Gene Detectives

Janssen Pharmaceutica NV, a Johnson & Johnson company, has funded the development and publication of this article, including a consultancy fee for Professor Bolz and Dr. Herrmann. The views expressed in the article are those of the authors and publisher, and do not necessarily reflect the views of Janssen Pharmaceutica NV and/or Johnson & Johnson.

Although relatively rare in the general population with a prevalence rate of around 1:1380, inherited retinal diseases (IRDs) still affect approximately 5.5 million people worldwide (1), making them collectively the leading cause of vision loss for individuals aged between 15 and 45 years old (2). For patients with a potential IRD, genetic testing can act as an important tool in helping ophthalmologists identify the genetic basis of a retinal disease, with around 56-76 percent of IRD patients being accurately diagnosed through the use of next-generation sequencing (NGS) which often includes quantitative readout for copy number variant analysis (3)(4). Being able to accurately uncover the cause of vision loss can provide patients with answers that will put them back in control of their eye health, from understanding the cause (genetic vs. non-genetic) potential of disease progression and extent (isolated vs. syndromic) and risks to other family members (mode of inheritance), to determining their eligibility for clinical trials or emerging targeted treatments (5)(6)(7).

However, a current lack of awareness around IRDs often results in delays in diagnosis for these patients. A multinational European survey conducted in 2021 found that the time to genetic diagnosis can vary among countries, from around four weeks to over 10 years in some extreme instances (8). To work towards addressing this issue of prolonged waiting times and delayed diagnostics, it is imperative that eye care specialists work closely together with other specialists, combining their clinical and genetic expertise to help people suspected of an IRD receive testing and diagnoses sooner.

But how can we ensure that more people suspected of having an IRD are tested earlier? And what are the first steps towards achieving an accurate diagnosis?

“From a geneticist's perspective, first of all we have to confirm or rule out whether a disease is indeed a genetic, inherited issue,” explains Professor Hanno Bolz, head of Bioscientia Human Genetics, Ingelheim, Germany. “In many cases, a genetic cause is obvious because of the phenotype – retinitis pigmentosa (RP), for example, is a monogenic trait, albeit non-genetic phenocopies do exist (9) – and/or familial occurrence, but a genetic diagnosis always helps to clarify (5) – as soon as we come across a gene mutation, we can be sure that this mutation is the cause of the disease. In contrast, and as in cases of other inherited conditions, a non-genetic cause is much harder or even impossible to prove.”

One of the most common types of gene therapy within ophthalmology, Bolz adds, is RPE65 gene (replacement) therapy. Mutations in the RPE65 gene are responsible for both RP and Leber congenital amaurosis (LCA), a group of genetically diverse congenital retinal dystrophies (10). As is well documented within ophthalmology, LCA is characterized by congenitally severe visual impairment (11). In case of RPE65, there is a therapeutic window before photoreceptor cells will undergo degeneration (11), meaning it’s crucial for genetic testing to be performed as early as possible. Bolz stresses it is important that, “as soon as the patients receive their diagnosis, they know what gene they should be interested in”, going on to recommend organizations like Foundation Fighting Blindness and PRO RETINA, which provide patients with the most up-to-date information on their specific disease, as well as giving patients the ability to upload their data onto its patient registry.

Much like LCA, early genetic detection for all IRDs to ensure early and accurate diagnosis is essential. It allows patients greater decision-making in regards to their disease, the ability to better identify appropriate treatment opportunities or clinical studies they may be eligible for, and, ultimately, improve their outcomes (5).

“You're sitting there with the patient and often they've been running around in circles,” says Philipp Herrmann, head of the Inherited Retinal Disease Clinic at the University Eye Hospital Bonn, Germany. “At that point, different doctors have looked at their eye and assessed what sort of disease it might be, the patient has good phenotyping, and yet still they have a feeling that they've not got the right diagnosis. So genetic testing is really about closing that chapter, stopping the patient from feeling like they’re running in circles and pinpointing the actual gene mutation that is causing the disease. I think this is also a psychologically important step for IRD patients.”

This early diagnosis achieved through genetic testing can help to improve the health literacy of the patient, empowering them to make informed decisions as to their future care and treatment (12)(13). This sense of patient empowerment is a finding that has been reported previously in the cases of other rare diseases, and it is this type of empowerment – the sense of autonomy over one’s body and healthcare decisions – that has been documented to contribute towards more sustainable healthcare systems across Europe 
(14).

It should also be noted that genetic testing can be applicable to any age group (5): “For example, if you have a very young patient, there could be hidden extra-ocular symptoms that you only discover through gene testing,” (7) notes Bolz. “But then you may also meet adult patients with, say, diabetes – those common conditions that occur alongside vision issues – and still it can be due to a single gene defect (7). We encounter that all the time: Patients who have all kinds of long-term health problems and have been dealing with those issues for decades already, and they have been misdiagnosed or not diagnosed at all, and then you can suddenly clarify that through gene testing. We can sometimes encounter very surprising diagnoses in older people, where we see that their long-term health problems can all be traced back to the same genetic cause. For example, a patient with early retinal degeneration, diabetes, high blood lipids, short stature and developmental delay may be diagnosed with Alström syndrome through the detection of ALMS1 mutations (15) – and suddenly everything falls into place.”

In the case of Germany, where both Bolz and Herrmann are based, Herrmann states that “there are many labs that offer genetic testing – also for eye diseases – and so, because of high-throughput NGS technology, the production of data is no longer bottlenecked.” Bolz adds, “In Europe we are very privileged to have access to genetic testing and treatments for everyone through national healthcare systems, more or less independent from insurance status. Taken globally, I think that is a very privileged position to be in.”

However, Bolz admits that even with this high level of testing available to the general public, there can still occur situations “where patients have to find out, to some extent on their own, where to go and what they might have.” As such, for ophthalmologists “it's very important to communicate all the information about these rare diseases to patients, and to refer any patients suspected of having an IRD to specialist clinics, such as the one in Bonn, where they can get the right diagnostics and treatment.” 

And Herrmann confirms that while this level of genetic testing is broadly available throughout Germany, this is not necessarily the case for every European country (8): “We’re currently working on having this type of access available on the same level throughout Europe. For a large swathe of the European population it exists to some degree, so that's good. But there is room for improvement on that level, definitely.”

Speaking of improvement, advances in molecular diagnostic technologies and therapies – as evidenced in NGS tests and, more recently, in CRISPR development – have resulted in significant improvements in how we understand IRDs, as well as increasing our likelihood of correctly identifying causative variants in individuals with IRDs; NGS is enabling geneticists and clinicians to better diagnose IRDs. These advancements also spotlight the need for increasing awareness of human genetics on a broader scale, as well as how CRISPR therapy – though still in its preclinical stages – could open up future personalized treatment options for patients (5)(16).

This shifting landscape has also brought into focus the need for better training in genetic diagnostics for ophthalmologists. That said, ocular genetics has now been introduced as a subspecialty within the profession, and though at the moment it’s mostly confined to academia, this new specialty does seem to be witnessing an upsurge in training programs and fellowships aimed specifically at genetic testing for ophthalmologists (17).

“Overall,” Herrmann reflects, “we could still do better as a whole community to be aware of these huge developments we’ve seen in the last decade in the field of genetic medicine.” On this point, Bolz is in agreement with Herrmann: “I think the interaction and cooperation between ophthalmologists and geneticists is very important – to exchange information and knowledge, and to discuss what can be done, in terms of the timely diagnostic implementation of new technologies, and the possibilities they offer.” As the first lab worldwide, Bioscientia recently launched diagnostic long-read whole-genome sequencing for sensory disorders such as retinal dystrophies (18), marking a major milestone for diagnosing those tricky cases that can confound even the greatest minds of ophthalmology.

“We need a complete paradigm change,” adds Herrmann. “In the last few decades, we have seen this huge evolution in the field of genetic testing (19). But from the patients’ perspective, especially if they are a bit older, they come from a period where a doctor would say, ‘Well, you have an IRD, you're going to be blind, you don't have to come back.’ Sometimes you can see that bleak outlook remains, lingering from the past. Now that we have such innovative technology at our fingertips, this reality has completely changed.”