This study investigates the genetic detection rates of wide-panel testing in Black and non-Hispanic White patients with IRDs.
Key Points
Question
What is the association of race on the detection of pathogenic variants via genetic testing for inherited retinal diseases?
Findings
In this 2-group comparison study, Black and White patients with inherited retinal diseases were included. Black patients were less likely to obtain a conclusive genetic diagnosis relative to White patients; older age was also independently associated with decreased genetic diagnosis detection rates.
Meaning
In this study, genetic testing for inherited retinal diseases was associated with lower detection rates in Black patients.
Abstract
Importance
The association of race and detection of pathogenic variants using wide-panel genetic testing for inherited retinal diseases (IRD), to our knowledge, has not been studied previously.
Objective
To investigate the genetic detection rates of wide-panel testing in Black and non-Hispanic White patients with IRDs.
Design, Setting, Participants
This 2-group comparison used retrospective patient data that were collected at the University of Michigan (UM) and Blueprint Genetics (BG). At UM, inclusion criteria included having a clinical IRD diagnosis, wide-panel genetic testing, and both parents and the patient self-identifying as the same race (Black or non-Hispanic White). Logistic regression analysis was used; the dependent variable was genetic test result (positive or negative/inconclusive) and the independent variables were race, age, sex, phenotype, and number of genes tested. In the BG database, patients with wide-panel testing and self-reported race were included; detection rate comparison analysis based on race was performed using χ2 test of independence. These data were analyzed from October 30, 2013, through October 26, 2022.
Main Outcome and Measure
Genetic test result was considered positive if pathogenic/likely pathogenic variants were detected.
Results
A total of 572 patients were included in UM, 295 were males (51.6%). Mean age was 45 years. There were 54 Black patients (9.4%) and 518 White patients (90.6%). Black race (odds ratio [OR], 0.25; 95% CI, 0.14-0.46; P < .001) and age (OR per 10 years, 0.84; 95% CI, 0.76-0.92; P < .001) were independently associated with decreased odds of a positive test. In the BG database, 142 of 320 of Black patients (44.4%) had a positive/likely positive test result, a proportion lower than White patients (1691 of 2931 [57.7%]) (χ2 = 18.65; df = 1; P < .001).
Conclusions and Relevance
Results from this study highlight a lower genetic detection rate for Black patients than for White patients with IRDs. This supports a concern that the current development of IRD therapeutics is highly dependent on the ability to identify the genetic cause of disease. Patients with no known genetic diagnosis may be disadvantaged in terms of prognostication, inheritance counseling, reproductive decision-making, and eligibility for potential therapeutic options, including clinical trials. As future treatments become available, these findings suggest the need to examine the genetic detection rates across majority and minority subgroups alike.
Introduction
Advances in gene discovery and next-generation DNA sequencing have enabled clinicians and researchers to provide genetic diagnoses for a growing proportion of patients with inherited retinal diseases (IRDs). The genetic etiology of an IRD is critical information for diagnostic confirmation, prognostication, genetic and reproductive counseling, and eligibility for both approved and investigative treatments. However, it is unknown whether the detection rate of currently available genetic testing platforms is consistent across racial groups. In the field of cancer genetics, African ancestry has been associated with a higher proportion of inconclusive genetic testing for BRCA1/BRCA2 breast cancer.1 Few IRD studies have disclosed the racial composition of the population being studied and, to our knowledge, none have compared the rate of causal gene detection in patients of different racial backgrounds.2,3
The detection rate of currently available genetic testing platforms is largely based on curation of variants for pathogenic or benign status.4 Genetic variants curated in the literature and by publicly available databases, such as the Genome Aggregation Database (gnomAD),5 are largely derived from White individuals from Europe and North America. Furthermore, founder effects of pathogenic variants in specific racial, ethnic, and geographic groups may be underrepresented in the general population. Therefore, many variants present in Black and other minority populations (whether common to these minority populations or not) are likely to be less familiar to variant curation databases and more difficult to classify, leading to a likely label of variant of uncertain significance in these cases, which may prevent a conclusive genetic diagnosis from being reached. Therefore, one potential limitation preventing a molecular diagnosis for every patient with a clinical diagnosis of an IRD is that the detection rate of currently available genetic testing platforms may be inconsistent across racial groups.6 Preliminary evidence supporting this hypothesis is present. Roberts et al7 studied the genetic etiology in indigenous African patients with IRDs through whole-exome sequencing and found the genetic cause of disease in 40% of the participants, which is lower than the 62.1% detection rate reported in other studies in the general population.2,8,9,10 Most IRD literature studying genetic detection rate on a population level did not specify the race of participants.9,11,12,13
In this study, we report the association between race, age, sex, phenotype, genetic testing panel size, and genetic testing detection rates in Black and non-Hispanic White patients. The largest patient minority in our dataset in terms of sample size was for Black patients. The other minorities in our sample were not large enough in size which would raise the possibility of insufficient statistical power to detect difference in genetic detection rate and a higher probability of a type II error when comparing groups. As such, we used the patient minority with the largest sample size and compared to the nonminority group.
Methods
This is a case series study that was compliant with the reporting guidelines outlined by Kempen et al.14 The study design was implemented by 2 institutions.
University of Michigan’s Kellogg Eye Center
This study was conducted at the University of Michigan Kellogg Eye Center. Institutional review board approval was obtained prior to initiation of the study (HUM00028413). This study adhered to the tenets of the Declaration of Helsinki and the regulations of the Health Insurance Portability and Accountability Act. Informed consent for this retrospective medical record review was not required by the University of Michigan institutional review board.
Data Collection
Data were obtained from the IRD clinic at the Kellogg Eye Center. Using electronic medical records, we obtained data on patients seen in the clinic and genetically tested between October 2013 and October 2022. Participants were given a clinical diagnosis of an IRD by a fellowship-trained IRD specialist (A.T.F., J.R.H., K.T.J.) based on a combination of clinical history, examination, pedigree analysis, electroretinography, optical coherence tomography, fundus autofluorescence, and Goldmann visual field testing. Inclusion criteria were: (1) a clinical diagnosis of any IRD, (2) wide-panel genetic testing from a Clinical Laboratory Improvement Amendments (CLIA)–certified laboratory, and (3) both parents of an affected individual self-identifying as Black or both self-identifying as non-Hispanic White. In this study, Black race refers to individuals who identify as being from the African diaspora (African American, Afro-Caribbean, or Afro-Latin-American), and White race refers to individuals who identify as non-Hispanic White. Only 1 affected individual (proband) from each family was included in the study. Collected data included age at time of genetic testing, sex, race (Black or non-Hispanic White), IRD phenotype (rod-cone, cone/cone-rod, macular dystrophy, or other trans-synaptic IRD), genetic testing results, information on the number of genes tested on the panel (panel size), pedigree-related data (affected relatives), IRD syndromic manifestations, and electroretinography wave amplitudes (consistent with criteria set by the International Society for Clinical Electrophysiology of Vision).15
The IRD clinic used wide-panel genetic testing from 3 different CLIA–certified laboratories: Blueprint Genetics (Helsinki, Finland), Ocular Genomics Institute, Harvard University (Boston, Massachusetts), and Molecular Vision Laboratory (before and after affiliation with the Casey Eye Institute, Oregon Health Sciences University, Portland, Oregon). These laboratories used next-generation sequencing following gene-panel capture or whole-exome captures. Patients who were found to have pathogenic or likely pathogenic variants (biallelic for recessive and monoallelic for dominant and X-linked disease) were considered to have a positive genetic result on wide-panel genetic testing. Patients found to have no reported variants were considered to be negative and those found to have only 1 or more variants of unknown significance or only a single disease-causing variant in an autosomal recessive gene were considered inconclusive.
Statistical Analysis
Data were summarized by race and statistically compared with Pearson χ2 test or Fisher exact test (categorical variables) and Welch t test (interval variable). To study the different factors that can affect the genetic testing detection rate (positive or negative/inconclusive result), we used a multivariable logistic regression model with independent (predictor) variables race, age, sex, phenotype, and size of the IRD panel. Given that this study spanned from 2013 through 2022, we performed a time-trend regression analysis of genetic testing detection rate: a regression analysis was performed between time in years from 2013 through 2022 and genetic testing detection rate. We performed the time-trend analysis to investigate the association of improving-with-time factors, that we were unable to specially measure, and genetic detection rate. Such factors could include genetic analysis techniques, platforms for sequencing, and interpretation changes due to implementation of the American College of Medical Genetics and Genomics16 variant classification guidelines and Exome Aggregation Consortium and gnomAD data for variant interpretation. Results of the time-trend regression analysis were displayed for the whole sample and for each race. In addition to the multivariable model, we performed a series of univariable analyses within each phenotypic group, in which Black and White patients with positive vs negative/inconclusive results were compared by applying the χ2 test of independence or the Fisher exact test. No correction for multiple comparisons was performed. IBM SPSS version 28.0 was used for statistical analysis.
Database Analysis by Blueprint Genetics
To further investigate the association of race and genetic testing detection rate in a larger and international population, we used the database of patients with IRD genetically tested at Blueprint Genetics. Blueprint Genetics is a CLIA–certified lab that performs genetic testing for patients who have IRDs diagnosed by an ophthalmologist. It receives testing samples from different patients with IRDs from all over the US and around the world. Using their genetic testing database, Blueprint Genetics (J.K., M.M.K.) extracted data of patients with IRDs who were tested on a large panel and identified their race as White or Black. The detection rate of IRD large panel testing was compared between White and Black patients using the χ2 test of independence.
Results
University of Michigan’s Kellogg Eye Center
The study sample consisted of 572 patients of which 295 were male (51.6%). Age ranged from 0 to 88 years with a mean (SD) age of 45 (20.1) years. There were 54 Black patients (9.4%) and 518 White patients (90.6%). The phenotypes for the sample were 328 rod-cone dystrophy (57.3%), 92 cone/cone-rod dystrophy (16.6%), 141 macular dystrophy (24.7%), and 8 other trans-synaptic IRD diagnoses (6 X-linked retinoschisis [1%] and 2 congenital stationary night blindness [0.4%]). One hundred twenty-two patients had an affected first-degree relative (21.3%), while 94 had a more distantly related relative (second to seventh degree) (16.4%). Prevalence of syndromic features (early-onset sensorineural hearing loss, kidney anomalies, polydactyly, intellectual disability with seizures) was 52 (9.1%). The most common genetic causes of disease were mutations in ABCA4 (70 [12.2%]), USH2A (55 [9.6%]), RPGR (31 [5.4%]), RHO (22 [3.8%]), PRPH2 (17 [3.0%]), EYS (14 [2.4%]), CRB1 (11 [1.9%]), and PRPF31 (11 [1.9%]). Overall, these demographics were similar for the Black and White patient subgroups (Table 1). The mean better and worse eye logMAR visual acuities were (0.68, 0.93) for White patients and (0.76, 1.02) for Black patients. No data were missing except for worse eye logMAR visual acuity for 1 patient who had an eye prosthesis. For that patient, “no light perception” was used for worse eye logMAR.
Table 1. Patient Demographics.
| Characteristic | No. (%) | |
|---|---|---|
| White | Black | |
| Sample | 518 | 54 |
| Age, y, mean (SD) [range] | 45.06 (20.3) [0.7-88.4] | 43.3 (19.2) [0.9-71.5] |
| Sex | ||
| Female | 252 (48.6) | 25 (46.3) |
| Male | 266 (51.4) | 29 (53.7) |
| Phenotype | ||
| Rod-cone dystrophy | 303 (58.5) | 25 (46.3) |
| Cone/cone-rod dystrophy | 79 (15.2) | 16 (29.6) |
| Macular dystrophy | 129 (24.9) | 12 (22.2) |
| Other trans-synaptic IRDs | ||
| X-linked retinoschisis | 5 (1.0) | 1 (1.9) |
| CSNB | 2 (0.4) | 0 (0.0) |
| Affected family member | ||
| First-degree relative | 113 (21.8) | 9 (16.7) |
| Non–first degree relative | 84 (16.2) | 10 (18.5) |
| Genotype | ||
| ABCA4 | 65 (12.5) | 5 (9.3) |
| USH2A | 54 (10.4) | 1 (1.9) |
| RPGR | 30 (5.8) | 1 (1.9) |
| RHO | 21 (4.1) | 1 (1.9) |
| PRPH2 | 16 (3.1) | 1 (1.9) |
| EYS | 12 (2.3) | 2 (3.7) |
| CRB1 | 10 (1.9) | 1 (1.9) |
| PRPF31 | 11 (2.1) | 0 (0.0) |
| RS1 | 7 (1.4) | 1 (1.9) |
| Presence of syndromic IRDs | 51 (9.8) | 1 (1.9) |
| Better eye logMAR VA, mean (SD), [Snellen equivalent] | 0.68 (0.96) [20/95] | 0.76 (0.92) [20/115] |
| Worse eye logMAR VA, mean (SD), [Snellen equivalent] | 0.93 (1.06) [20/170] | 1.02 (0.93) [20/209] |
Abbreviations: CSNB, congenital stationary night blindness; IRDs, inherited retinal diseases; VA, visual acuity.
Genetic testing on a wide IRD gene panel was performed on 572 patients. Of these 572 patients, 449 were tested by the Blueprint Genetics Laboratory (78.5%), 86 were tested by the Ocular Genomics Institute (15%), 25 were tested by the Molecular Vision Laboratory (4.4%), 7 were tested by Invitae (1.2%), and 5 were tested by eyeGENE (0.9%). The above-mentioned proportions did not differ when compared by race (χ2 test of independence, χ2 = 1.66; df = 3; P = .80). The mean (SD) panel size over the study period was 261 (47) genes for Blueprint Genetics, 247 (15) genes for Ocular Genomics Institute, 210 (59) genes for Molecular Vision, 307 (31.6) for Invitae, and 304 (1.2) for eyeGENE. There was no statistically significant difference between the mean panel size used for Black and White patients (Welch t test, t = −0.239; df = 66; P = .81).
A total of 389 patients received positive genetic test results that explained the clinical phenotype (68%). The genetic testing detection rate was lower among Black patients compared with White patients (38.9% vs 71%; P < .001) (eFigure 1 in Supplement 1). In subgroup analysis by phenotype, this difference persisted for 2 of 3 phenotypes: rod-cone (Black patients: 12 of 25 [48%] vs White patients: 227 of 303 [74.9%]; P = .004) and cone/cone-rod dystrophy (3 of 16 [18.7%] vs 47 of 79 [59.5%]; P = .003). Macular dystrophy showed a nonsignificant difference (5 of 12 [41.7%] vs 88 of 129 [68.2%]; P = .11) (Table 2) (eFigure 2 in Supplement 1). A multivariable model (Table 3) showed that Black race is independently associated with decreased odds of obtaining a conclusive genetic diagnosis (odds ratio [OR], 0.25; 95% CI, 0.14-0.46; P < .001) relative to White race. Older age is also independently associated with decreased genetic diagnosis detection rates (OR per 10 years, 0.84; 95% CI, 0.76-0.92; P < .001). Cone/cone-rod dystrophy phenotype was also independently associated with decreased detection rate (OR, 0.45; 95% CI, 0.27-0.73; P = .001) when compared with rod-cone dystrophy. This model shows that sex and panel sizes in this study are not statistically associated with genetic diagnosis detection rates. The time-trend analysis showed no significant change in detection rate over time; even though a minimal increase of detection rate per year was detected (β = 0.01), the statistical correlation was not significant (P = .54). Time-trend analysis showed the same result when analyzed within either race (Black patients, P = .51; White patients, P = .19).
Table 2. Genetic Testing Detection Rates.
| Characteristic, No. (%) | White patients | Black patients | P value |
|---|---|---|---|
| Overall | |||
| Total | 518 | 54 | <.001a |
| Negative/inconclusiveb | 150 (29) | 33 (61.1) | |
| Positivec | 368 (71) | 21 (38.9) | |
| Rod-cone dystrophy | |||
| Total | 303 | 25 | .004a |
| Negative/inconclusiveb | 76 (25.1) | 13 (52.0) | |
| Positivec | 227 (74.9) | 12 (48.0) | |
| Cone/cone-rod dystrophy | |||
| Total | 79 | 16 | .003a |
| Negative/inconclusiveb | 32 (40.5) | 13 (81.3) | |
| Positivec | 47 (59.5) | 3 (18.7) | |
| Macular dystrophy | |||
| Total | 129 | 12 | .11d |
| Negative/inconclusiveb | 41 (31.8) | 7 (58.3) | |
| Positivec | 88 (68.2) | 5 (41.7) | |
P value obtained by χ2 test of independence.
Negative or inconclusive testing results obtained on wide-panel genetic testing.
Positive testing results (pathogenic/likely pathogenic variants) obtained on wide-panel genetic testing.
P value obtained by Fisher exact test.
Table 3. Multivariable Logistic Regression for Genetic Testing Detection Rate.
| Variable | Reference | OR (95% CI) | P value |
|---|---|---|---|
| Adjusted analysis a | |||
| Race | |||
| Black | White | 0.25 (0.14-0.46) | <.001 |
| Phenotype | |||
| Cone/cone-rod dystrophy | Rod-cone dystrophy | 0.45 (0.27-0.73) | .002 |
| Macular dystrophy | Rod-cone dystrophy | 0.78 (0.50-1.21) | .27 |
| Sex | |||
| Female | Male | 1.0 (0.7-1.5) | .99 |
| Age (per increase by 10 y) | NA | 0.84 (0.76-0.92) | <.001 |
| Panel size (per increase by 10 genes) | NA | 0.97 (0.93-1) | .17 |
| Unadjusted analysis | |||
| Race | |||
| Black | White | 0.26 (0.14-0.46) | <.001 |
| Phenotypea | |||
| Cone/cone-rod dystrophy | Rod-cone dystrophy | 0.41 (0.26-0.7) | <.001 |
| Macular dystrophy | Rod-cone dystrophy | 0.72 (0.47-1.1) | .13 |
| Sex | |||
| Female | Male | 1.1 (0.7-1.5) | .80 |
| Age (per increase by 10 y) | NA | 0.84 (0.76-0.92) | <.001 |
| Panel size (per increase by 10 genes) | NA | 0.97 (0.93-1) | .01 |
Abbreviations: NA, not applicable; OR, odds ratio.
N = 564: 8 trans-synaptic inherited retinal diseases diagnoses (X-linked retinoschisis and congenital stationary night blindness) were excluded from the model due to the small sample size.
Database Analysis by Blueprint Genetics
A total of 3251 patients from Blueprint Genetics met the criteria; 320 of the sample self-identified as Black (9.7%). There were 142 of Black patients (44.4%) who had a definitive test result, which was a proportion lower than that for White patients (1691 of 2931 [57.7%]) (χ2 test of independence = 18.65; df = 1; P < .001).
Discussion
Our study reports the association of race and wide-panel genetic testing detection rates in Black and White patients given a clinical diagnosis of an IRD. Our results show that the odds of obtaining a molecular diagnosis is lower for Black patients than for White patients. Our analysis also indicated that older age and a cone dystrophy diagnosis are also factors associated with a lower detection rate.
Previous literature focusing on the detection rate of different genetic panels has not examined the effect of race8,9,11 and there is a lack of studies in which genetic test results are analyzed by race. Even though some articles have presented the racial makeup of their cohorts, race was not used as a variable to compare detection rate of genetic panel testing results.2,8
By only including participants who self-identified as either Black or White and reported that both parents were the same race, genetic admixture present in both groups was minimized. Although it is important to investigate other races as well, we lacked adequate sample size to include other races in our study. African populations have been the longest in existence, and thus have more genetic variation than other populations, such as Europeans.17 Variation in African American genetic material results from human migration with populations formed from migrations out of Africa occurring during the last 100 000 years, thereby giving rise to unique variants (eg, single-nucleotide polymorphisms) between populations.18 Lack of knowledge of genetic variation in the Black population confounds the interpretation of genetic test results, as most genomic studies have been in individuals of European ancestry and not African ancestry,19 and therefore many variants more common in patients of African ancestry are less likely to have been studied by laboratories or published in the literature. In patients with prostate cancer20 and hereditary breast cancer,1 genetic testing panels yielded inconclusive results in Black patients more frequently than in White patients. Similarly, complete gene sequencing of BRCA1 and BRCA2 genes in patients with breast cancer showed a higher percentage of variants of unknown significance in Black patients than in White patients.21 For ocular diseases, targeted genotyping of age-related macular degeneration–associated single-nucleotide variants showed a higher detection rate in White individuals than Black individuals.22 A study using whole-exome sequencing for indigenous African patients with IRDs was only able to find the causal genotype in 40% of the participants.7 This detection rate is comparable with the detection rate for the Black patients with IRDs in our study. Our findings are consistent with these previous studies and highlight the disparity in the detection rate of our current genetic testing tools for patients of different races.
Our genetic detection rate for specific phenotypes is also comparable with previous studies.12,13 Using a similar genetic testing platform, Whelan et al12 reported a genetic detection rate of 202 of 294 in rod-cone dystrophies (69%) (without stratification by race) resembling our detection rate of 158 of 216 for White patients (73%). We found a lower detection rate for macular dystrophies than for cone/cone-rod and rod-cone dystrophies. Similar results were previously reported by Shah et al,13 who reported a genetic detection rate of 18% when using phenotype-based panels. Our results indicated that older age is associated with a decreased molecular genetic detection rate, regardless of the phenotype. Similar results were reported by Shah et al, where genetic testing detection rates for patients with macular dystrophies who were younger than 50 years was higher (24%) than the detection rate in patients 50 years or older (18%).13 Glöckle23 and Perez-Carro et al24 also reported a lower genetic detection rate in late-onset macular dystrophy than in early-onset disease. It has been hypothesized that the lower detection rate of late-onset macular dystrophy may be due to many factors, such as complex gene-environment and gene-gene interactions.13
Limitations
The study’s findings are subject to a number of limitations that are inherent to retrospective studies. First, several different IRD genetic testing panels (including different numbers of genes) were used by the CLIA laboratories. Ideally, the same panel with the same detection capabilities should be applied for the whole sample. However, many IRD panels are available for clinicians from reputable CLIA laboratories and are considered by IRD specialists to have comparable genetic detection rates. The panel sizes and genetic testing methodology (for example, use of whole-exome sequencing) is also in constant flux over time, even for a single laboratory. However, we found that, when stratified by race, the proportions of Black and White patients who were tested on each of the 5 panels were similar to the numbers presented in the results section for the whole cohort of patients. We also found that the number of genes (panel size) tested for Black and White patients were almost the same. Second, our sample of Black patients represented only about 9% of the whole sample. This is a common limitation in genomic studies and Black patients may be less likely to order genetic testing through research studies, which could decrease available options for genetic testing for this population.25 However, the sample size is comparable with the US population proportion of Black individuals (12.4%)26 and provided enough statistical power to detect an association between race and genetic testing detection rate. Third, study participants may have inherited pathogenic variants from family members of mixed ancestry. Fourth, the sample included participants of all ages. Given that older age was found to have a lower genetic detection rate, we studied its association with genetic testing detection rates across the 3 phenotypes as a method to check for consistency of our detection rate findings. The distribution of ages among Black and White patients was comparable. Fifth, the duration of retrospective review (2013 through 2022) encompassed by our testing data may be a confounding factor if genetic testing improved with time. The different laboratories during the span of our study adopted the American College of Medical Genetics and Exome Aggregation Consortium/gnomAD data for variant interpretation at different time points, which possibly led to changes of variant identification and changes in genetic detection rates. However, our time trend regression analysis revealed that the date of genetic testing was not associated with significant increased or decreased genetic detection rates. Lastly, we lacked adequate sample size to include other races in our study.
Conclusions
The current development of IRD therapeutics is highly dependent on the ability to identify disease-causing mutations.27 Given that patients with no known genetic diagnosis have fewer options for receiving novel treatments, the equity of genetic testing directly impacts the equity of IRD clinical trials. As future treatments become available, we must critically examine the genetic detection rates across majority and minority subgroups alike. Our retrospective study highlights a lower genetic detection rate for Black patients than for White patients.
eFigure 1. Genetic testing detection rate for White and Black patients
eFigure 2. Genetic testing detection rate for White and Black patients based on phenotype
Data sharing statement
References
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Associated Data
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Supplementary Materials
eFigure 1. Genetic testing detection rate for White and Black patients
eFigure 2. Genetic testing detection rate for White and Black patients based on phenotype
Data sharing statement