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Management Of Inherited Retinal Diseases Through Genetic Testing
Inherited retinal diseases (IRDs) are genetic disorders that affect the retinal layers, layers that are responsible for converting the photos of light into three-dimensional images that we finally see.
Inherited retinal diseases (IRDs) are genetic disorders that affect the retinal layers, layers that are responsible for converting the photos of light into three-dimensional images that we finally see. They are a significant global cause of visual impairment. They can affect individuals of all ages, can progress at different rates, and may get worse over time leading to vision loss and blindness.
Knowing the genetic cause of an inherited disease or the risk of developing the disease can help manage the other factors; environmental, lifestyle etc., decide on the rehabilitation options, help in the overall disease management, and make us better prepared to take the right decisions and care for one's health. Disease-causing mutations can be identified with genetic testing which allows us to accurately study the inheritance pattern, thereby improving genetic counselling for affected individuals and their families.
Inherited Retinal Diseases
Inherited Retinal Diseases (IRDs) comprise of, over 20 different phenotypes like congenital stationary night blindness (CSNB), Leber congenital amaurosis (LCA), retinitis pigmentosa (RP), cone-dystrophy (CD), cone-rod dystrophy (CRD) optic atrophy (OA) and others. These conditions result from mutations in various genes that play a role in retinal structure and function. To date more than 250 genes have been identified to cause IRD. Some mutations follow dominant inheritance, requiring a single copy of the mutated gene for the condition to develop. Others will have recessive inheritance, necessitating two copies of the mutated gene for the condition to manifest. In the X-linked recessive (XLR) inheritance, the mutation is in a gene on the X chromosome, and since there is only one X chromosome in males, they manifest the disease, the females might either be asymptomatic or present with mild disease as they harbour two X chromosomes. With advancements in the field of genomics and genetic testing, if the firstborn suffers from an inherited eye disorder, today we have tests (like clinical exome, and whole exome sequencing) that can identify the genetic cause of his/her disease, test the parents and other unaffected siblings to know their carrier status and offer prenatal genetic testing for the unborn child.
Genetics in developing IRDs
When one parent carries a dominant mutation for an IRD, there is a 50% chance that each of their children will inherit the mutation and develop the condition. When both parents carry a copy of the recessive mutation for an IRD, there is a 25% chance that each of their children will inherit two copies of the mutation and develop the condition. For the X-linked recessive inheritance, when the mother is a carrier of the mutation, there is a 50% chance that each of her daughters will be a carrier and 50% chance that each of her sons will be affected. Whereas, when a man is affected with X-linked recessive IRD, all his daughters will be carriers, whereas none of his sons will be affected.
Symptoms and impact on vision
Symptoms of IRDs typically include night blindness, loss of peripheral vision, and decreased central visual acuity, which can progress to complete blindness over time. The impact of IRDs on vision can be profound, affecting an individual's ability to perform daily activities and significantly impacting their quality of life. There is currently no cure for IRDs, but treatments such as gene therapy and retinal implants are being developed and tested to slow or halt disease progression and improve vision.
Eligibility for genetic testing
Genetic Testing for Inherited Retinal Diseases
Genetic testing plays a vital role in identifying mutations, providing clinicians with better understanding of the disease, prognosis, leading to better disease management and possible therapy options. Depending on the genetic testing methodology used, results can be provided within 3-6 weeks.
Another vital part of genetic testing is the genetic counselling services which help individuals, and their families understand the inheritance pattern and thus the risk of developing the disease in other family members and for the next generation. Eye disorders if diagnosed correctly and early, can be managed better, resulting in better healthcare outcomes.
This article was authored by Dr N Soumittra, Disease Head, Ophthalmology, MedGenome
How Do People Inherit Hemophilia?
Hemophilia is a bleeding disorder that can affect the blood's ability to clot properly. In most cases, people inherit the gene variations for hemophilia in an X-linked recessive inheritance pattern.
Hemophilia is a condition that affects the blood's ability to coagulate, or clot.
It occurs when people have low amounts of a certain type of protein in the blood known as clotting factors. Clotting factors are responsible for normal blood clotting.
Genes provide the instructions to produce clotting factors. People with hemophilia typically have a gene variation in the genes responsible for clotting proteins. These alterations cause the body to produce too little of these proteins, which causes problems with coagulation.
In most cases, people inherit the gene variations responsible for hemophilia from their parents. However, it is also possible for people without a family history of hemophilia to develop the condition.
This article explores the inheritance pattern of hemophilia, including how it passes through families and who can carry the gene variations.
In most cases, hemophilia is a sex-linked recessive disorder.
More specifically, it is an X-linked recessive condition. This is because hemophilia occurs due to problems with blood clotting factors, and the genes responsible for blood clotting factors are present on the X chromosome.
Male offspring usually inherit one X chromosome from their female parent and one Y chromosome from their male parent. Females typically inherit an X chromosome from each parent.
Due to being an X-linked recessive disorder, hemophilia is more common in males. This is because males typically have only one copy of an X chromosome.
As such, they only need to inherit a single nonworking gene variation from their female parent to develop a deficiency in a clotting factor.
While it is rarer, females can also have hemophilia. In these circumstances, either both X chromosomes have the gene alteration or one has the variation and the other is missing or nonfunctioning.
If the male parent has hemophilia and the female parent is not a carrier of a gene variation, then none of the male children will develop hemophilia. However, all female children will be carriers of a gene alteration.
If the male does not have hemophilia and the female is a carrier, the chances of their offspring having hemophilia are as follows:
If the male has hemophilia and the female is a carrier, the chances of their children having hemophilia are as follows:
Most cases of hemophilia are genetic in nature. However, in rare cases, hemophilia can occur in a person with no personal or family history of diseases related to blood clotting.
This is known as acquired hemophilia. This type of hemophilia differs from the congenital types, as it is an autoimmune condition.
Instead of occurring due to genetic variations, it develops when the immune system produces antibodies that attack clotting factors, usually factor VIII.
Roughly half the cases of acquired hemophilia are idiopathic. This means the exact cause is unknown. The other 50% usually relate to other autoimmune conditions, cancer, or infections.
Both males and females can pass hemophilia gene alterations to their children.
A carrier refers to an individual who carries and can pass a genetic variant to their offspring, while they themselves do not typically have symptoms or features of that condition.
As such, males with hemophilia are not known as carriers. They typically either present with symptoms of hemophilia or do not have a gene variation.
However, due to the inheritance pattern of hemophilia, females who are daughters of a male with hemophilia will be carriers or have the condition. Some health experts may refer to these people as obligate carriers.
Females who are daughters of a female carrier have a 50% chance of being a carrier, sometimes known as a potential carrier.
Different genes responsible for producing different clotting factors are responsible for the different types of hemophilia:
These genetic alterations lead to a deficiency of the respective clotting factors, causing the bleeding problems associated with hemophilia.
Genetic testing describes a medical test that can help identify genetic variations. As such, it can help determine the risk of potentially passing on genetic conditions, such as hemophilia.
Carrier testing is available to help identify females who carry gene variations for hemophilia. A genetic test is more accurate than a test measuring factor levels. This is because a person carrying a gene variation may still have normal factor levels.
A genetic test can help determine a person's carrier status for either healthcare reasons or to know if they could pass it to their children. A doctor can also perform prenatal testing during pregnancy to determine whether the fetus has hemophilia.
Genetic counseling may be advisable for families with a history of hemophilia. A genetic counselor can provide valuable information and support for individuals and families affected by hemophilia. They can help people make informed decisions about family planning and healthcare.
In most cases, hemophilia is an inherited condition. It can occur if the child inherits a gene variation present on the X chromosome.
For male children, they only need to inherit one copy of the gene variation. For female children, either both X chromosomes will have the gene alteration, or one will have the variation and the other is missing or nonfunctioning.
If people with a known family history of hemophilia are considering pregnancy, they can undergo genetic testing and counseling. This can help individuals and families manage and make informed decisions about family planning.
Sex-linked Diseases: The Case Of Duchenne Muscular Dystrophy (DMD)
Prenatal diagnostic testing and embryo sexing for sex-linked recessive disease mutations bring up more than ethical issues, however. They also raise some interesting questions about how we as a society can affect the genetic structure of the human population at large, as Hastings (2001) emphasized in his study. Normally, a balance exists between mutation and selection. Deleterious mutations, such as sex-linked disease genes, disappear over time because affected individuals often die before they reach reproductive age or are unable to reproduce. In effect, these mutations are ousted from the gene pool by natural selection. Hastings argues that prenatal testing upsets this balance.
In the past, before prenatal testing or embryo sexing was an option, with no way to know whether a fetus had or might be carrying a deleterious sex-linked mutation, parents were not able to make these reproductive decisions. All fetuses affected with disease genes were born. Then, in the case of DMD, for example, if the affected child was a boy, he would mostly likely either die before reproducing or be incapable of reproducing, thereby removing that individual affected gene from the population. For this reason, diseases such as DMD have continued to occur at relatively low frequencies in the human population.
Hastings took a mathematical modeling approach to show how modern reproductive technologies have the opposite effect: They often result in an increased frequency of sex-linked, disease-causing mutations in a population. This is because, as Hastings argues in his paper, if a woman decides to terminate her pregnancy and then in the future tries to give birth to an unaffected child, a one-in-three chance exists that the next child will be a female carrier (meaning a daughter with one disease allele). So, instead of natural selection removing a mutation from the population, the population would actually gain a mutation. Over time, with many parents making this decision, the number of X-linked, disease-associated recessive mutations in the population would actually increase. In fact, Hastings calculated that the frequency of these mutations could increase as much as 33% or more, and in as quickly as two to five generations. Although easing their own family burden, parents could simultaneously contribute to an increased frequency of deleterious X-linked mutations in the population at large. It is debatable, however, whether this creates a problem for society, because even though the frequency of the lethal mutations would increase, the number of babies born with DMD would decrease.
In fact, based on the results of his mathematical simulations, Hastings argues that the only circumstance under which the number of babies born with lethal recessive X-linked mutations would actually increase, along with the frequency of the mutation itself, is when parents decide not to terminate a pregnancy, whether they have undergone prenatal testing or not, and instead practice another form of family planning. Specifically, parents who decide to let all pregnancies come to term and then, in the event of a baby being born with a fatal sex-linked disease, later "compensate" by having another child, contribute in the same way to the increasing population frequency of the disease allele; remember, there is a one-in-three chance that the next child will be a female carrier. By not terminating the pregnancy, the parents contribute to the number of babies being born with the disease.
Hastings's modeling results have yet to be verified with real data, so questions remain about whether recessive X-linked disease mutations are indeed increasing in frequency in populations in which these three reproductive technologies or behaviors (prenatal genetic testing, embryo sexing, or family planning) are being used on a widespread basis. Even then, questions would remain about whether the observed numbers were a direct or an indirect result of the widespread use of diagnostic tests; in other words, whether the diagnostic testing actually affects population structure, as Hastings predicts, or simply makes it easier to detect mutations that were previously undetectable (Casci, 2001).
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