Science
It is the optical tissue responsible for gathering light and relaying light signals through electrical impulses that are sent to the brain through the optic nerve. Retinal tissue consists of several types of neural cells, including the rods and cones, which are the primary vision cells.
The human retina is formed by light-sensitive neural cells called photoreceptors. There are two types of photoreceptors: the rods (120 million), responsible for black and white, peripheral and low-light vision, and the cones (about 6 million), responsible for seeing in color and in bright conditions.
It is a set of hereditary diseases that cause the gradual degeneration of the retina, leading to blindness. There are over 30 clinical entities known. This set of pathologies is primarily characterized by night blindness, loss of visual acuity, changes in electroretinographic response and a reduced field of vision. These traits may be congenital or appear gradually over one’s life.
For now, there is no effective treatment for most retinal dystrophies. However, advances in the design and construction of viruses to carry therapeutic genes, in synthesizing and transferring antisense oligonucleotides, and in gene editing methods (CRISPR) have opened new and very promising therapeutic options. The US FDA just approved (19/12/17) LUXTURNA, the first gene therapy drug developed by Spark Therapeutics to treat potential carriers of biallelic mutations in RPE65, the gene that causes Leber congenital amaurosis. There are currently over a dozen therapeutic trials in various clinical phases. It is important to note that these treatments are gene-specific. A genetic screening is a pre-requisite to accessing these treatments.
To learn the latest news on emerging therapies for treating retinal dystrophies, and their efficacy, go to news and events.
A gene is a sequence of DNA containing instructions to synthesize RNA and proteins. DNA is the molecule of inheritance and, at the chemical level, it is a polymer consisting of four nitrogenous bases: adenine (A), guanine (G), cytosine (C) and thymine (T). The order of these bases is the genetic message, that is, the instruction code for synthesizing proteins. Proteins are the molecules that cells need to function. Changes to the DNA sequence can alter the genetic message and cause abnormal proteins to be synthesized, resulting in a disease.
Mutations are changes to the DNA sequence caused by intrinsic or environmental biological factors called mutagens. Some mutations only alter one nucleotide, and others affect broader regions. The latter are associated with structural changes to the DNA, such as duplications or deletions. By changing the DNA sequence, mutations can alter the genetic message and cause proteins to be synthesized abnormally (or not at all), resulting in a disease. Not all mutations are associated with diseases. Some changes to DNA are neutral, and harmless to human health.
In humans, each cell contains 23 pairs of chromosomes, 22 are called autosomal chromosomes and the 23rd pair is the sex chromosome (XX for women, XY for men). In the autosomal chromosomes, each individual carries two genes, one from the father and the other from the mother. When the gametes form, a copy from each parent is passed on at random to the offspring. For example, in the case of a recessively inherited disease, if an individual carries two copies of the normal version of the gene, this individual will be healthy. A carrier of two mutated copies will be affected, and an individual carrying a mutated and a healthy copy will not develop the disease, and be an asymptomatic carrier. The affected individual with two mutated copies will pass one copy of the mutated gene to all of his/her offspring, and an asymptomatic carrier will pass the mutated gene to 50% of his/her offspring.
Not all hereditary diseases are autosomal recessive. There are diseases that depend on a single gene and exhibit dominant inheritance. The affected parent passes the mutated gene (and the disease) to 50% of his/her offspring. Finally, in the case of gender-related diseases (the gene is located on the X chromosome), a carrier mother will pass the mutated X chromosome to 50% of her girls (who will be healthy carriers) and 50% of her boys. Those who inherit it will be affected.
Retinal dystrophies are highly heterogeneous diseases, both clinically and genetically. Over 300 causative genes have been identified, though in each family only one gene causes the disease, which is inherited following a Mendelian pattern of inheritance: autosomal dominant, autosomal recessive or X-linked. Many different disease-causing mutations have been identified in each gene. In general, there are no prevailing mutations or a clear relationship between the type and location of the mutation and the clinical traits observed. Some retinal dystrophies are due to mutations in mitochondrial DNA, particularly those that affect the optic nerve.
Massive sequencing can be used to obtain thousands of gene variants per patient. Strict bioinformatic prioritization criteria are then applied to differentiate between variants that are normal and do not cause disease and those that are pathogenic.
We know of over 150 hereditary diseases that affect vision and cause the degeneration of various ocular tissues, such as the retina, the pigment epithelium, the optic nerve, the cornea, the iris and others. It is estimated that 60% of all childhood blindness cases are caused by hereditary diseases. A large number of eye disorders present in adults also stem from genetic causes, including glaucoma, retinal dystrophies, corneal dystrophies and a set of relatively infrequent syndromes that affect eyesight.
To date, over 500 genes responsible for both syndromic and non-syndromic eye diseases have been identified. These are inherited following different inheritance patterns.
The purpose of the diagnosis is to determine the cause of a patient’s symptoms by identifying the disease or the condition causing them. In contrast, a therapy is any method or treatment that is used to cure or alleviate a disease or some of its symptoms.
Currently, only 5% of genetic diseases can be treated or cured. However, novel gene and cellular therapies are being developed, and the eye is the best candidate for implementing these types of personalized therapies in the future. Plus, there are already treatments for some eye diseases that can help reduce the symptoms of the disease. Knowing with certainty the genetic diagnosis of your disease will let you access the most appropriate treatment.
Gene therapy consists of introducing genetic material into a patient in order to reestablish the normal function of a gene with a pathogenic mutation, alleviate the symptoms or slow the progression of a disease. Since this therapy is still being developed for hereditary eye diseases, clinical trials are only currently being done for known diseases caused by a single gene or by a primary gene. However, given the seriousness of eye diseases, there is a large number of tests on humans, or in animal models, in the clinical phase that allows for a moderate degree of optimism for gene and cell therapies in the near future.
Gene therapy can be divided into two categories: in vivo and ex vivo. Ex vivo gene therapy involves extracting cells into which genetic material is then introduced by some vector, primarily viral. Following this change, the cells are reinjected into the patient so as to reestablish a healthy phenotype. In contrast, with in vivo therapy, the genetic modification is done directly in the patient using a viral or nanoparticle-based vector. Cell therapy entails injecting the patient with stem cells, which have the potential to regenerate, or with differentiated cells, prepared to carry out the function that is altered in the patient. Both gene and cell therapy comprise approaches in personalized medicine aimed at patients with diseases caused by mutations in specific genes.
You can visit our blog on news and events, where we publish advances in therapies and other news on hereditary eye diseases.
Genetic screening
It is an analysis of the coding regions of an individual’s genome to identify possible genetic variants that cause hereditary eye diseases. The technique used by DBGen is massive sequencing (next-generation sequencing), which is used to quickly, simultaneously and reliably analyze the coding regions of genes that cause ocular pathologies.
For more information on the techniques used, please see the section on services.
DBGen has extensive experience in genetically diagnosing more than 50 hereditary eye diseases. You can see our list of diagnostic tests here. In case of doubt, we recommend you contact us. We may be able to offer you a suitable diagnostic test.
If you are in one of the following categories, you may want to contact us or a physician:
- You have symptoms associated with a hereditary disease and want to confirm the clinical diagnosis and determine how the disease is inherited.
- You have a family history of inherited eye diseases and want to know the likelihood that you or some other family member will develop the disease (even if there are no symptoms).
- Asymptomatic or symptomatic carriers of a certain eye disease who want to know the risk of passing the disease on to their offspring.
- It allows quickly and safely identifying the molecular causes of a disease and knowing how it is inherited.
- It confirms the clinical diagnosis, since in many cases it is difficult to define the patient’s clinical condition because the symptoms are not sufficiently specific.
- It provides additional diagnostic information that is very useful to the patient, since it can detect additional genetic changes in genes that affect the outlook of the disease. Moreover, new findings can suggest additional genetic testing for the family.
- It allows identifying asymptomatic carriers who could exhibit symptoms in the future and that pass on the defective gene.
- An early diagnosis can be used to get help before the disease appears, as well as to take preventive measures and manage factors that benefit the patient’s live.
- The screening is essential to genetic counseling in the event of a prenatal and preimplantation diagnosis.
- It is essential for accessing more effective treatments when available, and very relevant in light of the emerging gene therapies for eye diseases, some already approved by the FDA and others in the clinical study phase.
Remember that this is a personal decision. Do your research and get all your questions answered before making a decision. DBGen has a specialized team that can answer any question that may come up during the process. Don’t hesitate to contact us.
Knowing the risk of inheriting a disease, as well as identifying asymptomatic carriers, can be used to get help and better plan those measures that will benefit the patient’s life, as well as to provide genetic counseling to the family. In addition, for eye diseases, whose therapeutic outcome depends on personalized medicine, a genetic diagnosis is an essential prerequisite for guiding the physician toward the most efficient therapeutic option when it becomes available.
Yes. Once the gene and the causative mutation(s) of the disease are identified in the patient, a simple genetic test can identify causative mutations in other members of the family. Asymptomatic carriers can also be diagnosed, as can the way in which the disease is inherited, even in cases where only one family member is affected.
The genetic diagnosis can be used to identify other family members who show no symptoms of the disease, either because it is a late-onset disease or because they are asymptomatic carriers of the mutation. In fact, the genetic diagnosis becomes more effective when several affected family members are studied at the same time. So when requesting the diagnosis, we recommend including the family’s full medical history. We also recommend genetically diagnosing other family members when the inheritance mechanism suggests there may be carriers who have yet to exhibit symptoms of the disease.
The diagnostic strategy relies on the automated and simultaneous sequencing of DNA on Illumina HiSeq 2000 sequencers that are specially designed for this kind of high-performance analysis.
DBGen uses three genetic diagnostic strategies:
- Gene panels: allows focusing the diagnosis on specific genes that are exclusively involved in certain eye diseases. It is based on selecting and enriching the genes of interest using probes specifically designed by DBGen, in order to subsequently amplify and sequence these selected regions in the patient’s DNA using the Illumina sequencing platforms. This strategy offers the best cost-to-benefit ratio when the eye disease is identified and the clinical diagnosis is certain.
- Exome (WES): used to simultaneously sequence all of the coding regions in the patient’s genome (some 20,000 genes). Bioinformatics is then used to prioritize the genetic variants associated with hereditary eye diseases. Bioinformatic prioritization relies on genetic and populational criteria and takes into account the type of inheritance, the genes causing the disease and a comparison with a control population.
- Genome (WGS): Simultaneous sequencing of the coding (exons) and non-coding (introns and regulatory sequences) of the human genome with an average coverage greater than 30x. Subsequently, using bioinformatics programs, any genetic variants found in the genes that cause hereditary eye diseases are analyzed. Unlike analysis by specific panels or whole exome sequencing, whole genome sequencing allows to identify any type of mutation: single nucleotide variants, copy number variation and large genomic rearrangements.
If there are doubts concerning the clinical diagnosis or the eye disease is unknown, WES is the most exhaustive strategy with the best diagnostic performance.
The ultimate goal of our strategies is to offer a conclusive genetic diagnosis that identifies the gene(s) responsible for the patient’s disease. The final step is to verify the mutations identified by using Sanger sequencing.
To select the diagnostic strategy suited to each patient, do not doubt to contact us, and we will recommend you the best strategy for your specific case.
Since DNA is present in almost every cell in the body, there are several sample types that can be used. However, given the ease of collection, we recommend sending in a saliva sample (using the saliva kit that you can request to have sent to you) or blood sample (you can have the blood drawn at a specialized laboratory), or you can send us the extracted DNA directly.
A rigorous medical report that includes any genetic variants identified, their relationship to the pathology and genetic counseling. The results of the genetic test are important for defining a strategy since the prevention, prognosis and the course of action in terms of therapeutic strategies is enormously dependent on an accurate diagnosis.
Sometimes mutations are detected that were not previously described, or for which there is insufficient information available to determine if it is pathogenic or not. In these cases, gathering additional information could help clear up the result. That is why the genetic test should be administered to other family members. The DBGen team is constantly updating its knowledge with new findings in the scientific literature, where the number of mutations and variants described in always on the rise. This also serves to make the genetic diagnosis more efficient and rigorous.
Even when the relationship between causative mutations and the pathology is very direct in hereditary diseases, detecting the causative mutation(s) of a disease is no guarantee that this pathology will develop with the same symptoms. Even if two people have the same mutation, one could develop severe symptoms and the other a mild version of the disease. Genetic interactions with other mutations in modifying genes, as well as epigenetic factors (different from genes) and environmental factors could account for these differences.
It is a service offered by DBGen that involves a personalized meeting that can be requested before or after the genetic diagnosis to provide an exact and updated explanation of the pathology affecting the family, and the benefits and limits of the genetic test. This meeting is also intended to alleviate the emotional factors, explain the ethical consequences associated with genetic testing and provide an outlook based on the results of the tests.
If your individual or family situation merits a specific evaluation due to involving a syndromic case or a complex clinical diagnosis.
If you have a prior diagnosis and you want to reevaluate it or do additional tests to improve it.
If after receiving the results of the genetic diagnosis from DBGen, you need additional clarifications that require personalized care.
If you need guidance or information on new therapeutic treatments (gene therapy) or other mitigating treatment, especially for syndromic diseases (only applicable to some diseases).
Procedure
The first step is to fill out the form and send in the biological sample. We will then conduct the genetic analysis and send the results to the physician, the patient or the guardian. You can also request genetic counseling with our experts at DBGen, who will provide guidance in specific cases. If you have any question, please contact us.
Yes, you should contact us if you have questions or if you are not sure which test to request. The DBGen team is always at your disposal.
In cases requiring a specific evaluation, you can also request genetic counseling. We recommend counseling in the following cases:
- If your individual or family situation merits a specific evaluation due to involving a syndromic case or a complex clinical diagnosis.
- If you have a prior diagnosis and you want to reevaluate its results or do additional tests to improve it.
- If you need guidance or information on new therapeutic treatments (gene therapy) or other mitigating treatment, especially for syndromic diseases (only applicable to some diseases).
Only the legal guardian can request it by filling out the form with the minor’s information. It is the guardian who will receive the results.
Yes, you can request the test from anywhere in the world. You can contact us for information on how to ship the sample.
When you request the service, you will receive an invoice by email. You can transfer the funds to the DBGen bank account from anywhere in the world.
If your sample is collected at one of our agreed centers, the center will take care of the shipment.
If that is not the case, after collecting the sample, you have to send it in as quickly as possible at room temperature. Samples can be refrigerated before shipping. In hot weather a cool pack can be used. The sample has to be sent to the address shown in the link. You also have to call or write us to confirm that you sent the sample. We recommend sending in the sample early in the week. No weekend delivery.
A rigorous genetic report in PDF format will be sent to the physician, the patient or the legal guardian. Contact us if you have questions about the report, or in cases requiring special attention, you can request genetic counseling.
Between 12 and 14 weeks following receipt of the fee, the sample and signed informed consent form (not applicable to physicians).
You can always contact us, or if you require specialized care, request genetic counseling.
One of the main goals of DBGen is to ensure that patients and families understand the genetic data, to address any emotional factors, explain the ethical consequences associated with the genetic tests and plan the future based on the results of the tests.
Your DNA sequence not only provides information on your genetic condition. Since DNA is shared among siblings, parents and other family members, it also offers genetic information on other relatives. Therefore, DNA information requires utmost confidentiality. At DBGen we adhere to every national and international bioethical standard. We ensure the privacy and confidentiality of your diagnosis, as well as of other genetic information (ocasional findings), by following the recommended bioethical principles.