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. Author manuscript; available in PMC: 2020 Nov 1.
Published in final edited form as: Am J Ophthalmol. 2019 Jun 8;207:77–86. doi: 10.1016/j.ajo.2019.06.002

Spectrum of Disease Severity and Phenotype in Choroideremia Carriers

Ruben Jauregui 1,2,3, Karen Sophia Park 1,2, Akemi J Tanaka 4, Ahra Cho 1,2,5, Maarjaliis Paavo 1, Jana Zernant 1, Jasmine H Francis 6, Rando Allikmets 1,4, Janet R Sparrow 1,2,4, Stephen H Tsang 1,2,4,§
PMCID: PMC7579725  NIHMSID: NIHMS1535552  PMID: 31181178

Abstract

Purpose:

To characterize and bring awareness to the disease spectrum of female choroideremia patients, as severity can vary from mild, to severe disease comparable to that observed in males.

Design:

Retrospective cohort study.

Methods:

12 female carriers of disease-causing variants in the CHM gene confirmed by molecular genetic sequencing were characterized clinically and imaged with short-wave fundus autofluorescence (SW-FAF), spectral-domain optical coherence tomography (SD-OCT), and color fundus imaging.

Results:

Twelve unrelated female patients with a clinical and genetic diagnosis of choroideremia carriers were included in this study. Disease severity among these phenotypes ranged from mild to severe resembling the typical presentation of choroideremia in males. Mild disease presented with retinal pigment epithelium mottling, a patchy pattern of hypoautofluorescent speckles on SW-FAF, and intact retinal layers on SD-OCT. Severe disease presented with widespread chorioretinal atrophy as shown by SW-FAF and SD-OCT. Each of the identified genetic variants in CHM was predicted to be disease-causing according to in silico prediction software. Disease progression analysis of four patients with follow-up showed a decline in visual acuity for two patients, with progression observed on SD-OCT in one of the patients. No significant disease progression on SW-FAF was observed for any of the patients.

Conclusions:

Female carriers of choroideremia can present with a wide range of clinical phenotypes and disease severity, from mild to severe disease similar to males. Symptomatic females should be considered for current and upcoming gene replacement therapy clinical trials.

Introduction

Choroideremia (CHM, OMIM: 303100) is an X-linked disorder characterized by degeneration of the retina, retinal pigment epithelium (RPE), and choroid due to mutations in the CHM gene. Patients afflicted with the disease typically present with poor night vision followed by a gradual loss of peripheral vision that encroaches upon the macula, often culminating in legal blindness in the fourth or fifth decade. On a molecular level, mutations in CHM lead to a loss of Rab escort protein 1 (REP1), which functions in tandem with other Rab proteins to control intracellular vesicular transport.1 Clinically, these molecular disturbances most commonly manifest as retinal and choroidal atrophy, sometimes to the extent of scleral exposure. Abnormal findings, such as patchy areas of chorioretinal degeneration, can be observed in fundoscopy, while fundus alterations that progress over time can be observed on short-wave fundus autofluorescence (SW-FAF).2–6

With a prevalence of one in 50,000 individuals, choroideremia is rare, occurring even less frequently as a symptomatic disease in women given its X-linked inheritance. Thus far, most clinical trials for choroideremia involving gene addition therapy have excluded female carriers of CHM, as the presentation due to X-inactivation in females is typically associated with no or milder symptoms as compared to males.7–10 A minority of female carriers, however, may present with significant retinal and choroidal atrophy that leads to night blindness and visual impairment comparable to that seen in affected males.2,3,11–13 Such severe choroideremia phenotypes in carriers are hypothesized to occur due to the phenomenon of skewed X-inactivation, in which an abnormally high percentage of somatic cells express the X chromosome carrying the mutated CHM gene.2,14 Nevertheless, some studies do not support a correlation between inactivation status and abnormal retinal phenotype.2

In the present study, we characterize twelve female choroideremia carriers with pathogenic variants in CHM identified by clinical exome or targeted sequencing that present with a wide spectrum of disease severity, from mild to an unusually severe phenotype. Given the extent of disease progression observed to occur in some carriers as evidenced by our findings, we advocate their inclusion in future clinical trials for choroideremia.

Methods

Patients

All study procedures were defined and patient consent was obtained as outlined by the protocol #AAAR0284 approved by the Institutional Review Board at Columbia University Medical Center. The study adhered to the tenets of the Declaration of Helsinki. None of the data presented in this study, including images and genetic testing results, are identifiable to individual patients. A retrospective review of our registry for female patients that are choroideremia carriers was conducted at the Department of Ophthalmology at Columbia University. The clinical diagnosis was made based on presenting symptoms, family history, fundus examination, and subsequently supported by clinical imaging and genetic testing. A total of sixteen female choroideremia carriers were identified. From this patient cohort, only twelve patients had genetic testing confirming the carrier status of choroideremia and we present these patients in this study.

Clinical Examination and Characterization

Each patient underwent a full ophthalmic examination by a specialist (SHT) in retinal dystrophies at our institution. Ophthalmic examinations included a slit-lamp and dilated funduscopic examination, best corrected visual acuity (BCVA), short-wavelength fundus autofluorescence (SW-FAF, 488 nm excitation), spectral-domain optical coherence tomography (SD-OCT), and color fundus photography. Imaging across all modalities was conducted after pupil dilation (>7 mm) with phenylephrine hydrochloride (2.5%) and tropicamide (1%). SW-FAF imaging and horizontal foveal SD-OCT scans were acquired with the Spectralis HRA+OCT (Heidelberg Engineering, Heidelberg, Germany). Color fundus photographs were obtained with either an FF 450plus Fundus Camera (Carl Zeiss Meditec AG, Jena, Germany) or ultra-widefield color imaging acquired with an Optos 200 Tx (Optos PLC, Dunfermline, United Kingdom).

Molecular Genetic Analysis

For each patient, peripheral blood was collected and DNA was isolated for sequencing. The CHM variant for four patients (1, 2, 6, 10) was found via whole-exome sequencing (WES) performed at the Center of Personalized Genomic Medicine of Columbia University Medical Center (CUMC). For Patient 4, WES was performed in the lab of Dr. Rando Allikmets at CUMC. The CHM variant for three patients (5, 7, 11) was found by next-generation sequencing from a 31-gene panel known to cause inherited retinal dystrophies from Prevention Genetics (Marshfield, Wisconsin, USA). Two patients (9, 12) received single-gene next-generation sequencing at the Casey Eye Institute Molecular Diagnostics Laboratory (Portland, Oregon, USA). The remaining two patients (3, 8) received single-gene next-generation sequencing at GeneDx DNA Diagnostic Laboratory (Gaithersburg, Maryland, USA). Each of the variants were further analyzed with the in silico prediction programs MutationTaster and Combined Annotation Dependent Depletion (CADDv1.4) to assess their disease-causing potential.15,16 Neither MutationTaster or CADD are applicable to frameshift variants.

Results

We identified twelve unrelated female choroideremia carriers in our patient registry. Most patients were referred to our clinic for evaluation with either an uncertain (Patients 1, 5, and 6) or incorrect (Patients 2, 4, 9, and 10) diagnosis, ranging from retinitis pigmentosa to macular degeneration. Four patients (7, 8, 11, and 12) presented with no visual complaints and were screened for a carrier status because a male member of their family has a diagnosis of choroideremia. Of the eight symptomatic patients, three experienced disease onset in their sixties, two in their thirties, two in their twenties, and one in her forties. Patient 1, aged 23, was the youngest presenting patient, with onset of symptoms developing on her early twenties. Most patients presented with BCVA better than 20/70, with only Patient 4 presenting with BCVA of 20/150 and HM on the right and left eyes, respectively. Per the history obtained during clinical presentation, Patients 1, 2, and 4 have no family member with a diagnosis of choroideremia. Furthermore, patients were stratified into three categories based on the severity of their disease: mild, intermediate, and severe. Clinical characterization of the patients is summarized in Table 1.

Table 1.

Clinical characterization of the female choroideremia carriers.

Patient ID Age at Presentation (yr) Age of Onset (yr) BCVA (OD; OS) Severity of disease Reason for referral Other Medical History Family History of Choroideremia
1 23 20s 20/20; 20/30 Severe Retinal evaluation IDH2 brain glioma s/p resection No
2 76 40s 20/30; 20/40 Severe Retinitis pigmentosa n/c No
3 60 30s 20/70; 20/60 Severe Choroideremia carrier n/c Yes: father, grandson, paternal uncle
4 61 30s 20/150; HM Severe Macular degeneration n/c No
5 77 60s 20/30; 20/60 Intermediate Findings of
RPE atrophy		 n/c Yes: son
6 64 60s 20/25; 20/40 Intermediate Retinal evaluation Diabetic retinopathy, s/p PRP Yes: father, male cousin
7 63 n/a 20/25; 20/25 Intermediate Asymptomatic screen n/c Yes: son, father
8 50 n/a 20/20; 20/20 Intermediate Asymptomatic screen n/c Yes: son
9 68 60s 20/20; 20/20 Mild Macular degeneration n/c Yes: son
10 29 20s 20/20; 20/25 Mild Retinitis pigmentosa n/c Yes: 2 brothers, 3 maternal uncles
11 53 n/a 20/40; 20/40 Mild Asymptomatic screen n/c Yes: son, brother
12 51 n/a 20/20; 20/20 Mild Asymptomatic screen n/c Yes: son
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BCVA = best-corrected visual acuity; HM = hand motion; IDH2 = isocitrate dehydrogenase 2; n/a = nonapplicable; n/c = non-contributory; PRP = panretinal photocoagulation; RPE = retinal pigment epithelium.

Severe Disease

We defined severe disease when widespread retinal atrophy is observed throughout the posterior pole. In total, four patients presented with severe disease (Patients 1–4). Patients 1 and 2 presented with a male-like SW-FAF phenotype similar to that observed in males. Large areas of hypoautofluorescence were observed throughout the posterior pole, corresponding to areas of extensive chorioretinal atrophy. Both patents exhibited central islands of spared retinal tissue on the macular area with scalloped, sharply-demarcated borders. On fundoscopy, relative pale fundi were observed due to illumination of the sclera behind degenerated retinal layers. In Patient 1, the underlying white sclera was visible in immediate areas superior and inferior to the optic disc of the right eye. In Patient 2, extensive areas of chorioretinal atrophy surrounded the optic disc on both eyes, with the underlying white sclera also visible. Patients 3 and 4 also presented with large areas of dense hypoautofluorescence on the posterior pole, covering the optic disc and, in the case of Patient 4, the macula area In these areas of chorioretinal atrophy, the underlying white sclera was appreciated, as observed, for example, on the temporal aspect of the optic disc bilaterally on Patient 3. SD-OCT scans revealed retinal thinning and loss of the outer retinal layers on areas with chorioretinal atrophy, leading to collapse of the overlying layers. Loss of the RPE was also suggestive by the increased SD-OCT signal transmittance on the areas of chorioretinal atrophy. On Patient 3, in the areas where the underlying white sclera of the right eye was visible on fundoscopy, SD-OCT scans revealed that the remaining retinal layers were detached from the basement membrane. Patient images are shown in Figure 1.

Figure 1. Clinical presentation of the female choroideremia carriers with severe disease.

Figure 1.

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Color fundus photography (left panel), short-wave fundus autofluorescence imaging (SW-FAF, right panel), and spectral-domain optical coherence tomography scans (SD-OCT, bottom panel) of Patients 1–4. On fundoscopy and SW-FAF imaging, clear, well-delineated areas of chorioretinal atrophy occupying most of the posterior pole were observed bilaterally, creating pale fundi due to the illumination of the bare sclera. SD-OCT scans demonstrated that in these areas of chorioretinal atrophy, the outer retinal layers had atrophied. In these areas, hypertransmission of SD-OCT signal into the choroid was pronounced, further suggesting outer retinal atrophy and retinal pigment epithelium loss.

Intermediate Disease

We defined intermediate disease as presenting with a smaller, localized area of chorioretinal atrophy. We observed four patients with intermediate disease (Patients 5–8). As observed by fundoscopy and SW-FAF, the localized areas of atrophy occurred in proximity or covering the optic disc in all patients, with the underlying white sclera appreciated. The atrophic areas were of asymmetrical size between the right and left eyes on all the patients, always sparing the fovea. RPE mottling could be appreciated on the periphery. Patient 6 exhibited peripheral lesions due to previous panretinal photocoagulation treatments for diabetic retinopathy. Similar to the patients with advanced stage disease, SD-OCT scans revealed conservations of the retinal layers on areas of spared tissue, whereas the outer retinal layers had atrophied on the areas of chorioretinal atrophy, with increased signal transmittance observed. Patient images are shown in Figure 2.

Figure 2. Clinical presentation of the female choroideremia carriers with intermediate disease.

Figure 2.

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Fundus photography (left panel), short-wave fundus autofluorescence imaging (SW-FAF, right panel), and spectral-domain optical coherence tomography (SD-OCT, bottom panel) scans of Patients 5–8. Fundoscopy and SW-FAF imaging revealed localized asymmetrical areas of chorioretinal atrophy between fellow eyes, with mottling of the retinal pigment epithelium in the periphery. On SD-OCT scans, preservation of the retinal layers could be appreciated on areas of spared tissue, whereas the outer retinal layers had atrophied in areas of chorioretinal atrophy.

Mild Disease

We observed four patients (9–12) with mild disease, defined as presenting without areas of chorioretinal atrophy. On fundoscopy, fundi with RPE mottling on otherwise spared tissue were observed. On SW-FAF, fine speckles of hypoautofluorescence could be appreciated diffusely throughout the posterior pole, creating a patchy, mosaic-like pattern. Sometimes, these fine speckles coalesced to form larger, coarse areas of hypoautofluorescence, as observed in Patient 9. Given that no areas of chorioretinal atrophy were present, SD-OCT scans revealed intact retinal layers. Patient images are shown in Figure 3.

Figure 3. Clinical presentation of the female choroideremia carriers with mild disease.

Figure 3.

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Fundus photography (left panel), short-wave fundus autofluorescence imaging (SW-FAF, right panel), and spectral-domain optical coherence tomography scans (SD-OCT, bottom panel) showing the clinical presentation of Patients 9–12. On fundoscopy and SW-FAF, fundi with RPE mottling were observed on otherwise spared retinal tissue. SW-FAF revealed fine speckles of hypoautofluorescence, creating a patchy, mosaic-like pattern. SD-OCT scans revealed intact retinal layers.

Genetic Analyses

Genetic sequencing from each patient revealed disease-causing variants in the CHM gene. Three of the variants were found to be nonsense (p.Arg239*, p.Arg253*, p.Trp58*), five were missense (p.Val34Asp, p.Ser453Ser, p.Gln63His, p.Arg450Met, p.Gly314Arg), one intronic (c.49+1G>A), and three frameshift (p.Ser473Trpfs*4, p.Val529Hisfs*7). Each variant was predicted to be disease-causing by in silico prediction software, including MutationTaster and Combined Annotation Dependent Depletion (CADD).15,16 Genetic characterization of the patients is summarized in Table 2.

Table 2.

Characterization of the disease-causing CHM variants found in the choroideremia carriers.

Patient ID Nucleotide Change Amino Acid Change Reported in Females Reported in Males MutationTaster Prediction16 CADD15
1 c.715C>T p.Arg239* Yes24 Yes25 Disease causing (1.0) 37.0
2 c.101T>A p.Val34Asp No No Disease causing (0.99) 26.8
3 c.757C>T p.Arg253* No Yes18 Disease causing (1.0) 36.0
4 c.173G>A p.Trp58* No Yes25 Disease causing (1.0) 35.0
5 c.49+1G>A NA No Yes19 Disease causing (1.0) 33.0
6 c.1584_157 delTGTT p.Val529Hisfs*7 Yes26 Yes27 n/a n/a
7 c.1359C>T p.Ser453Ser Yes28 Yes28 Disease causing (0.99) 13.62
8 c.189G>C p.Gln63His No No Disease causing (0.99) 22.2
9 c.1349G>T p.Arg450Met No No Disease causing (0.99) 24.6
10 c.940G>A p.Gly314Arg No No Disease causing (1.0) 23.5
11 c.1584_157 delTGTT p.Val529Hisfs*7 Yes26 Yes27 n/a n/a
12 c.1414_1510del p.Ser473Trpfs*4 No No n/a n/a
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CADD = combined annotation dependent depletion; n/a = not applicable.

Patients with Clinical Follow-up

A follow-up visit was available for four patients (2, 4, 7, 8) in our cohort. For both Patient 2 and 4, BCVA had deteriorated in the follow-up visit as compared to the initial presentation. Patient 2 presented for follow-up approximately two years later, with a BCVA of 20/50 on both eyes, as compared to 20/30 and 20/40, right and left eye respectively, on her initial visit. Patient 4 presented for follow-up approximately three years later. On that visit, BCVA had deteriorated to 20/200 and light perception on the right and left eyes, respectively, as compared to 20/150 and hand motion on initial presentation. Both Patient 7 and 8 presented for a follow-up visit approximately four years later, and BCVA had remained stable at 20/25 in both eyes for Patient 7 and 20/20 in both eyes for Patient 8. On SW-FAF imaging, there did not seem to be obvious disease progression for any of these patients. SD-OCT scans on Patient 2 revealed a shortening of the ellipsoid zone (EZ) line bilaterally on the temporal aspect. No changes could be identified on SD-OCT scans for the remaining patients. Patients images are shown in Figure 4.

Figure 4. Disease progression of four choroideremia carriers.

Figure 4.

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Short-wave fundus autofluorescence imaging (SW-FAF) and spectral-domain optical coherence tomography (SD-OCT) scans of Patients 2, 4, 7, and 8 at initial presentation (top panel) and follow-up visit (bottom panel). The time between initial presentation and follow-up visit was approximately two years for Patient 2, three years for Patient 4, and four years for Patients 7 and 8. SD-OCT scans for Patient 2 demonstrated a shortened ellipsoid zone (EZ) line temporally at follow-up as compared to the initial visit, suggesting disease progression (green vertical line). No obvious changes that signify disease progression were observed for any of the patients on SW-FAF imaging.

Discussion

In this study, we present twelve unrelated patients that demonstrate the spectrum of clinical phenotype and disease severity in female choroideremia carriers. Previous studies have established that female carriers present with a classic characteristic phenotype in SW-FAF: a mosaic pattern of patchy, speckled hypoautofluorescence, that some also describe it as a “fishnet” pattern.3,5 Nevertheless, a recent study Edwards et al. extended the phenotypes observed in SW-FAF into four characteristic patterns: fine, coarse, geographic, and male-like.13 The previously described “classic” phenotype resembles the fine phenotype from the four-pattern classification. By analyzing each phenotypic pattern with microperimetry, a milder functional deficit was observed in both the fine and coarse groups as compared to the geographic and male-like pattern groups.13 Given the wide phenotypic spectrum that we observed in our cohort of choroideremia carriers and our knowledge of the disease in male patients, we advocate a unifying phenotype of disease in the female carriers rather than divisive sub-classifications into phenotypes. We believe that the patients presented in this study with different phenotypes represent a continuum of disease, and just as in the males, SW-FAF findings depend on the stage of the disease and some patients will be more affected than others.3 Thus we describe our patients as presenting either with mild, intermediate, or severe disease.

Furthermore, it is important for clinicians to obtain familiarity with the different phenotypic presentations of female carriers, as their disease is often incorrectly diagnosed at presentation. Unknown to many retinal physicians, female carriers can present with pathology as severe as that of male choroideremia patients. From the patients presented, four (Patients 2, 4, 9, and 10) were referred to our clinic with an incorrect diagnosis, ranging from retinitis pigmentosa to macular degeneration. With the advent of gene therapy as a treatment modality of retinal dystrophies, it is important that these patients receive the correct diagnosis so they can be referred to the appropriate treatment centers.

In accordance to the natural history of choroideremia, most patients presented with preservation of central vision and BCVA better than 20/60. Even at the latter stages of disease, there is macular preservation, with chorioretinal atrophy impacting the periphery and encroaching on the macula. Patient 4 was the only case where we observed heavy macular involvement, accounting for the poor visual acuity (20/150; HM). In addition, we found a possible correlation between age of onset and the disease presentation. In general, the patients with severe disease had an earlier age of symptom onset, ranging from twenties to forties, whereas those with intermediate or mild disease became symptomatic at a later age or remained asymptomatic.

We were able to present clinical characterization from a follow-up visit for four patients (Figure 4). Although BCVA deteriorated in both Patient 2 and 4, it remained stable for Patients 7 and 8. In attempting to understand the deterioration of visual function, we analyzed two structural parameters, preserved area of RPE on SW-FAF imaging and preserved EZ line on SD-OCT scans, parameters that have been shown to be reliable structural measurements in choroideremia patients.17 With SD-OCT scans, disease progression was evident for Patient 2, as there was shortening of the EZ line on the macular area bilaterally, accounting for the decrease in BCVA. No changes on SD-OCT scans were observed for Patient 4 despite the decrease in BCVA, although we believe this is due to a combination of her advanced stage of disease and consequently poor quality of the imaging obtained. Despite the changes on BCVA, no obvious changes were observed on SW-FAF imaging. BCVA remained stable for Patients 7 and 8, with no changes observed in either SD-OCT scans or SW-FAF imaging. A previous study by Renner et al. studied long-term follow-up of disease progression in two choroideremia carriers was by SW-FAF and electroretinography. Although the authors observed progression of fundus alterations on fundoscopy and SW-FAF, these occurred over a period of 17 years of follow-up for one carrier and 11 years for the other, suggesting that disease progression is slow.6 Based on our four patients with progression, we also believe that disease progression is slow, and that the reason why visual function deteriorated in two patients is because of the unfortunate inclusion of the fovea by slowly progressive degenerative changes.

The CHM gene is intolerant to loss of function (LoF) variation (pLI=1.00) in which 100% of reported nonsense variants (15/15) and 73% of reported null frameshift variants (8 of 11 total) are pathogenic.18 All of the variants identified in our patients are absent or occur at low frequency in the Genome Aggregation Database (gnomAD) exomes and genomes, indicating that the variants are not common benign polymorphisms in the populations represented by these databases. Each variant has been predicted to be disease-causing by in silico prediction software, including MutationTaster and Combined Annotation Dependent Depletion (CADD).15,16 Furthermore, all of these variants have been reported in either males with choroideremia, carrier females, or both, except for the variants p.Gln63His, P.Arg45oMet, p.Gly314Arg, and p.Ser473Trpfs*4 (Table 2). These variants have not previously been reported and are absent in the gnomAD exomes and genomes and is predicted to be deleterious to protein structure and/or function. Although the majority of pathogenic variants in CHM are nonsense or large deletions predicted to ablate protein function, some missense variants have been shown to impact protein structure and thus cause pathogenicity.19,20

Ocular gene therapy is an appealing form of treatment for retinal dystrophies, given that (1) the eye is a less immunologically reactive organ compared to others and (2) these disorders are usually monogenic.21,22 Recently, a Phase 3 clinical trial confirmed the safety and efficacy of voretigene neparvovec as treatment for Leber Congenital Amaurosis caused by the gene RPE65, leading to the first Food and Drug Administration (FDA)-approved in vivo gene therapy treatment in humans.23,24 This success on RPE65-LCA encouraged the application of gene therapy to other retinal dystrophies, including choroideremia. In 2014, MacLaren et al. reported safety and efficacy data for the first human trial where an AAV vector encoding REP1 was administered subfoveally and unilaterally to 6 male patients.7 At 6 months post-treatment, there was an improvement in visual acuity in two patients, and these results were maintained according to a follow-up study 3.5 years post-treatment.7,8 In other recent studies, Dimopoulos et al. encouraged the use of fundus autofluorescence as an objective outcome measure for future studies, while Lam et al. concluded that sustained improvement or maintenance of BCVA can be achieved, suggesting BCVA as a possible primary outcome measure in gene therapy studies.9,10

Among all of these trials for CHM gene therapy, a common theme is the absence of female patients. We thus present this study to increase awareness of the wide spectrum of disease severity that female carriers may exhibit. Results from clinical trials in male patients have demonstrated a minor improvement in acuity in a minority of the most affected individuals, but not halt disease progression.9,10,25 Despite these results, we encourage the inclusion of symptomatic female patients in future clinical trials for choroideremia as a possible means of benefiting a small but affected minority of females that may exist among the population of CHM carriers. In patients with symptomatic intermediate disease, we would hope that disease progression could either be halted or delayed. For symptomatic patients with severe disease, a case-by-case selection should be made, as the disease in patients without any spared retinal tissue might have progressed too far to observe any benefit from gene therapy. The results from the inclusion of female carriers will allow the investigators and the ophthalmology community to learn about the effects of treatment in the carrier state of choroideremia and compare to the results observed in the male population.

Acknowledgements

A. Funding/Support: This work was supported by the National Institutes of Health P30EY019007, R01EY018213, R01EY024698, R01EY026682, R21AG050437], National Cancer Institute Core [5P30CA013696], Foundation Fighting Blindness [TA-NMT-0116–0692-COLU], the Research to Prevent Blindness (RPB) Physician-Scientist Award, unrestricted funds from RPB, New York, NY, USA. R.J. is supported by the RPB medical student eye research fellowship.

B. Financial Disclosures: None to report

C. Other Acknowledgements: None

Footnotes

CONFLICT OF INTEREST

The authors declare that there is no conflict of interest.

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