Implementation of a registry and open access genetic testing program for inherited retinal diseases within a non‐profit foundation

Abstract The Foundation Fighting Blindness is a 50‐year old 501c(3) non‐profit organization dedicated to supporting the development of treatments and cures for people affected by the inherited retinal diseases (IRD), a group of clinical diagnoses that include orphan diseases such as retinitis pigmentosa, Usher syndrome, and Stargardt disease, among others. Over $760 M has been raised and invested in preclinical and clinical research and resources. Key resources include a multi‐national clinical consortium, an international patient registry with over 15,700 members that is expanding rapidly, and an open access genetic testing program that provides no cost comprehensive genetic testing to people clinically diagnosed with an IRD living in the United States. These programs are described with particular focus on the challenges and outcomes of establishing the registry and genetic testing program.

starting peripherally and moving centrally and Usher syndrome, for diseases that involved hearing loss in addition to vision loss. With the increased knowledge about the genetic cause of disease, however, there has been a greater focus on a gene-specific disease nomenclature. For instance, pathogenic variants in the gene USH2A, while initially identified as the cause of Usher syndrome type 2A, are now known to be the most common cause of disease in AR non-syndromic RP (Pontikos et al., 2020). Similarly, the genes CRX and PRPH2 are each implicated in at least three different retinal diseases-Leber congenital amaurosis, RP, and cone/cone-rod dystrophies (Leroy, Pennesi, & Ohnsman, 2018). For most of the diseases, there is no clear genotype-phenotype relationship (Cremers, Boon, Bujakowska, & Zeitz, 2018). Eye and Ear at Harvard Medical School, which in 1990 described the first genetic basis of RP (Dryja et al., 1990) and initiated the near exponential increase in IRD gene discovery. As the increasing genetic diversity and overlap between RP and other IRD grew, the Foundation was renamed to the Foundation Fighting Blindness. The Foundation continues to invest 25% of its funds in gene discovery and characterization, supporting increasingly sophisticated genetic tools to discover the genetic cause of the remaining 40-45% of unsolved IRD cases (Bronstein et al., 2020), and supports a nationwide Israeli IRD consortium performing clinical and genetic mapping of the entire Israeli IRD population . In total the Foundation has raised over $760 M for IRD research with an annual research budget of over $20 M that supports over 73 investigators across 14 countries.
The current mission of the Foundation is to support the development of treatments and cures for the inherited retinal dystrophies and age-related macular degeneration where there are clear genetic drivers of disease. To achieve this goal, the programs of the Foundation cover a broad spectrum (Shaberman & Durham, 2019)  Currently a natural history study of diseases caused by pathogenic variants in the USH2A gene, called RUSH2A (NCT03146078) is following 127 patients over 4 years is in progress (Duncan et al., 2020) and a second study on people with pathogenic variants in the EYS gene called Rate of Progression in EYS Related Retinal Degeneration (Pro-EYS) (NCT04127006), a cause of AR RP, is also in progress.

| THE RD FUND
Historically the Foundation has raised funds through traditional community-based nonprofit approaches which it invested in awards to investigators that range from $30,000 to $500,000 per year. However, to accelerate the pace of clinical progress in moving from labora- The Foundation had maintained a patient registry for many years, that grew to 11,000 names, but was little more than a contact list of patients with IRD, but had limited disease information. In 2014, to improve data quality and depth a more detailed on-line registry was launched, under an Institutional Review Board (IRB) approved protocol, branded My Retina Tracker® Registry https://www. fightingblindness.org/my-retina-tracker-registry (Fisher, Bromley, & Mansfield, 2016). The goals of the Registry are to provide a single, integrated source of information about, and connection to, all people with an IRD; and to share those data, de-identified, with researchers and partners, in order to accelerate the development of treatments and cures. The Registry provides a convenient, secure database to aggregate information about people affected with an IRD (Figure 1).
Membership is initiated when an affected person chooses to join and provides online informed consent to share de-identified data, and be contacted by Registry staff if there is an opportunity, they may be interested in. Members own and control their own data. Once In 2020, the Registry underwent a major upgrade. Key upgrades included enhanced security features; global compliance with data F I G U R E 1 Structure of the My Retina Tracker Registry. People affected with an inherited retinal disease (IRD) join the Registry through a Member Portal https://www.fightingblindness.org/my-retina-tracker-registry Following an online informed consent, members are presented with surveys to capture their objective experience of living with an IRD. During a visit to a clinician, the member can request the clinician enter the clinical ophthalmic exam results through a Clinician Portal on the same web site. To simplify use, clinical data entry is one way, requires no prior authorization, username or password, and initially enters a holding database. Clinical data is released from the holding database into the members profile once an algorithm run by the Registry Coordinator identifies a matching profile in the Registry database. Genetic testing data generated by the CLIA-certified genetic testing partner lab can be downloaded electronically from the lab directly into the registry and matched to the correct member profile. Both the pdf genetic report and the complete set of sequence variants detected are transferred into the database along with their classification. Researchers, approved for access, can view and download de-identified data either through a dedicated researcher portal or in collaboration with the Registry staff who may perform searches on their behalf privacy rules, including GDPR and U.S. data and patient protection laws; and mobile-SMS integration to facilitate new and existing surveys and provide a more interactive platform. The validated Patient-Reported Outcomes Measurement Information System® 29 question survey (PROMIS-29), a tool designed to measure selfreported physical, mental and social health and wellbeing (Cella et al., 2019) and determine quality adjusted life years (QALYs) (Craig et al., 2014) was implemented. Other validated patient reported outcomes (PRO) and outcomes research instruments are planned.
Since launch, over 15,700 people have created an online Registry profile. The baseline growth of the Registry is 100 new members per month, but with the introduction of no-cost genetic testing, that growth has averaged over 370 per month and continues to increase.
The Registry also houses the contact information for the 11,000 registrants from the earlier registry, although many of those have failed to re-engage, possibly representing the age and history of the information.
The total 26,700 Registry membership is 48% male, 45% female with the remainder choosing not to declare their sex and the average age 50.2 years (±20.6 1SD). For the 15,700 actively engaged members who have created a profile since the Registry went online, the membership is 44% male, 43% female with the remainder choosing not to declare their sex and an average age of 44.3 years (±20.7 1SD).
The composition of the current Registry data by clinical diagnosis is shown in Figure 2. RP, including Leber congenital amaurosis, accounts for 51% of the members' diagnoses. Stargardt disease and all forms of Usher syndrome account for 10% each followed by juvenile inherited macular dystrophy at 6%. Currently 5% of cases are clinically characterized as unknown.
Data in the Registry is currently accessible via the Registry staff.
Non-profit use is supported at no cost, while for-profit users sign a consulting contract to help offset the costs of Registry operation.
De-identified data, lacking names, contact information or demographics below state/province level can be requested. If researchers are interested in contacting Registry participants, an IRB approved contact letter must be submitted to Registry staff outlining the identity of the interested party, their reason for contacting the Registry member, and contact information for the member to use if they wish to pursue the opportunity. Once approved, Registry staff send a In January 2017 the Foundation launched a pilot program to understand the patient and clinical interest in genetic testing by funding a comprehensive IRD genetic testing and counseling service at no cost to patient, clinician or insurance. The program was limited to people living in the United States and designed to address the problems faced within the United States for access to testing. Models seeking to minimize the cost using patient insurance were considered, but reimbursement rules, and the Foundation acting essentially as a co-insurer, created administrative complications and would specifically exclude Medicaid patients who only receive last resort coverage.
To reduce the Foundations administrative workload, and provide a consistent dataset for later analysis, a single genetic testing provider was selected. Key considerations were for a comprehensive IRD gene panel test with strong coverage of the genetic regions known to be difficult, such as the 1kb long purine rich region of ORF15 within the RPGR gene (Vervoort et al., 2000;Vervoort & Wright, 2002) which is reported to account for 80% of all cases of RPGR mutations, sensitivity for the increasing number of deep intronic pathogenic variants being discovered in genes like ABCA4 (Sangermano et al., 2019), and high sensitivity copy number detection, since these variants may represent 9% of IRD cases (Zampaglione et al., 2020).
Turn-around time was also important. In the past, Registry members had sought Registry staff help to obtain results for genetic testing they had participated in many years prior. Expecting results in weeks, members expressed frustration and lack of confidence in testing when there had been no communication of results after a year, often more, and their enquiries not returned. In most cases the member had participated in an academic research study, which had failed to identify a genetic cause. Communicating the difference between research studies and a CLIA-certified test, and education that a CLIA-certified test would provide a prompt result, even if negative, was important. Given the complexity of a genetic result, and the enquiries we had previously from constituents who had been tested, but results had not been explained to them, genetic counseling was considered an essential aspect for our program. Genetic counseling was provided through genetic counselors associated with IRD centers when available, or otherwise provided by InformedDNA telegenetic counselors who could support patients nationwide. Blueprint Genetics was selected as the genetic testing lab. Initially 10 clinicians with a strong IRD expertise were approved to order the test. Demand from patients and clinicians to expand the program led, over 22 months, to over 180 approved clinicians across 149 geographically diverse practice groups, of which 40% were academic and 60% private, ordering over 6,300 tests. An analysis by InformedDNA of referral data from two of the clinics with the highest referral rates, showed that prior to the program 75% of patients referred for testing reported they did not complete pre-test genetic counseling appointments or obtain genetic testing, primarily because of lack of insurance coverage and/or cost, with genetic counseling, or testing, or both. The program reversed the trend with >98% participation of referred patients completing genetic testing through this research protocol. In 2019 a survey of the satisfaction with genetic counseling showed that 98% considered the counseling important, feeling more informed about their genetic risks and better equipped to make informed decisions about their retinal condition.
As demand from the program grew, the Foundations administrative burden ensuring eligibility and tracking invoicing became unscalable. Common challenges were patients not being in the Registry, clinicians overlooking the entry of the diagnosis and/or BCVA in the Registry and the need for ordering clinicians, especially in academic centers, to seek their IRB approval before submitting patient data into the third-party Registry. These created significant backlogs in the testing pipeline, delaying results to patients.
To scale more efficiently an Open Access genetic testing program however, is to support rapid market penetration when a product reaches market. As mentioned previously, many IRD are relatively rare and any single IRD center of excellence may only be aware of a hand- the Registry genetic testing programs. A breakdown of the genetic causes of disease for the first 5,879 probands tested is shown in Figure 2. One hundred and forty-eight genes were implicated in a clear genetic diagnosis. Of these the top five genes: ABCA4 (20%) USH2A (13%), RPGR (7%), PRPH2 (5%) and RHO (5%) accounted for almost 50% of the genetic diagnoses, and the top 25 genes accounted for just over 75% of the genetic causes (Table 1). These results for the U.S. population are similar to the findings of a similarly sized U.K. IRD population study (Pontikos et al., 2020). Notable differences within the top five genes were a 1.5-fold higher incidence of RHO in the U.S. population, consistent with the founder effect of the RHO P23H variant (Farrar et al., 1990), accompanied by a similar 2.2-fold increased incidence of EYS, the most common cause of AR RP. While the incidences may be more broadly representative of the genetic incidence of IRD in the United States than single site studies (Stone et al., 2017), we anticipate more accuracy as the Open Access genetic testing program expands to a wider spectrum of referring clinicians.  (3), Norrie Disease (1) and Wagner Disease (1).