1. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
CURRENT
OPINION The current status of molecular diagnosis of
inherited retinal dystrophies
John (Pei-wen) Chianga
and Karmen Trzupekb
Purpose of review
We are witnessing lightning-fast advances in the molecular diagnosis of inherited retinal dystrophies,
mainly due to the widespread use of next-generation sequencing technologies. The purpose of this review is
to highlight the breadth of findings from this in-depth testing approach, and to propose changes to our
traditional testing and diagnostic paradigms. Lessons learned from modern molecular testing suggest that
the previous concept of inherited retinal dystrophies as a group of ‘single gene diseases’ may require a
significant update.
Recent findings
All of the known retinal dystrophies genes can now be sequenced. In many cases, this nonhypothesis
driven testing strategy is uncovering mutations in unsuspected genes, generating data that challenges
established concepts of genetic mechanisms and provides insights regarding genes previously thought to be
exclusively related to syndromic disease. Recent advances in testing have improved not only the breadth,
but also the depth of genetic data. For example, deep intronic sequencing has uncovered many novel
intronic mutations/variations in the ABCA4 gene.
Summary
Currently, in approximately 50–60% of patients with nonsyndromic retinal dystrophy, the disease
mechanism can be identified. The presence of pathogenic alleles in more than one gene is not uncommon.
Retinal dystrophy, with relatively defined clinical presentations and a large but limited number of genes
involved, is becoming a model for the next-generation study of molecular disease mechanisms.
Keywords
genetic testing, molecular diagnosis, mutation, retinal dystrophy, retinitis pigmentosa
INTRODUCTION
Retinitis pigmentosa is the most common form of
inherited retinal dystrophy, affecting one in 3500 to
one in 4000 people in the USA and Europe (Genetic
Home Reference, http://ghr.nlm.nih.gov/condition/
retinitis-pigmentosa). Increasingly, molecular diag-
nosis is becoming an integral part of clinical diag-
nosis. Variable disease expression, genotypic
heterogeneity (one phenotype caused by more than
one gene), phenotypic heterogeneity (different
mutations in one gene resulting in different pheno-
types), reduced penetrance, and the progressive
nature of these diseases complicate clinical diagnosis.
Molecular testing has long aided diagnosis, but
unclear inheritance patterns in families and the large
number of genes involved has traditionally compli-
cated the task of choosing the appropriate genes to
test. With the arrival of next-generation sequencing
(NGS), however, large numbers of genes can be
sequenced simultaneously. At the same time, poten-
tial modifiers can be unraveled. Molecular testing is
gradually becoming the gold standard in clarifying
diagnoses and elucidating the underlying genetic
mechanisms.
Before whole genome sequencing becomes the
universal testing for every genetic condition, the
current testing strategies are based on either single
gene testing or panel testing. Cost and confidence of
making accurate clinical diagnosis for conditions
with strong phenotype and genotype correlations
are important factors to be considered when
a
Casey Eye Institute Molecular Diagnostic laboratory, OHSU, Portland,
Oregon and b
InformedDNA, St. Petersburg, Florida, USA
Correspondence to John (Pei-wen) Chiang, Casey Molecular Diagnostic
laboratory, Biomedical Research Building, Room 253G, 3181 SW Sam
Jackson Park Road, Portland, OR, USA. Tel: +1 503 494 5838; fax: +1
503 494 6261; e-mail: chiangj@ohsu.edu
Curr Opin Ophthalmol 2015, 26:346–351
DOI:10.1097/ICU.0000000000000185
This is an open-access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where
it is permissible to download and share the work provided it is properly
cited. The work cannot be changed in any way or used commercially.
www.co-ophthalmology.com Volume 26 Number 5 September 2015
REVIEW

2. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
ordering single gene testing. X-linked juvenile ret-
inoschisis (RS1 gene), Stargardt disease (ABCA4
gene), Choroideremia (CHM gene), and Vitelliform
macular dystrophy (PRPH2/RDS or BEST1 genes) are
the conditions with more single testing. In contrast,
a condition such as retinitis pigmentosa is more
ideal to be tested by a large gene panel. One
additional advantage for panel testing is that modi-
fiers, digenic mutations, and multiallelic inter-
actions can also be identified through panel
testing. Taken together, testing by a comprehensive
panel is more ideal for retinal dystrophy.
ABCA4, the gene which when mutated can
result in Stargardt disease, is one of the most studied
ocular disease genes and also one of the most com-
monly mutated genes in retinal dystrophies. We will
use this as an example of how modern sequencing
strategies can be applied.
Stargardt disease affects, approximately, one
in 8000 to one in 10 000 individuals (Genetic
Home Reference, http://ghr.nlm.nih.gov/condition/
stargardt-macular-degeneration). With its distinct
clinical presentation, relative high disease incidence
and high mutation concentration in a single gene,
ABCA4 can become a paradigm for the study of
retinal dystrophy disease mechanisms. However,
mutations in ABCA4 can present with a wide array
of phenotypes. Several interesting aspects of ABCA4
molecular genetics are worth discussing:
Correlation of phenotypes with mutation
severities
The correlation of phenotypes with mutation
severity in ABCA4 has long been proposed [1,2].
Mutation detection rate also appears to correlate
with age of onset. Younger patients usually have
two or more mutations identified in ABCA4 [3,4].
A quantitative threshold effect of mutation load is
likely at work, which may conflict with the
traditional concept of single gene Mendelian inher-
itance. Mutations in ABCA4 can cause Stargardt,
cone or cone–rod dystrophy and retinitis pig-
mentosa, with Stargardt disease frequently harbor-
ing less severe mutations [5]. In many cases,
however, no clear genotype–phenotype corre-
lations emerge. The presence of genetic modifiers
may be the missing link. Recently, a rare combi-
nation of mutations in ABCA4 and GRM6 was
reported in a patient with atypical Stargardt disease
and an unusual electroretinography (ERG) pheno-
type more consistent with congenital stationary
night blindness (CSNB) [6]. Two mutations in ABCA4
and two mutations in GRM6 were identified in the
patient. Although this specific combination may be
extremely rare, the identification of pathogenic var-
iants in additional retinal disease genes is common
when a large number of genes are sequenced. Histori-
cally,clinicians and researchersstop testing when the
presumed disease-causing mutation(s) is identified.
With NGS technologies, secondary mutations are
increasingly being identified.
Deep intronic variants in ABCA4
Numerous reports have confirmed that approxi-
mately 15% of patients with a clinical diagnosis
of Stargardt disease have only one identifiable
mutation in the coding region of ABCA4. Two recent
studies shed light on some of the missing mutations
[7
,8
]. In the first report, five deep intronic
mutations in ABCA4 were identified, increasing
the detection rate of finding two mutations to
91.8% in the studied cohort [7
]. In the second
report [8
], 114 patients with only one previously
known ABCA4 mutation were studied. Deep
intronic mutations were identified in an additional
27/114 (23.7%); no second mutations were ident-
ified in 36/114 (31.6%) and intronic variants of
unknown significance were identified in the
remaining 51/114 (44.7%) patients. The increase
in mutation detection by incorporating these five
deep intronic mutations was confirmed in two other
studies [9,10]. However, the prediction and confir-
mation of pathogenicity for the additional intronic
variants has proven difficult, especially when the
variant is rare [8
]. The detection of rare deep
intronic variants in a highly polymorphic gene such
as ABCA4 is not uncommon. Some of these deep
intronic variants likely do not directly contribute to
the patient’s disease.
KEY POINTS
Next-generation sequencing offers unprecedented
opportunities especially to conditions such as retinal
dystrophy.
Retinal dystrophy, with its main clinical presentation
specific to retina and its limited number of, but well
characterized, genes involved is becoming a model for
the study of rare genetic conditions.
For the first time, almost the entire genes involved can
be sequenced simultaneously and specifically with deep
coverage. Comprehensive and large scale sequencing
efforts are changing our understanding of genetic
mechanisms.
Molecular diagnosis of retinal dystrophy is becoming
an integral part of clinical diagnosis and it may even
become the first line of diagnostic tool in the near
future.
Molecular diagnosis of inherited retinal dystrophies Chiang and Trzupek
1040-8738 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. www.co-ophthalmology.com 347

3. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Looking in the wrong place?
Even following whole gene and deep intronic
sequencing, some patients have only one identifi-
able ABCA4 mutation. Do some of these patients
actually have a mutation in a different gene? The
carrier rate of ABCA4 mutations is approximately
2–3% in the general population. Also, we cannot
rule out the combined effect of two mutations in
two different retinal disease genes, normally func-
tioning synergistically. One of our recent cases illus-
trates this complexity. A patient with the clinical
diagnosis of simplex cone dystrophy diagnosed
approximately age 10 was tested using our Retinal
Dystrophy SmartPanel v2 (154 genes). Two variants
were identified in the ABCA4 gene: p.T829M:
c.2486CT (rs139250920; predicted to be benign
by PolyPhen-2) and c.4253þ43GA (rs61754045).
The p.T829 mol/l:c.2486CT variant has been
reported as a mutation in the literature once. The
clinical significance of the c.4253þ43GA variant is
unclear, and could be a hypomorphic allele. How-
ever, patients with cone or cone-rod dystrophy
typically have more severe mutations in ABCA4
[5]. In addition to the ABCA4 variants, a heterozy-
gous frameshift mutation (c.6120delC) was also
identified in GPR179– a gene associated with reces-
sive complete CSNB. As the disease mechanism
remained unclear, whole exome sequencing was
later performed and a heterozygous deletion of
the entire CRX gene was identified. Unfortunately,
parental samples were not available to determine
whether the CRX deletion was de novo in the patient.
Large deletions of CRX are known to be associated
with dominant de-novo cases of Leber Congenital
Amaurosis and early-onset cone dystrophy. This
case may raise more questions than it answers:
are the ABCA4 variants a ‘red herring’, unrelated
to the patient’s disease? Could ABCA4 be a modifier
of disease expression in this case? At what point is
clinical sequencing complete in retinal dystrophy
patients with positive results? In patients with
only one identifiable mutation in ABCA4, after
sequencing the entire coding regions and the
reported deep intronic mutations, how many
actually possess additional mutation(s) in different
gene(s)? A systematic and comprehensive mutation
detection strategy may be warranted for this group
of patients.
A powerful tool in assisting variant calling
With the progress of several large scale whole exome
and whole genome-sequencing projects, allele fre-
quency for a significant portion of variants are now
well characterized (http://exac.broadinstitute.org/).
Variations from 60 706 unrelated individuals have
been recorded and allele frequency from different
races are shown for each variant. Interestingly,
this new tool has also generated uncertainties to
some published mutations. For examples, allele fre-
quency for the common Whites ABCA4 mutation
p.G1961E (rs1800553) is 0.004723 in Europeans
(non-Finnish) but it is 0.01498 in South Asians.
Typically, allele frequency cutoff is set at 0.005 for
a rare genetic disease. By this standard, a variant
with an allele frequency of 0.01498 is not called as a
mutation, assuming disease incidence is not drasti-
cally higher in the population. Similarly, p.R2107H
(rs62642564) in ABCA4 is also a reported mutation.
Allele frequency in Europeans (non-Finnish) is
7.506e-05 but it is 0.02002 in Africans. The biggest
challenge is apparently to some reported dominant
mutations. For example, the GUCA1A p.P50L
(rs104893968) variant was reported as a dominant
mutation. However, allele frequency for this variant
is 0.00103. Based on our family studies, this variant
has been identified in normal family members.
This variant, if truly pathogenic, likely requires
additional mutations from other genes to cause
disease. Clearly, evaluation of dominant mutations
should be more cautious. Allele frequency of domi-
nant mutations can be instructive in the evaluation
of pathogenicity [11]. Allele frequency of any domi-
nant mutation should be less than the disease
incidence. Pathogenicity of some of the published
dominant mutations are in question. Multiallelic
interactions may be considered in some cases.
Next-generation sequencing
As little as a few years ago, RHO was probably the
most commonly sequenced gene for patients with
retinitis pigmentosa. Mutation detection rate was
poor for patients with simplex or presumed autoso-
mal recessive retinitis pigmentosa, and there was
little clinical utility of genetic testing. Presumed
inheritance type guided molecular testing, and
typically only a few genes were tested for any given
patient. This approach is especially problematic for
conditions such as retinal dystrophies, wherein at
least 200 disease-associated genes are known
(https://sph.uth.edu/retnet/) and genotypic and
phenotypic heterogeneity makes it difficult to
predict genotype (and thus the gene to select for
testing) based on phenotype. Our past narrow
interpretation of inheritance modes and mutation
mechanisms will require some, if not significant,
modifications. When large number of genes are
sequenced, some patients have identified possibly
pathogenic variants in multiple genes or mutations
in a single gene that were not expected based on
phenotype. The presence of multiple presumed
Ocular genetics
348 www.co-ophthalmology.com Volume 26 Number 5 September 2015

4. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
pathogenic variants in multiple genes with various
inheritance modes can complicate interpretation of
disease mechanisms. The hallmarks of dominant
inheritance – variable expression, variable age of
onset, and penetrance may be explained in the
future by the presence or absence of additional
pathogenic variants.
The challenges of modern genetic testing
Despite its advantages, the introduction of clinical
NGS testing has created challenges. Because the
technologies are new, clinical diagnostic labora-
tories are still learning and adapting. The advent
of NGS testing has identified a large number of
variants of uncertain significance. Data interpret-
ation has become a challenge. There is often no
consensus on interpretation of sequence variants
that are not clearly pathogenic. The initial hope
that whole exome sequencing (WES) would replace
disease-specific gene panels is gradually fading
away. Panel testing is frequently more sensitive than
WES testing [12
]. The reason is mainly due to the
method utilized in the target enrichment step.
Currently, many laboratories use hybridization-
based method (capture method) to enrich targets
for sequencing. Gene hybridization relies on
sequence homology. However, hybridization also
enriches DNA from additional regions with hom-
ologies such as pseudogenes and gene family mem-
bers. The ratio of out-of-target captures versus on-
target captures vary to different extents depending
upon the genes involved. Some genes have pseudo-
genes and some others do not. Certain genes belong
to gene families (with several members of similar
genes in the families). Additionally, no specific
capture baits can be designed for some repetitive
regions. Also hybridization condition is not univer-
sal for every target region. Therefore, the target
regions can never be evenly represented in the
captures. Sequencing depth then becomes critical
in coverage. For specific gene panels, the issues
raised above are less critical due to less genes are
covered.
Equally important, data analysis becomes very
demanding when large number of genes are
sequenced. How to filter out false-positive variants
without filtering out true mutations is essential in
order to reduce false-negative rate. The practice of
setting sequencing depth at a lower range (such as
5Â or 10Â depths) in order to increase coverage can
be problematic. When sequencing depth is lower,
more false-positive variants appears (variants ident-
ified when only sequenced five times are less
reliable than variants identified by sequencing
100 times).
Mutation detection rate
Retinal dystrophies are one of the most hetero-
geneous group of genetic diseases. In order to
increase mutation detection rate, a large number
of genes must be sequenced. NGS testing of several
retinal dystrophy patient cohorts have been
reported recently, with published mutation detec-
tion rates for nonsyndromic retinal dystrophy of 37
[13
], 51 [12
], 55 [14], 60 [15], and 70% [16], using
targeted enrichment NGS panel tests.
This wide range in mutation detection rate is not
necessarily directly attributable to the number of
genes analyzed. Eisenberger et al. reported the high-
est mutation detection rate but the lowest number
of included genes. Instead, mutation detection
depends upon the makeup of the patient cohort
and the inclusion of additional methodologies to
increase detection of variants not easily identified
with sequencing. The lowest detection rate reported
(37%; Wang et al.) was obtained from a cohort of
‘unsettled’ probands with simplex or presumed
recessive retinitis pigmentosa, not previously solved
using gene-directed sequencing. Laboratory
analyses used in these different studies variably
included techniques such as copy number
variant analysis, long range PCR amplification of
‘hard-to-sequence’ targets to increase coverage of
highly repetitive sequences, and mutation-specific
analysis of deep intronic mutations. All of these
techniques should increase mutation detection in
a retinal dystrophy cohort, due to the presence of
deep intronic mutations (e.g., ABCA4 and USH2A),
highly repetitive regions (e.g., RPGR ORF15), and
large deletions (e.g., EYS and USH2A). Still, certain
regions in these genes can be missed due to uneven
coverage from the capture panel design in these
studies.
The unexpected
The cost of WES has reduced dramatically over the
last several years. Even with broad WES testing, a
significant proportion of retinal dystrophy patients
still has no mutations identified. The reasons are
likely multiple including: novel, as yet undiscovered
genes; the potential presence of mutations in genes
not previously known to be associated with retinal
diseases; the presence of mutations outside the
target regions; uneven coverage of target genes;
epigenetic mechanisms; inaccurate variant calling,
especially of mild alleles in syndromic genes; and
uncertain clinical diagnoses. The identification of
CLN3, which when mutated was previously known
to cause a form of neuronal ceroid lipofuscinosis, as
a nonsyndromic retinal dystrophy gene is the latest
example of a syndromic gene getting reclassified as a
Molecular diagnosis of inherited retinal dystrophies Chiang and Trzupek
1040-8738 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. www.co-ophthalmology.com 349

5. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
retinal dystrophy gene [14]. Likewise, mutations in
BBS1, long known to cause Bardet–Biedl syndrome,
were identified in some nonsyndromic retinitis
pigmentosa patients [17]. Mutations in IFT140
can cause early-onset severe retinal dystrophy as
the first presentation of a more complex disease
with high risk for renal involvement [18]. The recent
identification of mutations in MMACHC, normally
associated with a severe disorder of vitamin B12
metabolism, in an adult patient with bull’s eye-
appearing macular lesions also reminds us of the
complexity of molecular diagnosis of retinal dys-
trophy [19].
CONCLUSION
Retinal dystrophies have long proven to be a chal-
lenge for molecular diagnosis. Overlapping clinical
presentations leading to uncertainty in clinical diag-
nosis, unclear inheritance patterns, allele hetero-
geneity, variable ages of onset, and the huge
number of genes involved all made molecular diag-
nosis extremely difficult in the past. However, the
arrival and the broad application of NGS has revo-
lutionized molecular diagnosis of retinal dystrophy.
In fact, retinal dystrophies now have a much higher
molecular detection rate than some other con-
ditions, such as autism and most forms of inherited
cardiomyopathy. Also, it is very likely that most of
the common retinal dystrophy genes have been
identified. For the first time, all of the known retinal
dystrophy genes can now be sequenced for less than
US$3000. This sequencing approach currently
makes more sense because it offers higher coverage,
more confidence in data interpretation, lower cost,
and better clinical utility. New phenotype and gen-
otype correlations are beginning to emerge from the
vast amount of data generated. Traditional concepts
of inheritance are being challenged. Further, some
reported mutations in the past are now being
revisited in light of a richer allele frequency data-
base. Syndromic genes are being considered as can-
didate genes for apparently nonsyndromic disease
and vice versa. Quantitative threshold effect and
milder mutation alleles may be in play. Finally, it
will take collaboration throughout the genetics
community to coordinate variant calling and data
sharing. Despite all these achievements, many
patients can still not access commercial genetic test-
ing, particularly given that insurance companies do
not always cover genetic testing for rare conditions.
Making genetic testing in the less developed
nations, where the burden of genetic disease may
be even higher, remains a significant challenge. One
of the greatest hurdles moving forward will be not
just to improve testing methodologies, but to
lower testing costs. Our greatest challenge may be
democratizing genetic testing to ensure that all
affected patients and families can benefit from the
progress that has already occurred. The best is yet
to come.
Acknowledgements
None.
Financial support and sponsorship
There was no financial support or sponsorship for the
works.
Conflicts of interest
Casey Molecular Diagnostic Laboratory is a commercial
genetic testing laboratory.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
of outstanding interest
1. van Driel MA, Maugeri A, Klevering BJ, et al. ABCR unites what ophthalmol-
ogists divide(s). Ophthalmic Genet 1998; 19:117–122.
2. Maugeri A, van Driel MA, van de Pol DJ, et al. The 2588G!C Mutation
in the ABCR gene is a mild frequent founder mutation in the western
European population and allows the classification of ABCR mutations
in patients with Stargardt disease. Am J Hum Genet 1999; 64:1024–
1035.
3. Miraldi Utz V, Coussa RG, Marino MJ, et al. Predictors of visual acuity and
genotype-phenotype correlates in a cohort of patients with Stargardt disease.
Br J Ophthalmol 2014; 98:513–518.
4. Lambertus S, van Huet RAC, Bax NM, et al. Early-onset Stargardt disease –
phenotypic and genotypic characteristics. Ophthalmology 2015; 122:335–
344.
5. Sheffield VC, Stone EM. Genomics and the eye. N Engl J Med 2011;
364:1932–1942.
6. Huynh N, Jeffrey BG, Turriff A, et al. Sorting out co-occurrence
of rare monogenic retinopathies: Stargardt disease co-existing with
congenital stationary night blindness. Ophthalmic Genet 2014; 35:51–
56.
7.
Braun TA, Mullins RF, Wagner AH, et al. Nonexomic and synonymous variants
in ABCA4 are an important cause of Stargardt disease. Hum Mol Genet
2013; 22:5136–5145.
A pivotal study that identified five deep intronic mutations in the ABCA4 gene. This
study has set the example for potential future works on other disease genes when
only one mutation is identified.
8.
Zernant J, Xie YA, Ayuso C, et al. Analysis of the ABCA4 genomic locus in
Stargardt disease. Hum Mol Genet 2014; 23:6797–6806.
This was a systematic and large scale hunting for deep intronic mutations in the
ABCA4 gene. Clearly, there is no shortage of finding private deep intronic variants
of unknown significance. Mutation calling of these variants is still at the rudimentary
stage.
9. Bauwens M, De Zaeytijd J, Weisschuh N, et al. An augmented ABCA4 screen
targeting noncoding regions reveals a deep intronic founder variant in Belgian
Stargardt patients. Hum Mutat 2015; 36:39–42.
10. Bax NM, Sangermano R, Roosing S, et al. Heterozygous deep-intronic
variants and deletions in ABCA4 in persons with retinal dystrophies and
one exonic ABCA4 variant. Hum Mutat 2015; 36:43–47.
11. Strom SP, Gorin MB. Evaluation of autosomal dominant retinal dystrophy
genes in an unaffected cohort suggests rare or private missense variants may
often be benign. Mol Vis 2013; 19:980–985.
12.
Consugar MB, Navarro-Gomez D, Place EM, et al. Panel-based genetic
diagnostic testing for inherited eye diseases is highly accurate and repro-
ducible, and more sensitive for variant detection, than exome sequencing.
Genet Med 2015; 17:253–261.
WES, with its wide applications in NGS testing, was billed as ‘panel
killer’. Surprisingly, its efficacy has rarely been thoroughly analyzed. This
study was the first task in the evaluation of WES and panel testing for retinal
dystrophy.
Ocular genetics
350 www.co-ophthalmology.com Volume 26 Number 5 September 2015

6. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
13.
Wang F,Wang H,Tuan H-F, et al.Next generationsequencing-based molecular
diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype
correlation and clinical refinements. Hum Genet 2014; 133:331–345.
This was arguably one of the most significant works in the NGS of retinal
dystrophy. CLN3, the gene many heath care professionals specifically requested
to exclude from NGS testing in the past, now became one of the most common
nonsyndromic retinal dystrophy genes.
14. Glockle N, Kohl S, Mohr J, et al. Panel-based next generation sequencing as a
reliable and efficient technique to detect mutations in unselected patients with
retinal dystrophies. Eur J Hum Genet 2014; 22:99–104.
15. Zhao L, Wang F, Wang H, et al. Next-generation sequencing-based molecular
diagnosis of 82 retinitis pigmentosa probands from Northern Ireland. Hum
Genet 2015; 134:217–230.
16. Eisenberger T, Neuhaus C, Khan AO, et al. Increasing the yield in targeted
next-generation sequencing by implicating CNV analysis, noncoding exons
and the overall variant load: the example of retinal dystrophies. PLoS One
2013; 8:e78496.
17. Estrada-Cuzcano A1, Koenekoop RK, Senechal A, et al. BBS1 mutations in a
wide spectrum of phenotypes ranging from nonsyndromic retinitis pigmento-
sa to Bardet-Biedl syndrome. Arch Ophthalmol 2012; 130:1425–1432.
18. Khan AO, Bolz HJ, Bergmann C. Early-onset severe retinal dystrophy as the
initial presentation of IFT140-related skeletal ciliopathy. J AAPOS 2014;
18:203–205.
19. Collison FT, Xie YA, Gambin T, et al. Whole exome sequencing identifies an
adult-onset case of methylmalonic aciduria and homocystinuria type C (cblC)
with nonsyndromic bull’s eye maculopathy. Ophthalmic Genet 2015; 17:1–6.
Molecular diagnosis of inherited retinal dystrophies Chiang and Trzupek
1040-8738 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. www.co-ophthalmology.com 351