The Role of Genetic Testing in Avoiding Diagnostic Delays in Inherited Retinal Disease

Abstract

Purpose:

To identify and highlight potential delays in diagnosis and improve the characterization of the providers referring individuals affected with suspected IRDs for specialty care, we performed an analysis of the patients with IRDs seen by an ophthalmic genetics specialty service. In addition, we analyzed the diagnostic yield of genetic testing in patients with IRD in our series and compared this information with other previous studies.

Methods:

We analyzed 131 consecutive patients with suspected IRDs referred to an ophthalmic genetics specialty service at a tertiary hospital. Provider referral patterns, delays in diagnosis and the diagnostic yield of genetic testing were evaluated.

Results:

Mean age in the cohort was 24 years. From the 51 patients that underwent genetic testing, the diagnostic yield was 69%. Of these, genetic testing revealed 51% of patients had an incorrect initial referral clinical diagnosis. The average delay to reach a correct diagnosis was 15 years. Ophthalmologists represented the largest referral base at 80%, followed by neurologists representing 5% of referrals. Pediatric and retinal specialists were the largest referral of ophthalmic subspecialties at 44% and 35%, respectively.

Conclusion:

A significant number of patients experienced a prolonged delay in reaching a correct diagnosis largely due to a delay in initiating the genetic evaluation and testing process. The initial suspected clinical diagnosis was incorrect in a significant number of cases, revealing that affected patients were potentially denied from appropriate recurrence risk counseling, relevant educational resources, specialty referrals in syndromic cases, and clinical trial eligibility in a timely manner.

Summary Statement:

This report characterizes a patient population with IRDs managed by an ophthalmic genetics specialty service to highlight potential diagnostic delays, improve the characterization of referring providers, compare our genetic testing diagnostic yield with past studies, and present a discordance between the referring initial clinical diagnosis and the final molecular diagnosis.

Introduction

Inherited retinal diseases (IRDs) are a heterogeneous collection of disorders characterized by abnormalities in photoreceptor cells. IRDs are a leading cause of visual impairment in children and adults in developed countries, and has an incidence of approximately 1 in 2000 persons worldwide¹. Variants in over 300 genes have been associated with IRDs². Factors including variable expressivity, incomplete penetrance, vision abnormalities often manifesting in the presence of a normal appearing fundus, and overlapping clinical features among the different IRDs present significant diagnostic challenges when making a diagnosis based on clinical suspicion alone without incorporating genetic testing.

Gene therapy was approved by the U.S. Food and Drug Administration in 2017 to treat patients with biallelic RPE65 variants, which are present in a subset of individuals with Leber congenital amaurosis or retinitis pigmentosa, and several clinical trials with disease-modifying treatments for additional IRDs are underway. In addition, coping with a genetic eye disease may pose a significant emotional burden on the patient and family. Therefore, even among the IRDs without an associated treatment or potential therapeutic interventions being studied, affected individuals may still benefit immensely from obtaining a molecular diagnosis to establish a diagnosis, and obtain knowledge of recurrence risk and access to resources specific to the diseases of concern. For these reasons, it is critical to establish a diagnosis in a timely manner.

To our knowledge, the ophthalmic genetics specialty service at our institution is the only program in the state specifically dedicated to managing patients suspected with inherited ophthalmic diseases. With a purpose to identify and highlight potential delays in diagnosis and improve the characterization of the providers referring individuals affected with suspected IRDs for specialty care, we performed an analysis of the patients with IRDs seen in this service over a select period. In addition, we analyzed the diagnostic yield of genetic testing in patients with IRDs in our series and compared this information with other previous studies.

Methods

A retrospective review was performed on all patients referred to the ophthalmic genetics specialty program at our tertiary hospital in the VCU Health System from July 2018 until July 2021. Patients were identified through the electronic medical record system. Individuals were included in the study if an IRD was presumed based on the initial referral clinical diagnosis, which was defined in the study as the referring provider’s clinical diagnosis as documented in referral documents; this working diagnosis preceded an ophthalmic genetics evaluation and genetic testing by our specialty program. In contrast, the final molecular diagnosis was defined in the study as the diagnosis obtained after return of a positive genetic testing result identifying the pathogenic variant(s) responsible for causing disease. Patients were excluded from the study if retinal pathology was not suspected from the referring provider’s initial referral clinical diagnosis, or if the patient had already obtained molecular confirmation from a positive genetic testing result prior to their ophthalmic genetics visit with our specialty team. To note, patients sent to our specialty program whom have already obtained a molecular confirmation are generally being referred for genetic counseling aspects including recurrence risk counseling, reviewing available resources and clinical trial eligibility. Records were reviewed retrospectively to extract patient demographics, transportation distances to the clinic, age from each patient’s initial onset of visual symptoms to age when a final molecular diagnosis was obtained, provider specialty referral information, initial referral clinical diagnosis, and the final molecular diagnosis from genetic testing. The protocol for the research was approved by the Institutional Review Board (IRB HM20019594).

Results

Patient Demographics

There were 131 consecutive patients with inherited retinal disease identified over a 37-month period. The mean age of the cohort was 24 years. Of the patients seen, 45% were male and 55% were female. The self-identified demographic breakdown of the patient population shows a majority of 60% identifying as White, followed by 30% identifying as Black. There were 5% identifying as Hispanic, 2% identifying as Asian, and 2% were grouped as identifying as “other” minority ethnicities. For 1% of patients the race/ethnicity was unknown (Table 1).

Table 1:

Demographics of the patient population

Race/Ethnicity	Percentage of Population
Asian	2%
Black or African American	30%
Hispanic	5%
Other	2%
White	60%
Unknown/Not Reported	3%

The average distance traveled was 49 miles, with a standard deviation of 96 miles. The median travel distance was 19 miles, indicating that most patients were coming from the greater Richmond area. Some patients traveled across state lines, with the maximum travel distance at 945 miles.

Provider Referral Patterns

Most referrals to the Ophthalmic Genetics program came internally within the institution (71%). Among both internal and external referrals, ophthalmologists provided the most patient referrals to the clinic, representing 79% of the total referrals overall, with the second most number of patients referred by neurologists (5%) (Table 2). Other referrals came from human genetics (4%), pediatrics (3%), optometrists (2%), dermatologists (1%) and otolaryngologists (1%). As ophthalmology provided the overwhelming majority of referred patients, we investigated subspecialties. Pediatric and retinal specialists were the highest referral bases at 44% and 35% of patients, respectively, among ophthalmology referring providers (Table 3). The next highest referral ophthalmology subspecialists were neuro-ophthalmologists (6%), glaucoma specialists (5%) and comprehensive ophthalmologists (5%).

Table 2:

Referring medical providers information of all patients with IRDs seen at the eye genetics specialty clinic over the study period.

	Internal Referral	External Referral	Total	Percentage
Dermatology	1	0	1	1%
Human Genetics	5	0	5	4%
Neurology	6	0	6	5%
Ophthalmology	77	28	105	80%
Optometry	0	3	3	2%
Otolaryngology	1	0	1	1%
Pediatrics	1	3	4	3%
Other	2	4	6	5%
Total	93	38	131	100%

Table 3:

Referring provider information for subspecialties in ophthalmology of all patients with IRDs seen at the eye genetics specialty clinic over the study period.

	Internal Referral	External Referral	Total	Percentage
Comprehensive	1	4	5	5%
Cornea	1	2	3	3%
Glaucoma	4	1	5	5%
Neuro-ophthalmology	5	1	6	6%
Oculoplastics	2	0	2	2%
Pediatrics	33	13	46	44%
Retina	31	7	38	35%
Total	77	28	105	100%

Delays in Diagnosis

Of the 131 patients seen at the clinic, 60 patients proceeded with panel-based genetic testing for IRD, and 51 had received molecular test results at the time of study analysis. Among the 51 patients that received molecular testing, 35 received a positive molecular diagnosis, resulting in a diagnostic yield of 69%. Among these individuals, the average time to reach a diagnosis was 15 years, with a standard deviation of 17 years; the longest delay was 69 years. The median duration was 11 years. Of these patients that received genetic testing, 14% received a molecular result within one year of their onset of symptoms, 20% received molecular results between 1–5 years, 14% received results between 5–10 years, and 53% received results after 10 or more years.

Table 4 shows the initial referral clinical diagnosis compared to the final molecular diagnosis obtained from genetic testing. Among the 35 patients that received a positive molecular diagnosis, 51% of patients received a final molecular diagnosis that differed from initial referral clinical diagnosis of the patient; if a patient was referred with a suspected non-syndromic inherited retinal disease and the final molecular diagnosis revealed a genetic syndrome, discordance was noted. Table 5 shows the diagnostic yield calculated in our study compared to that of other studies. The diagnostic yield was calculated by assessing the number of patients receiving a positive molecular diagnosis for an inherited retinal disease, divided by the total number of patients that underwent genetic testing. The diagnostic yield calculated in this study from the 51 patients that received molecular testing was found to be 69%.

Table 4:

Initial diagnosis compared to final molecular diagnosis in the 35 patients that received genetic testing.

Categories of Initial Referral Clinical Diagnosis	Count	Categories of Final Molecular Diagnoses Obtained from Genetic Testing (count of patients)
Retinitis pigmentosa, non-syndromic	10	Usher syndrome type 2A (3), Subtypes of retinitis pigmentosa, non-syndromic (6), Stargardt disease (1)
Stargardt disease	5	Stargardt disease (5)
Cone dystrophy	4	Subtype of retinitis pigmentosa, non-syndromic (1), Achromatopsia (1), Cone-rod dystrophy (2)
Nystagmus	4	Oculocutaneous albinism (3), Leber congenital amaurosis (1)
Retinal dystrophy	3	Subtype of retinitis pigmentosa, non-syndromic (1), Cone-rod dystrophy (1), Stargardt disease (1)
Macular degeneration, unspecified	2	Stargardt disease (1), Subtype of retinitis pigmentosa, non-syndromic (1)
Vision loss, unspecified	2	Usher syndrome type 2A (1), Occult macular dystrophy (1)
Color Blindness	1	Leber congenital amaurosis type 2 (1)
Oculocutaneous albinism	1	Oculocutaneous albinism (1)
Bietti Crystalline dystrophy	1	Bietti crystalline dystrophy (1)
Choroideremia	1	Choroideremia (1)
Optic Atrophy, unspecified	1	Dominant optic atrophy (1)

Table 5:

Diagnostic yield of genetic testing in evaluating for inherited retinal disease in various studies.

Source	Diagnostic Yield (%)
Consugar et al3.	51
Jiman et al4.	49
Lionel et al5.	46
Lee et al6.	58
Glöckle et al7.	55–80
Lenassi et al8.	78
Sheck et al9.	59
Ellingford et al10.	51
Current Study	69

Discussion

Previous studies have investigated select characteristics of individuals affected with IRD, most notable the diagnostic yield. Consugar et al. in 2015 identified 98 patients with a range of IRDs, for which molecular genetic testing had a diagnostic yield of 51%³. Jiman et al. (2020) identified 52 individuals with a probable molecular IRD diagnosis, and a molecular diagnostic yield of 49%. Of those individuals, patients that had a prior clinical diagnosis had a diagnostic yield of 71%, whereas patients without one had a diagnostic yield of 25%⁴. Lionel et al. (2018) identified a range of IRDs in 11 out of 24, resulting in a diagnostic yield of 46%⁵. Lee et al identified 15 individuals with IRDs, with a diagnostic yield of 58%⁶. Glöckle et al identified 170 patients with retinal dystrophy. Out of these, 62 out of 112 individuals suspected with retinitis pigmentosa had variants detected, yielding a detection rate of 55%, and 21 out 26 suspected with Usher- and Bardet–Biedl syndrome had variants detected, yielding a detection rate of 80%⁷. Lenassi et al. (2019) identified 59 pediatric individuals with an IRD, and revealed a diagnostic yield of 78%, with an overall diagnostic yield of 64% for pediatric inherited eye disorders (IEDs)⁸. Sheck et al. (2021) performed a case series with 488 patients with a range of IRDs and a diagnostic yield of 59%⁹. Lastly, Ellingford et al. (2016) performed diagnostic next generation sequencing on 537 patients identified with clinical indications of IRD, and found a diagnostic yield of 51%¹⁰. Our diagnostic yield of 69% was similar to those presented in other reports as outlined in Table 5, although there are limitations in making direct comparisons to past studies, as there are differences within each patient population and type of genetic testing utilized in each study.

The provider referral breakdown indicated mainly internal referrals within our health system (71%). Most referrals came from ophthalmology (80%). Within the ophthalmology subspecialties, it was noted that the most patients were referred from pediatric ophthalmologists (44%), followed by retinal specialists (35%). This is likely due to many IRDs being commonly identified with an early onset in neonatal and pediatric patients and subsequently being already managed by pediatric ophthalmologists, and as the primary anatomical structure affected is the retina, these conditions often require care from a retinal specialist.

Of the patients that had genetic testing completed, the average diagnostic delay was 15 years from time of onset of visual symptoms and when a molecular confirmation was obtained, with the longest delay being a patient whom obtained molecular confirmation 69 years after the onset of vision problems. A large contribution to this range is due to the wide age group of patients seen at the clinic. Our results showed that approximately half of patients received a diagnosis more than 10 years from their initial symptoms, highlighting that most patients faced a large diagnostic delay. In addition to a need for greater awareness of investigating for a genetic etiology among individuals with IRDs, the skew towards older ages may also be in part due to genetic test panels becoming available during the past 10 years, allowing for younger patients to receive genetic testing at an earlier age.

Another factor contributing to diagnostic delays can be attributed to the lack of access to ophthalmic genetic specialty services, resulting in a burden of transportation faced by patients. Reliable transportation is known to be a common and large burden associated with obtaining health care for some patients. Traveling long distances with limited personal or public transportation options is not feasible for many patients. Having more individuals trained in genetic eye diseases, increasing the number of ophthalmic genetics specialty care clinics, and utilizing telemedicine may help reduce the burden for patients to gain access to care.

The importance of incorporating genetic testing is also evidenced by the discordance between the referring initial clinical diagnosis and the final molecular diagnosis in 51% of the patients in our cohort. Obtaining a genetic molecular diagnosis to establish or confirm a suspected diagnosis may help to guide recurrence risk counseling, afford the patient and family with resources, and develop a management strategy that includes making appropriate referrals for syndromic cases for which other organ systems may be at risk for problems.

Establishing an accurate diagnosis in a timely manner is critical. As clinical trials and treatment options expand for those affected with IRDs, the need for genetic counseling and testing will continue to increase⁶. In summary, from our analysis of patients with IRD, it appears that many patients experienced a lengthy period of delay in reaching a correct diagnosis largely due to a delay in initiating the genetic evaluation and testing process. In addition, the initial suspected clinical diagnosis may be incorrect in a significant number of cases in patients with suspected IRD, revealing that affected patients could be denied from obtaining appropriate recurrence risk counseling, relevant educational resources, specialty referrals in syndromic cases, and clinical trial eligibility in a timely manner. These findings highlight the importance of including genetic testing in the management of these patients to assist in establishing a correct molecular diagnosis, and not relying on clinical suspicion alone. Patients may be willing to travel long distances to incorporate a genetics evaluation and testing strategy, however, it may be incumbent upon the provider to be aware of the potential benefits of genetic testing to initiate the referral process. Although these findings represent a small subset of patients at a single institution, they warrant further investigation into the underlying challenges of patients and families with IRDs.