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. 2024 Sep;14(9):a041287. doi: 10.1101/cshperspect.a041287

History of Finding Genes and Mutations Causing Inherited Retinal Diseases

Stephen P Daiger 1,✉, Lori S Sullivan 1, Elizabeth L Cadena 1, Sara J Bowne 1
PMCID: PMC11368188  PMID: 37788881

Abstract

This is a brief history of the work by many investigators throughout the world to find genes and mutations causing inherited retinal diseases (IRDs). It largely covers 40 years, from the late-1980s through today. Perhaps the best reason to study history is to better understand the present. The “present” for IRDs is exceptionally complex. Mutations in hundreds of genes are known to cause IRDs; tens of thousands of disease-causing mutations have been reported; clinical consequences are highly variable, even within the same family; and genetic testing, counseling, and clinical care are highly advanced but technically challenging. The aim of this review is to account for how we have come to know and understand, at least partly, this complexity.

In reporting progress in gene discovery for inherited retinal diseases (IRDs), it is important to keep in mind the ultimate goal of the research. The goal was, and is, to find the underlying cause of inherited retinal disease in each affected individual (those who wish to participate in the research) and to use this information to provide clinical benefits to patients and their families. A secondary, although integral, goal is to use this information to better understand the pathophysiology of ocular diseases and the biology of normal vision to improve health and welfare in general. We should be judged on how well we are meeting these goals, not just on advances in gene discovery per se. Other works have touched on these goals and show that, indeed, great progress has been made, although perhaps not as fast as we might wish.

HISTORICAL CHANGES IN TERMS AND CONCEPTS

There are several terms and concepts that have evolved over the years, but which, realistically, are still in flux.

First, there is the question as to whether IRDs are “dystrophies,” “degenerations,” or simply “diseases.” Dystrophy implies an abnormality present early in development; degeneration implies a progressive disorder. But some IRDs only affect the retina later in life and some conditions are congenital but not progressive. “Disease” has the advantage of being neutral, but still implies a substantial burden on the patient, which is certainly true of IRDs.

Second, IRD-causing genes may be referred to by the disease name, the gene name, the protein name, the disease symbol, the gene symbol, or the protein symbol. Further, the names and symbols have changed through the years. For example, the locus, gene, and protein on the short arm of chromosome 1 causing Leber congenital amaurosis (LCA) has alternatively been called LCA2, RP20, RPE65, retinal pigment epithelium-specific 65 kD protein, and retinoid isomerohydrolase RPE65 (RPE65 database; www.ncbi.nlm.nih.gov/gene/6121). Each IRD gene has its own naming history. As a rule, be aware of alternate names and symbols, and state clearly to which you refer.

Third, IRDs are assumed to be monogenic, Mendelian diseases. That is, it is expected that in a given affected individual, and usually in affected first-degree relatives, only one specific gene is involved, although the gene may be autosomal or X-linked, and the mode of inheritance either dominant or recessive. It is also assumed that there are no common phenocopies, that is, diseases that are not monogenic but mimic the symptoms of an IRD. We already know exceptions to these rules. For example, some forms of retinitis pigmentosa (RP) are caused by a mutation in PRPH2 plus a mutation in ROM1 (i.e., digenic disease; Dryja et al. 1997). Symptoms of early-onset age-related macular degeneration may overlap with Stargardt disease (Cremers et al. 2020). And, most strikingly, mutations in some genes can be either dominant-acting or recessive (Sullivan et al. 2014, 2017).

Fortunately, these are relatively rare cases and the assumption of monogenic disease without phenocopies is generally valid. However, it is important to not lose sight of these possibilities. Also, it remains to be seen whether these assumptions hold for the 20%, at least, of IRD patients and families whose genetic cause cannot be determined yet.

Finally, perhaps the most important conceptual change over the past 40 years is recognition that these are not unrelated disorders, with unique, nonoverlapping names (e.g., RP, LCA, Stargardt disease). In fact, although there are many different IRD-causing genes, and many possible clinical consequences, these blinding diseases overlap in symptoms, causes, and shared disease pathways, and probably in ways not yet understood. Fundamentally, there is no one-for-one mapping between the disease name and the underlying causative gene. For this reason, it has been suggested that, after clinical evaluation and genetic testing, the “name” for the condition in an affected individual should be the mode of inheritance, the disease gene, and clinical type (e.g., “dominant rhodopsin [RHO] retinitis pigmentosa”). How best to name the condition in a way of most value to the patient and family but of sufficient accuracy for technical use is an ongoing discussion.

RESEARCH SUPPORT

Although not limited to genetics alone, it is important to acknowledge the remarkable, absolutely essential financial support for IRD research provided by foundations and agencies for decades. For example, the Foundation Fighting Blindness (FFB), originally called the National Retinitis Pigmentosa Foundation, has funded nearly $1 billion U.S. dollars of research on IRDs since its founding in 1971 (www.fightingblindness.org/about/mission-and-history). Many additional national and international organizations, all working together, have provided comparable support. These include Retina International, established in parallel with the FFB in the 1970s, and FFB chapters and allied organizations in most U.S. states and several countries (www.fightingblindness.org). Further, the National Eye Institute (NEI) of the U.S. National Institutes of Health (NIH) has had a specific, strategic focus on IRDs since the 1980s. This has directed several billion U.S. dollars to IRD research in both NIH extramural and intramural programs (National Eye Institute, www.nei.nih.gov/sites/default/files/2022-04/NEI%20FY%202023%20CJ%20Chapter_508_Final.pdf). Comparable funding has been awarded by government programs in Europe and Asia. This is a very incomplete list; it is just a reminder that no progress would have been made, or will be made in the future, if not for the incredibly generous support by individual donors, dedicated foundations, and committed governments.

1850–1980: EARLY RESEARCH

Any history of genetics should include a reminder of the enormous advances in understanding human inheritance in the past 150 years. There have been a series of scientific revolutions: Darwinian evolution, Mendel's rules of inheritance, Garrod's inborn errors of metabolism, chromosomal biology, and the structure of DNA leading to the “Central Dogma,” culminating (for now) in the Human Genome Project (HGP) (Cohn et al. 2023). All of these findings and concepts are directly relevant to inherited eye diseases and part of the shared language spoken by experts in this field. This review assumes these as background, but it is important to remember that this is not universally shared, common knowledge, hence the need for, among other clinical specialists, genetic counselors to work with IRD patients and families.

Among the earliest descriptions of RP, and recognition of RP as an inherited disease, were publications by Donders (1855, 1857) and von Graefe (1858) in German.

There followed a series of papers in the early 1900s demonstrating the Mendelian nature of RP. In 1981, Heckenlively described 20 RP cases, clearly demonstrating either dominant, recessive, or X-linked inheritance (Heckenlively et al. 1981). Other forms of inherited retinal disease were reported in turn, and by 1985 it was clearly established that RP, LCA, and other inherited retinopathies were Mendelian in nature and amenable to detection by genetic techniques then in development (Marmor et al. 1983; Heckenlively 1988).

1980–1990: CHROMOSOMAL ASSIGNMENT

Arguably, the first useful technique for finding IRD genes was linkage mapping (Ott 1991). After many DNA-based, polymorphic genetic markers were discovered (e.g., restriction-fragment length polymorphisms [RPFLs]) (Lander and Botstein 1986), it became possible to assign disease-causing genes to specific chromosomal regions. The linkage regions were (and are) large relative to actual genes, that is, millions of DNA base pairs (BPs) versus thousands but, still, mapping firmly localized the disease genes. Among the early successes were mapping retinoblastoma to chromosome 13q14.2 (Sparkes et al. 1983), X-linked RP to Xp11.23 (Bhattacharya et al. 1984), and autosomal-dominant RP (adRP) to 3q22.1 (McWilliam et al. 1989). However, these early successes did not lead directly to the causative genes and they only began to hint at the underlying genetic heterogeneity of IRDs. Nonetheless, by the year 2000, more than 100 IRD genes had been localized by linkage mapping (RetNet; web.sph.uth.edu/RetNet).

1990–2000: EARLY BENEFITS OF THE HUMAN GENOME PROJECT

The official start of the HGP was in 1990 (Lander et al. 2001; Venter et al. 2001). One of the revolutionary aspects of funding for the HGP was that sequence data had to be released to the public very quickly, even within 24 h of sequencing. For geneticists working on IRDs, this meant that, drop-by-drop, sequence data were released that might overlap with one of the mapped genes.

For those of us doing linkage mapping, it was a ritual to come into work each morning and look at GenBank, the go-to sequence database, to see if data covering our favorite region had been released overnight. If so, we immediately began sequencing patient DNAs to see if we could find the actual, underlying disease-causing gene and mutation or mutations. In general, this was called positional cloning or reverse genetics: for a monogenic disease, independent of any hypothesis as to the cause, use linkage mapping to localize the gene, then sequence the region and find the likely DNA damage. Often, once the gene was found, the essential next step was to try to understand why this gene was the cause of retinal disease, that is, to generate an actual hypothesis.

From 1900 to 2000, roughly 75 IRD genes were identified by positional cloning (RetNet, web.sph.uth.edu/RetNet), all dependent on sequence data from the HGP. This was the beginning of recognition that these are exceptionally heterogeneous disorders. One ironic consequence of finding genes based on overnight data was that many new IRD genes were reported nearly simultaneously by groups working independently. For example, the RPE65 gene causing recessive LCA (Gu et al. 1997; Marlhens et al. 1997) and RP1 gene causing adRP (Pierce et al. 1999; Sullivan et al. 1999) were each discovered, independently, by more than one group. Although this was, and is, daunting for researchers, it is hugely beneficial to patients.

In response to the rapid identification of novel IRD genes during this period, the RetNet database was initiated in 1996 (RetNet, web.sph.uth.edu/RetNet). RetNet, the Retinal Information Network, is a currated list of IRD genes, including the disease (or diseases) known to be caused by mutations in the gene, primary references, and other information. Web pages are updated as new genes are reported. The number of IRD genes known at various times in the past can be ascertained from archived RetNet pages. Finally, skipping ahead to the next decade, one profound outcome of identification of a myriad of IRD-causing genes was recognition of broad biochemical and pathological pathways underlying many of these diseases (Wright et al. 2010). A concomitant development was recognition that many of the IRDs with distinctively different clinical names actually overlap in causative genes and shared pathways (Berger et al. 2010). This is the justification for referring to all of the named, inherited retinal diseases as a single category, “IRDs.”

2000–2010: THE MODERN ERA OF HUMAN GENETICS

The HGP transformed biology across the board, of course, not just for inherited diseases. In addition to the sequence data—by now encompassing millions of humans and tens of thousands of other species—the HGP introduced a steady stream of new, more powerful sequencing techniques and analytical methods (Heather and Chain 2016). Manual Sanger sequencing was replaced by automated, fluorescent Sanger sequencing; then Sanger sequencing was displaced by short-read, high-throughput, next-generation sequencing (NGS). Single-molecule, long-read sequencing, for example using Oxford Nanopore technology or PacBio sequencing, is the follow-on from NGS (Mastrorosa et al. 2023). Most recently, a combination of methods was used to produce the first, intact, telomere-to-telomere, human DNA sequence (Nurk et al. 2022).

These extraordinary technology advances were accompanied by equally exceptional computational advances. Many extremely powerful analytic methods for sequence analysis were developed in parallel. Extremely large DNA sequence databases were compiled, and powerful visualization methods, for example, the UCSC and Enterez genome browsers (Sayers et al. 2021; Nassar et al. 2023), were released. Most of the analytical and database resources were, and are, publicly available. In combination, informaticists refer to this as the “analytic pipeline,” connecting raw sequence data with final conclusions regarding disease-causing genes and mutations, and, ultimately, clinical care.

These developments revolutionized finding genes and mutations causing IRDs. Far beyond this, though, to geneticists living through this period, the HGP was among the greatest scientific achievements in human history, with yet unimaginable benefits and risks.

All of these developments contributed to very rapid progress in finding the causes of IRDs. During this period, at least 80 new IRD genes were reported and the number of known disease-causing mutations increased to more than 1000 (Stenson et al. 2020; RetNet, web.sph.uth.edu/RetNet). This was the first clear recognition that, first, IRDs are genetically heterogeneous; second, in a population of patients, each disease gene will have many different pathogenic variants (allelic heterogeneity); and, third, testing just a few genes in an affected person will have low yield. To illustrate this last point, by 2007 it was known that mutations in more than 20 genes could be the cause of adRP (Daiger et al. 2007).

2010 TO PRESENT: BECOMING A MATURE CLINICAL SCIENCE

Major Trends

It is reasonable to describe the period from 2010 to the present as the consolidation and maturation of IRD genetics as a clinical science (but perhaps naive since there is much yet to do). During this period:

  • the number of known IRD genes and mutations increased substantially;

  • new genetic technologies were applied to IRD testing; and large-scale population screening was undertaken;

  • genetic data became widely available through international databases; and

  • genetic testing became an essential component of diagnostics, natural history studies, and clinical trials; and testing standards and guidelines were developed and promulgated.

Three broad developments define this period. First, as knowledge of IRD genetics increased profoundly, and genetic testing methods improved in parallel, it became possible to find the underlying disease-causing gene and mutation or mutations in the majority of IRD patients and families. Roughly speaking, it is now possible to determine the disease-causing genotype in 60%–70% of IRD cases based on certified testing in a commercial or academic laboratory, and in an additional 15% of cases based on research testing (Duncan et al. 2018; Thompson et al. 2020).

Second, noncommercial and commercial services have made substantial contributions to genetic testing, not just to advance knowledge of the field but, principally, as a prerequisite to developing and administering gene-specific and mutation-specific therapies.

Third, with each passing year, the subject of IRD genetics has become more complicated, novel mutation types have been discovered, and more exceptions to “textbook” genetics have been discovered. In retrospect, this last is the natural outcome of in-depth understanding of a complex area of human biology, but it presents a distinct challenge in communicating genetic findings to patients and families.

By 2010, roughly 150 IRD genes had been identified; currently more than 350 are known (RetNet, web.sph.uth.edu/RetNet).

Definition of an IRD Gene

There is a trivial debate regarding the definition of an “IRD gene”—although it has substantial clinical implications. Most of the first IRD genes discovered cause “simple” forms of retinal disease, either nonsyndromic such as RP or neurosensory such as Usher syndrome (Zahid 2018). As more genes were found, though, it became clear that many cases of inherited retinal degeneration were accompanied by additional symptoms (e.g., developmental abnormalities, neurologic disorders, and/or kidney disease). Further, some fall into the class of “ciliopathies,” affecting ciliated processes throughout the body. Generically, the latter are syndromic and/or systemic disorders (Bujakowska et al. 2017; Chen et al. 2019). Whether these are all “true” IRDs is basically irrelevant; they are part of any reasonable count of IRD genes since they affect the retina and the earliest symptoms are often seen by ophthalmologists. However, the fact that so many IRD genes are syndromic or systemic, that is, pleiotropic in a genetic sense, has major implications for diagnosis, prognosis, and treatment.

Population-Based Genetic Screening

Reasonable estimates are that more than 300,000 Americans are affected with one or another form of IRD and millions worldwide (Daiger et al. 2007). As the number of known IRD genes grew, there was an obvious need to optimize genetic testing and to screen as many affected people as possible. Diagnostic testing was originally limited to certified academic laboratories, but a number of commercial testing facilities now dominate the field. Testing was restricted to genes associated with the patient's diagnosis (e.g., genes causing recessive LCA). This proved problematic, though. Since different mutations in the same gene may cause distinctly different diseases, limiting testing to the “typical” disease associated with a gene excludes other possibilities. Two alternative approaches are whole exome sequencing or whole genome sequencing. Both have advantages and disadvantages. Currently, most IRD testing is based on panel testing of all known IRD genes, specifically, exome sequencing augmented with noncoding sequences known to harbor IRD mutations and optimized for sequencing-refractory regions of the genome (Consugar et al. 2015). This is an evolving area of genetic testing, in general, likely to change significantly in coming years.

The need to know the full spectrum of disease-causing genes and mutations, and the hope of placing patients into gene-specific clinical trials, spurred development of several large IRD screening projects. One of the earliest, eyeGENE, the National Ophthalmic Disease Genotyping and Phenotyping Network, was established in 2008 by the National Eye Institute of the NIH (Goetz et al. 2012). Currently, more than 6400 eyeGENE patient samples have been tested for mutations in IRD genes using a variety of methods. In 2014, the Foundation Fighting Blindness, Columbia, MD, began My Retina Tracker to register IRD patients on a voluntary basis, and offer genetic testing if requested (Fisher et al. 2016; Zhao et al. 2021). To date, more than 20,000 individuals are registered and 10,000 have completed genetic testing.

A similar service, ID Your IRD, is offered by Invitae Corporation and Spark Therapeutics (McClard et al. 2022). Similar IRD screening services exist in Europe, Asia, and elsewhere; and several large-scale, focused screening projects have been conducted, for example, the Irish Target 5000 project (Stephenson et al. 2021). This list is necessarily very incomplete, and does not do justice to the many academic, regional, national, and international IRD screening projects. Suffice it to say, genetic screening of IRD patients and families has been a hugely successful worldwide enterprise, and the number of genotype-known patients is greater than 100,000.

Mutation Databases

The success in finding IRD genes (and many other disease genes, of course), and the ever-increasing number of reported IRD mutations, motivated development of comprehensive, gene-specific mutation databases. An early example is the Human Gene Mutation Database (HGMD), which became publicly available in 1996 (Cooper and Krawczak 1996). More recently, Leiden Open Variation Databases (LOVD), proposed in 2006 by Leiden University, The Netherlands, have served as templates for a number of mutation databases (Fokkema et al. 2005). Mutations in thousands of genes are now registered in one or more LOVD, covering all, or nearly all, known IRD genes (Cremers et al. 2014).

Determining Pathogenicity

One of the most pressing problems in genetic testing is distinguishing pathogenic from nonpathogenic variants. This is a multifaceted problem. First, sequencing strategy, such as sequencing coverage and depth, affects which rare variants are detected and whether other, potentially pathogenic variants are missed. Second, different analytical methods may give different conclusions regarding pathogenicity or are uninformative. Third, confirming segregation of a potentially pathogenic variant in a family is informative but may not be feasible. Similarly, published reports of the variant found in other IRD patients is supportive of pathogenicity, but absence of a published variant is uninformative. Further, it is helpful to look for the variant in large databases, such as gnomAD (Gudmundsson et al. 2022), since if the variant is not extremely rare it is probably not pathogenic. However, if the patient is from a population that is underrepresented in the database this can be misleading. Finally, and fundamentally, pathogenicity must be confirmed by functional testing, including, for example, computer modeling of protein folding (Buel and Walters 2022), and animal, cellular, and organoid models (Ludwig and Gamm 2021; Moshiri 2021).

There has been exceptional progress in all of these areas for all human DNA variants, not just IRD mutations. Still, a significant fraction of possible IRD mutations is classified as “variants of uncertain significance (VUSs),” to the frustration of patients, clinicians, and counselors alike.

Of the many developments in evaluating pathogenicity of rare human DNA variants, two are particularly relevant to the present state of IRD genetics. The first is “standards and guidelines for the interpretation of sequence variants” proposed by the American College of Medical Genetics and Genomics (ACMG) in 2015 (Richards et al. 2015). The ACMG guidelines propose several lines of evidence and suggest specific variant categories: pathogenic, likely pathogenic, uncertain significance, likely benign, and benign. With a number of refinements since then, these have become the de facto requirements for rating potential disease-causing variants, including IRD mutations.

The second development was a response to the need for validation of disease-causing genes and mutations for gene-based therapies. This is applicable to all inherited diseases but especially to IRDs since the first FDA-approved gene therapy drug, Luxturna, effectively set the stage for future approvals (Russell et al. 2017). Discussions with the FDA, and reasonable expectations, suggest that pathogenicity of potential disease-causing mutations should be confirmed prior to initiation of therapy (Duncan et al. 2018; Thompson et al. 2020). To address this need, the NIH National Human Genome Research Institute (NHGRI), has established the ClinGen program to set standards for confirming that mutations in specific genes are the cause of specific inherited diseases, and has designated ClinVar as the authoritative database for validated, pathogenic variants (Rehm et al. 2015). ClinGen committees specific to inherited retinal diseases include the Leber Congenital Amaurosis/early-onset Retinal Dystrophy Variant Curation Expert Panel (LCA/eoRD), Optic Nerve Atrophy Variant Curation Expert Panel, and the X-linked Inherited Retinal Disease Variant Curation Expert Panel (Lee et al. 2021).

Finally, standards for genetic testing of patients with inherited eye diseases, including retinal diseases, have been proposed by the America Academy of Ophthalmology (Stone 2003; Stone et al. 2014 [AAO Task Force on Genetic Testing; www.aao.org/education/clinical-statement/recommendations-genetic-testing-of-inherited-eye-d]).

IRD Genetics Expands Understanding of Human Genetics

In addition to a profound improvement in finding genes and mutations causing IRDs, genetic testing for these disorders has revealed novel, or at least underappreciated, concepts in human genetics broadly. Examples include:

  • Novel mutations in genes first identified as causing autosomal-recessive IRDs may cause dominant disease and vice versa. For a dominant disease, it is not surprising that compound heterozygous or homozygous mutations may cause more complex diseases or may not be viable. However, in some cases, two IRD mutations in a “dominant” IRD gene may also cause retinal disease, and retinal disease alone, albeit usually a more severe form than the dominant phenotype. Examples include rare, homozygous mutations in two genes, RP1 and HK1, both known to cause adRP (Sullivan et al. 1999, 2014; Kabir et al. 2016). Conversely, some mutations in genes commonly associated with recessive retinal disease (e.g., SAG), may be dominant-acting (Sullivan et al. 2017). That this occurs is not surprising since functional consequences of different mutations in the same gene may range from extremely mild to severe, but it reinforces that there is no simple mapping from an IRD gene to the clinical phenotype.

  • Although many IRD mutations are rare, and limited to one or a few families, some have achieved appreciable frequency as a result of founder effect. For rare inherited diseases, a single mutation seen in unrelated patients may arise because of recurrent mutations (e.g., a mutation “hotspot”) or from a single ancestral source (e.g., as a founder mutation) (Jobling et al. 2004). That is, a recessive mutation may attain appreciable frequency by drift alone, and a dominant mutation may segregate in families over many generations if the disease is of late onset or has limited effect on reproduction. “Common” IRD mutations are predominately founder mutations, whereas recurrent mutations are uncommon. The most striking example is the RHO Pro23His mutation, which causes adRP. This is a frequent cause of adRP in the United States but rare elsewhere: It is a founder mutation that arose in a single European ancestor several hundreds of years ago (Dryja et al. 1990). Another example is the SAG Cys147Phe mutation, which is a common cause of adRP in Hispanic families in the Southwest United States but rare otherwise (Sullivan et al. 2017). Finally, a recessive example is the intronic CEP290 2991 + 1655A → G mutation, which is a common cause of LCA—as high as 21% of cases—in Canada and Europe, but rare elsewhere (den Hollander et al. 2006).

  • Mutations in the same gene may cause distinctly different phenotypes, even within the same family. It is a truism that there is considerable clinical variation within and between IRD families, especially in age of onset and rate of progression (Heckenlively 1988). However, in many cases, clinical variability is even more striking. First, some mutations causing dominant disease may skip generations, that is, are nonpenetrant, for example in PRPF31 (Rivolta et al. 2006; Venturini et al. 2012). Second, for example, mutations in the USH2A gene cause recessive Usher syndrome, other USH2A mutations cause RP, and still others cause variable forms of disease even among individuals with the same genotype within the same family (Koenekoop et al. 2023). Third—another example—RPGR mutations may cause X-linked RP in males, or cone-rod dystrophy, or both within a family (De Silva et al. 2021); and female carriers may be unaffected or have symptomatic RP, again, varying within families (Fahim and Daiger 2016; Fahim et al. 2020). Fundamentally, exceptional clinical variability is a hallmark of IRD-causing genes. Again, there is no one-for-one relationship between genes and clinical phenotype. However, this raises the possibility that factors modifying clinical expression, once understood, will reveal novel therapeutic targets.

  • Large families with multiple affected individuals over several generations may have more than one disease-causing gene segregating independently. It is reasonable to hypothesize that every affected member of a multigeneration IRD family has the same underlying disease genotype; indeed, this is the rational for linkage mapping. However, there are now several published instances of more than one disease genotype segregating independently in a family (Jones et al. 2017). Note that this is distinct from mutations in different genes that, working together, cause IRD in a single person (i.e., digenic disease). This is further confirmation that as IRD screening encompasses more patients and families, many “non-textbook” possibilities are to be expected.

  • Although highly diverse, IRD genes fall into broad biochemical and functional categories, revealing novel biological pathways. Over all, perhaps the most underappreciated aspect of the impact of finding IRD genes is the numerous contributions to understanding the basic biology of vision. Although the functions of IRD genes are highly diverse, many fall into broad categories such as phototransduction, the visual cycle, or photoreceptor structure (Berger et al. 2010; Wright et al. 2010). Finding new genes in these pathways adds to our understanding of vision. However, other genes are surprises, suggesting previously unsuspected retinal biology. The most striking example is a set of genes coding for splice-complex proteins, PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, and SNRNP200 (Yang et al. 2021). Although the splice complex is an essential component of all nucleated eukaryotic cells, specific mutations in each of these genes cause adRP with no other apparent findings. Why this is so is not known, but it clearly hints at a component of mRNA splicing unique to the retina. A final example is the broad class of ciliopathies, inherited diseases that affect cilia, including the connecting cilium in photoreceptors (Bujakowska et al. 2017; Chen et al. 2019). Many of the earliest examples of this class of disease were identified as the cause of one or another form of IRD, although it is now known that many other human diseases are the result of ciliary dysfunction.

These few examples just skim the surface of the deep biological insights that finding genes and mutations causing IRDs have revealed over the past 40 years.

PRESENT AND NEAR FUTURE

How well have we met the explicit goal of IRD genetics, that is, to assist in finding treatments and cures for these diseases? A fair appraisal: We have accomplished a great deal but there is more to do. We have a much better understanding of genes and mutations causing IRDs, and there are extensive commercial and noncommercial services for testing. Genetic testing is now a routine part of clinical care for IRD patients in many communities. Testing is effective, that is, provides positive results, in from 60% to 80% of patients, depending on the tests available and patient demographics. Genetic test results are now integral to the many clinical trials and natural history studies currently underway. This is success, indisputably.

But substantial problems and issues remain. First, we need to find the remaining “elusive” genes and mutations causing IRDs, that is, to solve the 20%–40% of unsolved cases. This includes determining pathogenicity of VUSs. To address this, the near future will provide advanced sequencing methods, improved computational pipelines, rapid functional assays, and other tools. Second, we need a better understanding of factors that contribute to variation in clinical expression, including environmental factors, lifestyle choices, and biological modifiers. These studies are long term but made possible by access to genotype-known patients, if they wish, through programs such as My Retina Tracker and the Irish Target 5000 Project.

Third, there is a critical gap in understanding the relationship between genotype and phenotype: the pathway between an IRD mutation at conception and the clinical consequences is essentially unknown for any form of IRD. Solving this will require advances in molecular, biochemical, cellular, and histological research, among other disciplines. As challenging as this may be, in the long term, this information will be critical for developing safe and effective therapies. Further, IRDs are the ideal candidates for these studies, and are certain to improve our understanding of the basic biology of all diseases, as they have already for decades.

Finally, it is time to address equity, fairness, and access to care. For all complex medical problems, but especially for IRD patients, there is a need for expert clinical evaluation, knowledgeable counseling, appropriate testing, effective follow-up, and many other resources. Additionally, initial treatments are, and will be, expensive, requiring specialized facilities. For some patients and families these resources are immediately available, but not for most. Solutions are not at all obvious or easy, but must be considered.

But what a wonderful opportunity! Decades of research on inherited retinal diseases have brought us to the point where preventing the loss of vision, and restoring vision, are not only possible but are in our immediate future. Now we need to figure out how to make this available to the widest number of people possible, as soon as possible.

Footnotes

Editors: Eyal Banin, Jean Bennett, Jacque L. Duncan, Botond Roska, and José-Alain Sahel

Additional Perspectives on Retinal Disorders: Genetic Approaches to Diagnosis and Treatment available at www.perspectivesinmedicine.org

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