic disease-causing mutations in the RDH12
gene. This cohort is the largest sample reported so
far. The findings of this study significantly expand
the knowledge about RDH12-related retinal dysfunction.
The clinical and electrophysiological phenotypes
were variable, which may be related to genetic or ethnic
variations and/or environmental factors. In particular,
petal-shaped macular atrophy seemed to be
a prominent feature of RDH12 retinopathy, and the
patients who harbor RDH12 mutations tended to have
progressive vision loss. The severe and early-onset
rod-cone dystrophy associated with mutations in
RDH12 probably reflects a unique feature of the encoded
enzyme.6 Future research will be conducted on
animal models of the disease to gain a better understanding
of the role of RDH12 in photoreceptor
physiology.
Key words: cone-rod dystrophy, early-onset severe
retinal dystrophy, Leber congenital amaurosis, nextgeneration
sequencing, RDH12 gene, retinitis pigmentosa.
Acknowledgments
The authors thank the patients who participated in
the study. Next-generation sequencing was performed
at the Functional Genomic Core (FGC) facility at
Baylor College of Medicine.
References
1. Valverde D, Pereiro I, Vallespín E, et al. Complexity of
phenotype-genotype correlations in Spanish patients with
RDH12 mutations. Invest Ophthalmol Vis Sci 2009;50:
1065–1068.
2. Stockton DW, Lewis RA, Abboud EB, et al. A novel locus for
Leber congenital amaurosis on chromosome 14q24. Hum
Genet 1998;103:328–333.
3. Haeseleer F, Jang GF, Imanishi Y, et al. Dual-substrate specificity
short chain retinol dehydrogenases from the vertebrate
retina. J Biol Chem 2002;277:45537–45546.
4. Perrault I, Hanein S, Gerber S, et al. Retinal dehydrogenase 12
(RDH12) mutations in Leber congenital amaurosis. Am J Hum
Genet 2004;75:639–646.
5. Janecke AR, Thompson DA, Utermann G, et al. Mutations in
RDH12 encoding a photoreceptor cell retinol dehydrogenase
cause childhood-onset severe retinal dystrophy. Nat Genet
2004;36:850–854.
6. Schuster A, Janecke AR, Wilke R, et al. The phenotype of
early-onset retinal degeneration in persons with RDH12 mutations.
Invest Ophthalmol Vis Sci 2007;48:1824–1831.
7. Thompson DA, Janecke AR, Lange J, et al. Retinal degeneration
associated with RDH12 mutations results from decreased
11-cis retinal synthesis due to disruption of the visual cycle.
Hum Mol Genet 2005;14:3865–3875.
8. Fingert JH, Oh K, Chung M, et al. Association of a novel
mutation in the retinol dehydrogenase 12 (RDH12) gene with
autosomal dominant retinitis pigmentosa. Arch Ophthalmol
2008;126:1301–1307.
9. Beheshtian M, Saee Rad S, Babanejad M, et al. Impact of
whole exome sequencing among Iranian patients with autosomal
recessive retinitis pigmentosa. Arch Iran Med 2015;18:
776–785.
10. Sun W, Gerth C, Maeda A, et al. Novel RDH12 mutations
associated with Leber congenital amaurosis and cone-rod dystrophy:
biochemical and clinical evaluations. Vision Res 2007;
47:2055–2066.
11. Xin W, Xiao X, Li S, Zhang Q. Late-onset CORD in a patient
with RDH12 mutations identified by whole exome sequencing.
Ophthalmic Genet 2016;37:345–348.
12. Huang L, Xiao X, Li S, et al. Molecular genetics of cone-rod
dystrophy in Chinese patients: new data from 61 probands and
mutation overview of 163 probands. Exp Eye Res 2016;146:
252–258.
12 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2018 VOLUME 00 NUMBER 00
Copyright a by Ophthalmic Communications Society, Inc. Unauthorized reproduction of this article is prohibited.
13. Mackay DS, Dev Borman A, Moradi P, et al. RDH12 retinopathy:
novel mutations and phenotypic description. Mol Vis
2011;17:2706–2716.
14. Li L, Xiao X, Li S, et al. Detection of variants in 15 genes in 87
unrelated Chinese patients with Leber congenital amaurosis.
PLoS One 2011;6:e19458.
15. Li Y, Pan Q, Gu YS. Phenotype-genotype correlation with
Sanger sequencing identified retinol dehydrogenase 12
(RDH12) compound heterozygous variants in a Chinese family
with Leber congenital amaurosis. J Zhejiang Univ Sci B 2017;
18:421–429.
16. Wang H, Wang X, Zou X, et al. Comprehensive molecular
diagnosis of a large Chinese leber congenital amaurosis cohort.
Invest Ophthalmol Vis Sci 2015;56:3642–3655.
17. Koenekoop RK. An overview of Leber congenital amaurosis:
a model to understand human retinal development. Surv Ophthalmol
2004;49:379–398.
18. Foxman SG, Heckenlively JR, Bateman JB, Wirtschafter JD.
Classification of congenital and early onset retinitis pigmentosa.
Arch Ophthalmol 1985;103:1502–1506.
19. Gu SM, Thompson DA, Srikumari CR, et al. Mutations in
RPE65 cause autosomal recessive childhood-onset severe retinal
dystrophy. Nat Genet 1997;17:194–197.
20. Paunescu K, Wabbels B, Preising MN, Lorenz B. Longitudinal
and cross-sectional study of patients with early-onset severe
retinal dystrophy associated with RPE65 mutations. Graefes
Arch Clin Exp Ophthalmol 2005;243:417–426.
21. Chen X, Liu X, Sheng X, et al. Targeted next-generation
sequencing reveals novel EYS mutations in Chinese families
with autosomal recessive retinitis pigmentosa. Sci Rep 2015;5:
8927.
22. Wang M, Gan D, Huang X, Xu G, et al. Novel compound
heterozygous mutations in CNGA1in a Chinese family affected
with autosomal recessive retinitis pigmentosa by targeted
sequencing. BMC Ophthalmol 2016;16:101.
23. Lazar CH, Mutsuddi M, Kimchi A, et al. Whole exome
sequencing reveals GUCY2D as a major gene associated with
cone and cone-rod dystrophy in Israel. Invest Ophthalmol Vis
Sci 2015;56:420–430.
24. Xu M, Eblimit A, Wang J, et al. ADIPOR1 is mutated in
syndromic retinitis pigmentosa. Hum Mutat 2016;37:246–249.
25. Li H, Durbin R. Fast and accurate short read alignment with
Burrows-Wheeler transform. Bioinformatics 2009;25:1754–
1760.
26. McKenna A, Hanna M, Banks E, et al. The Genome Analysis
Toolkit: a MapReduce framework for analyzing nextgeneration
DNA sequencing data. Genome Res 2010;20:
1297–1303.
27. Challis D, Yu J, Evani US, et al. An integrative variant analysis
suite for whole exome next-generation sequencing data. BMC
Bioinformatics 2013;13:8.
28. Sherry ST, Ward MH, Kholodov M, et al. dbSNP: the NCBI
database of genetic variation. Nucleic Acids Res 2001;29:308–
311.
29. 1000 Genomes Project Consortium, Abecasis GR, Auton A,
Brooks LD, et al. An integrated map of genetic variation from
1,092 human genomes. Nature 2012;491:56–65.
30. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation
of genetic variants from high-throughput sequencing
data. Nucleic Acids Res 2010;38:e164.
31. Liu X, Jian X, Boerwinkle E. dbNSFP v2.0: a database of
human non-synonymous SNVs and their functional predictions
and annotations. Hum Mutat 2013;34:E2393–E2402.
32. Shukla D, Kanungo S, Prasad NM, Kim R, et al. Surgical
outcomes for vitrectomy in Eales’ disease. Eye (Lond) 2008;
22:900–904.
33. Mason JO III, Colagross CT, Haleman T, et al. Visual outcome
and risk factors for light perception and no light perception
vision after vitrectomy for diabetic retinopathy. Am J
Ophthalmol 2005;140:231–235.
34. Coppieters F, Casteels I, Meire F, et al. Genetic screening of
LCA in Belgium: predominance of CEP290 and identification
of potential modifier alleles in AHI1 of CEP290-related phenotypes.
Hum Mutat 2010;31:E1709–E1766.
35. Aldahmesh MA, Safieh LA, Alkuraya H, et al. Molecular characterization
of retinitis pigmentosa in Saudi Arabia. Mol Vis
2009;15:2464–2469.
36. Benayoun L, Spiegel R, Auslender N, et al. Genetic heterogeneity
in two consanguineous families segregating early onset
retinal degeneration: the pitfalls of homozygosity mapping.
Am J Med Genet A 2009;149A:650–656.
37. Weleber RG, Francis PJ, Trzupek KM, Beattie C, et al. Leber
Congenital Amaurosis. Seattle, WA: GeneReviews 1993.
38. Abu-Safieh L, Alrashed M, Anazi S, et al. Autozygome-guided
exome sequencing in retinal dystrophy patients reveals pathogenetic
mutations and novel candidate disease genes. Genome
Res 2013;23:236–247.
39. Kuniyoshi K, Sakuramoto H, Yoshitake K, et al. Longitudinal
clinical course of three Japanese patients with Leber congenital
amaurosis/early-onset retinal dystrophy with RDH12 mutation.
Doc Ophthalmol 2014;128:219–228.
40. Traboulsi EI. The Marshall M. Parks memorial lecture: making
sense of early-onset childhood retinal dystrophies–the clinical
phenotype of Leber congenital amaurosis. Br J Ophthalmol
2010;94:1281–1287.
41. den Hollander AI, Roepman R, Koenekoop RK, Cremers FP,
et al. Leber congenital amaurosis: genes, proteins and disease
mechanisms. Prog Retin Eye Res 2008;27:391–419.
42. Gradstein L, Zolotushko J, Sergeev YV, et al. Novel GUCY2D
mutation causes phenotypic variability of Leber congenital
amaurosis in a large kindred. BMC Med Genet 2016;17:52.
43. Kolandaivelu S, Ramamurthy V. AIPL1 protein and its indispensable
role in cone photoreceptor function and survival. Adv
Exp Med Biol 2014;801:43–48.
44. Weleber RG, Michaelides M, Trzupek KM, et al. The phenotype
of severe early childhood onset retinal dystrophy (SECORD)
from mutation of RPE65 and differentiation from
Leber congenital amaurosis. Invest Ophthalmol Vis Sci 2011;
52:292–302.
45. AlBakri A, Alkuraya FS, Khan AO. Elevation deficiency in
children with recessive RDH12-related retinopathy. J AAPOS
2015;19:568–570.
46. Jacobson SG, Cideciyan AV, Aleman TS, et al. Crumbs homolog
1 (CRB1) mutations result in a thick human retina with
abnormal lamination. Hum Mol Genet 2003;12:1073–1078.
47. Jacobson SG, Cideciyan AV, Huang Y, et al. Retinal degenerations
with truncation mutations in the cone-rod homeobox
(CRX) gene. Invest Ophthalmol Vis Sci 1998;39:2417–2426.
48. Nichols LL II, Alur RP, Boobalan E, et al. Two novel CRX
mutant proteins causing autosomal dominant Leber congenital
amaurosis interact differently with NRL. Hum Mutat 2010;31:
E1472–E1483.
49. Nakamura M, Ito S, Miyake Y. Novel de novo mutation in
CRX gene in a Japanese patient with leber congenital amaurosis.
Am J Ophthalmol 2002;134:465–467. |
