Inherited retinal dystrophies (IRD) are a diverse group of progressive blinding genetic diseases that can present from birth through to late middle age.
Symptoms include loss of night vision, visual field, color, and central acuity. Sophisticated imaging modalities and electrophysiology permit genotype-phenotype correlations. Genetics is increasingly understood and has led to the development of gene therapy programs, one of which is now a licensed treatment.
Identifying these patients and establishing a genotype early is now of greater significance given the potential for treatment. Pediatricians need to understand the risk of systemic associations and equally, the developmental impact of blindness; supporting patients and families together with ophthalmology is vital.
Molecular diagnosis of IRDs is rapidly becoming the standard of care, allowing more accurate prognostic predictions and potential access to gene therapy. However, a lack of awareness of the importance of genetic testing among patients and medical professionals may result in barriers to access.
When performing an ocular genetics evaluation for a patient with a suspected IRD, it is important to ask the right questions in a language that the patient can understand. The discussion should cover the nature of the visual complaints that the patient is experiencing and the time of onset of their visual symptoms.
Information on the patient’s family is also required, to enable a pedigree to be drawn that can clarify the pattern of inheritance. The clinical diagnosis should be supported with specialized imaging, psychophysics, and electrophysiology (also referred to as ‘deep phenotyping’).
Finally, blood samples should be taken to permit the diagnosis to be confirmed with molecular testing (i.e. genotyping). Both aspects are required: genotyping is an essential part of the work-up of all IRD patients, and deep phenotyping is vital to help to interpret the results of genotyping.
An example of this process is the case of a 17-year-old male who presented with night blindness which he had experienced for several years. His visual acuity was normal, but the loss of sensitivity in the mid periphery was noted on Goldmann visual field testing.
Blue autofluorescence of the right eye showed hyper autofluorescence around the central macula, with some darker spots in the mid periphery. He was diagnosed with retinitis pigmentosa, initially defined as a simplex case (i.e. the first and only known occurrence within his family).
It then became apparent that the elder of the patient’s two sisters also suffered from night blindness. Examination of this individual revealed similar findings to those of her brother. Since the parents and the other sister were unaffected, it appeared that these cases represented autosomal recessive retinitis pigmentosa.
Whole exome sequencing was performed. Filtering the results for known IRD-causing mutations showed some possible causative mutations. To clarify which variant was the cause of the IRD, the molecular result had to be interpreted in the context of the clinical presentation.
Segregation analysis of variants in the affected sister and both unaffected parents was performed, which revealed that compound heterozygosity for variants of the CLN3 gene was the cause of isolated autosomal recessive retinitis pigmentosa in this family.
Biallelic mutations in this gene are also known to cause neuronal ceroid lipofuscinosis type 3 or Batten disease. With this knowledge, the family members were given closure, the possibility for pre-conceptual partner carrier screening became available, and preparations for potential future treatment were finalized.
This case demonstrates the complexities of diagnosing an IRD and highlights the importance of both a phenotypic and molecular assessment to reach a more accurate diagnosis.
The technology used for detecting mutations through genotyping is evolving, with Sanger sequencing rapidly being replaced by high-throughput, next-generation sequencing of the whole exome (the protein-coding regions of the genome).
In comparison to sequencing the whole human genome, exome sequencing reads only 1-2% of the genome and is, therefore, more cost-effective and less challenging to analyze.
Whole exome sequencing can reveal approximately 20,000-30,000 single-nucleotide variants in a single human exome.
Under terminology developed by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, these genetic variants are placed into one of five classes according to their clinical significance.
A classic polymorphism that has no bearing on disease is placed into class 1, while a disease-causing mutation is designated class 5. In between these extremes are a gradient from class 2 to class 4.
While the numbered classification system is used in the laboratory, standard wording that is more easily understood by the clinician is recommended for the reporting of these variants, with classes 1 to 5 described respectively as ‘benign,’ ‘likely benign,’ ‘uncertain significance,’ ‘likely pathogenic,’ and ‘pathogenic’.
Clinical phenotyping helps in the classification of variants according to this scheme. However, it is important to consider that gene therapies are directed at genes and not phenotypes. Molecular diagnosis of IRDs is becoming the standard of care, providing more precision when making a clinical diagnosis of an IRD.
This approach to classification of IRDs considers the phenotype as a secondary identifier, after the gene. As we make the paradigm shift toward the genotypic classification of IRD, the clinician retains an essential role in providing an interface between the patient and the molecular geneticist.
Communication is crucial. The clinician must interact with the molecular geneticist regarding the patient’s diagnosis and then discuss this information with the patient in terms that they understand.
Effective communication with the patient also provides the clinician with access to a wealth of information about the individual that may help to determine where the cause of the disease lies.
Receiving a definite molecular diagnosis provides a patient with an IRD with closure and allows for better prognostic predictions. In patients considering a family, having a diagnosis permits prenatal or pre-implantation testing to take place.
Finally, as more gene therapies become available, having a molecular diagnosis may allow the patient access to a specific treatment for their IRD.