GenomeX Data Exchange FHIR IG
0.2.0 - draft
GenomeX Data Exchange FHIR IG, published by MITRE. This guide is not an authorized publication; it is the continuous build for version 0.2.0 built by the FHIR (HL7® FHIR® Standard) CI Build. This version is based on the current content of https://github.com/CodeX-HL7-FHIR-Accelerator/GenomeX-DataExchange/ and changes regularly. See the Directory of published versions
Generated Narrative: DiagnosticReport PrenatalGenomicReportCouple
| Subject | Not done yet |
| When For | 2024-06-26 |
| Performers | Organization Generic Laboratories, Inc. Practitioner PractitionerJane Smith |
Report Details
| Code | Value | Flags | Note |
| Diagnostic Implication | Final | ## What is Factor XI Deficiency?\n\nFactor XI deficiency, also called hemophilia C, is an inherited disorder that can cause excessive bleeding. In many cases, the condition is relatively mild, and some individuals may have very few symptoms. The condition is caused by harmful genetic changes (variants) in the _F11_ gene. Individuals with the condition do not have enough factor XI protein. This protein helps platelets in the blood to clot, promoting blood vessel healing following injury. In individuals with factor XI deficiency, levels of factor XI are typically lower than normal. While bleeding problems tend to occur when factor XI levels are lower than 15% of the normal level, bleeding problems can occur when levels are as high as 70%. The severity of bleeding varies widely in individuals, even among members of the same family. \n\nIn individuals with factor IX deficiency, bleeding tends to be more severe after surgery, injury, or childbirth. Bleeding can be a problem after dental, tonsil, or urinary tract surgery. Individuals with factor XI deficiency may also be prone to bruising, nosebleeds, or having blood in their urine. Rarely, biological males with the disease will bleed heavily following circumcision. More than half of individuals with factor XI deficiency who menstruate have abnormally heavy and prolonged periods (menorrhagia). \n\nIt is uncommon for individuals with factor XI deficiency to bleed spontaneously for no obvious reason. However, there may be a delay in the onset of bleeding after an injury or surgery.\n\n\n### Additional considerations for carriers\n\nCarriers of factor XI deficiency are at elevated risk for bleeding problems. Studies have suggested that 20 to 50% of carriers of the disease show "excessive bleeding," although the definition of this phrase varies. Rarely, carriers have shown major bleeding problems.\n\n## How common is Factor XI Deficiency?\n\nThe incidence of factor XI deficiency in the general population is about 1 in 1,000,000. The disease is more common among families in northwest England, where 1 in 10,000 individuals have the disease. Is it also more common in Ashkenazi Jewish individuals, with an incidence of 1 in 450. \n\n## How is Factor XI Deficiency treated?\n\nThere is no cure for factor XI deficiency. The condition can be challenging to treat because bleeding can be unpredictable. In the United States, individuals may be treated with infusions of fresh frozen blood plasma. This blood plasma contains normal quantities of factor XI, thus temporarily enhancing the body\'s ability to clot. However, significant amounts of plasma may be required to achieve the desired clotting effect due to the low concentration of factor XI in plasma.\n\nIn Europe, several commercially available concentrated doses of factor XI can help improve clotting. In some cases, recombinant FVIIa protein is also used to improve clotting. In the case of bleeding in the mouth, nose, intestines, or uterus, several medications may be helpful, though they are not effective for major internal bleeding and can cause clotting throughout the body. Individuals who experience heavy menstrual bleeding may use hormonal birth control pills to help control the bleeding. \n\n## What is the prognosis for an individual with Factor XI Deficiency?\n\nFactor XI deficiency is not known to affect lifespan. In individuals who do not realize they have the disease, life-threatening bleeding is possible following surgery or injury., Factor XI deficiency is usually mild but can cause excessive bleeding after surgery, injury, or childbirth. People with factor XI deficiency may also be prone to bruising, nosebleeds, or blood in their urine. Treatment, when necessary, may involve blood transfusions or other medications. Factor XI deficiency is not known to affect a person\'s lifespan. | |
| Diagnostic Implication | Final | Risk not calculated for HFE-associated hereditary hemochromatosis, ###What Is HFE-Associated Hereditary Hemochromatosis (HFE-HHC)?\n\nHFE-HHC is a common and treatable inherited disease in which the body absorbs and stores too much iron, potentially damaging organs such as the liver, heart, and pancreas. If the disease is diagnosed and treated before symptoms develop, individuals with HFE-HHC typically have a normal lifespan. If the disease is untreated, however, it can lead to fatal liver and heart failure. HFE-HHC is caused by mutations in the _HFE_ gene. \n\nThe most common mutations that cause HFE-HHC are C282Y and H63D. Up to 90% of individuals with HFE-HHC have two copies of the C282Y mutation, while up to 8% of patients have C282Y and H63D. Other mutations very rarely cause HFE-HHC. \n\nFor reasons not well understood, the majority of individuals with the genetic mutations that cause HFE-HHC do not develop symptoms of the disease at any point in their lives. For these individuals, simple blood tests can determine whether or not the body is storing too much iron. If iron levels are too high, beginning treatment early can leave a person virtually symptom-free for life.\n\nStudies have found that men are more likely to develop symptoms of iron overload than women, perhaps because women\'s menstrual cycles regularly lower their iron levels. In men who have not been treated for HFE-HHC, the first symptoms of the disease typically begin between the ages of 30 to 50; for untreated women, symptoms usually begin later, after menopause.\n\nEarly symptoms often include weakness, abdominal pain, joint pain, weight loss, loss of interest in sex, chest pain, and a gray or bronze coloring to the skin that gets worse over time. Liver disease (either fibrosis or the more serious cirrhosis) is a common problem associated with HFE-HHC. Cirrhosis can lead to fatal liver failure and/or an increased likelihood of developing cancer of the liver.\n\nThe heart can also be affected by HFE-HHC, seen as an irregular heartbeat and/or congestive heart failure. Other problems caused by HFE-HHC can include diabetes, arthritis, impotence (in men), early menopause (in women), thyroid problems, and adrenal-gland problems.\n\n###How Common Is HFE-HHC?\n\nHFE-HHC mutations are extremely common, particularly among Caucasians. Approximately 11% of Caucasians are carriers of the condition. In the general population, 1 in 200 to 1 in 300 has two copies of the C282Y genetic mutation. It is important to note that most individuals who have these genetic mutations do not develop the disease.\n\nThe disease is less common among Hispanics, African Americans, Asians, and Native Americans. Roughly 13% of Hispanics, 8.5% of Asians, and 6% of African Americans are carriers for the mild mutation, H63D. An additional 3% of Hispanics, 2.3% of African Americans are carriers of the potentially disease-causing C282Y mutation.\n\n## How Is HFE-HHC Treated?\n\nIdeally HFE-HHC is treated before the organs of the body are damaged. However, not everyone who has the mutations that cause HFE-HHC develops symptoms or requires treatment. A simple blood test (serum ferritin concentration and transferrin-iron saturation levels) can determine whether the body is absorbing too much iron. When iron reaches a certain threshold, treatment is recommended. If iron levels have not reached that threshold, no treatment is necessary. Blood tests must be repeated periodically to check these iron levels. Early treatment is important to prevent long-term effects of the disease.\n\nIf a person has a high level of iron, treatment involves removing a certain quantity of blood at regular intervals. This is known as phlebotomy. Typically phlebotomy is performed frequently, perhaps weekly or twice a week, until certain iron levels are reached. After that, it is performed less frequently, often two to four times a year, indefinitely. This treatment is simple, inexpensive, and safe. An alternative to phlebotomy is removing iron-rich red-blood cells from the blood (erythrocytapheresis) and returning other important components of the blood back to the body. This form of treatment may be helpful for patients who have side effects from phlebotomy or who have heart disease. \n\nIf a person is already suffering from symptoms of HFE-HHC, treatment can lessen or relieve some of the symptoms. However, treatment cannot reverse damage to organs such as the heart, liver, or pancreas. Cirrhosis of the liver is unlikely to improve with treatment, although treatment may slow its progression. If liver disease has reached severe levels, liver transplantation may be an option. Those who have any amount of liver damage are advised to avoid alcohol.\n\nAll individuals with symptoms of HFE-HHC are advised to avoid taking iron or vitamin C supplements. They are also advised not to eat uncooked shellfish, as they are highly susceptible to a particular kind of bacterial infection.\n\n## What Is the Prognosis for a Person with HFE-HHC?\n\nThe prognosis for a person with the genetic mutations that cause HFE-HHC is generally good, as the majority of individuals in that situation do not develop symptoms of the disease. Most will not have dangerously elevated levels of iron in their blood, and therefore will not have any iron-overload problems.\n\nFor those that do have high iron levels in their blood, beginning treatment before symptoms appear is a critical part of ensuring a long, healthy life. Nearly all symptoms of the disease can be prevented with early and ongoing treatment. If a person with HFE-HHC is treated before he or she develops cirrhosis of the liver, he or she can expect a normal lifespan. Among individuals who already have cirrhosis associated with HFE-HHC, 72% will survive at least five more years and 62% will survive at least 10 more years. Those who already have cirrhosis are at an increased risk for developing a type of liver cancer., HFE-HHC is an adult-onset condition that causes the body to absorb and store too much iron, potentially damaging organs such as the liver, heart, and pancreas. However, the majority of people with the condition do not develop symptoms of the disease at any point in their lives. For those with symptoms, effective treatment is available and can allow for a normal lifespan. | |
| Diagnostic Implication | Final | Risk not calculated for fragile X syndrome, ## What is fragile X syndrome?\n\nFragile X syndrome (FXS), caused by extra CGG repeats in the _FMR1_ gene, is a condition that causes a variety of developmental and behavioral problems. Fragile X syndrome is an X-linked disease. This means that the _FMR1_ gene is on the X-chromosome. Males have one copy of the X-chromosome, while females have two copies. Because males only have one copy, a harmful change in the _FMR1_ gene typically causes more severe symptoms in males. Carrier females may be asymptomatic or may exhibit symptoms. Fragile X syndrome is the most common inherited form of intellectual disability. It is the leading single-gene cause of autism spectrum disorders.\n\nFragile X syndrome typically causes moderate intellectual disability (defined as an IQ below 70) in males. However, the severity of intellectual impairment varies from individual to individual. A few male patients do not have an intellectual disability. About one-third of females with fragile X syndrome have a mild intellectual disability.\n\nAs infants, children with fragile X syndrome may have weak muscles (hypotonia), stomach acid that comes up into the mouth (gastric reflux), and frequent ear infections. Their motor, mental, and speech milestones tend to be delayed. Children with fragile X syndrome often have behavioral problems such as anxiety, hyperactivity, hand flapping, biting, and temper tantrums. About one-third of males with fragile X syndrome have autism or autism-like behavior. Symptomatic females usually have milder symptoms than males. Behavioral problems in females may appear as depression, shyness, and avoidance of social situations. Some individuals with the condition have attention deficit disorder and cannot sustain focused attention on a specific task. Individuals with fragile X syndrome, particularly males, may lack impulse control, make poor eye contact, and be easily distracted.\n\nMales with fragile X syndrome often share characteristic physical features such as a long, narrow face with a prominent jaw and forehead, a large head, flexible joints, and large ears. These features become more apparent with age. These characteristics tend to be milder or absent in females with the condition. After puberty, males with fragile X syndrome typically have enlarged testicles.\n\nRoughly 15% of males and 5% of females with fragile X syndrome will experience seizures. While some experience heart murmurs (known as mitral valve prolapse), it is usually harmless and may not require treatment.\n\n#### Effects of a premutation\n\nMales and females with a premutation do not have fragile X syndrome but may experience specific physical symptoms. The main risks for carriers of a premutation are fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated premature ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND).\n\n_Fragile X-associated tremor/ataxia syndrome (FXTAS)_: FXTAS causes an inability to coordinate muscle movements that worsens over time (ataxia), tremors, memory loss, impaired ability to think or remember information (dementia), a loss of feeling and weakness in the lower legs, and some mental and behavioral changes. Approximately 40% of males over 50 years of age with a fragile X premutation will develop FXTAS. Between 8-16% of females with a fragile X premutation are affected by FXTAS. Typically, symptoms of FXTAS begin around age 60 with a tremor, followed several years later by the inability to coordinate muscle movements. \n\n_Fragile X-associated primary ovarian insufficiency (FXPOI)_: About 20% of females with a premutation experience FXPOI. This condition causes their menstrual periods to stop before age 40. Females with FXPOI will often have difficulty getting pregnant, and many will not be able to have children. Females with a full mutation are not at increased risk for POI.\n\n_Fragile X-associated neuropsychiatric disorders (FXAND)_: There is an increased rate of neuropsychiatric conditions among premutation carriers. These include depression, generalized and social anxiety, and attention deficit disorder. \n\n## How is fragile X syndrome inherited?\n\n**Fragile X syndrome is inherited in an X-linked manner. The inheritance is much more complex than many other genetic diseases. A healthcare professional, such as a genetic counselor, can help answer questions about this condition and the risk of transmitting it to the next generation.**\n\nFragile X syndrome is caused by changes in the _FMR1_ gene, which is located on the X-chromosome. This gene contains a segment of DNA called the "CGG repeat." The CGG repeat in the _FMR1_ gene is a pattern of DNA that repeats itself many times. By counting the number of CGG repeats in the parents, one can determine the likelihood that a child will have fragile X syndrome.\n\nThe CGG repeat in the _FMR1_ gene falls into one of the following four categories:\n\n| Category | _FMR1_ CGG repeat size |\n| ------------- | ------------- |\n| Normal | 5 to 44 repeats |\n| Intermediate | 45 to 54 repeats |\n| Premutation | 55 to 200 repeats |\n| Full mutation | More than 200 repeats |\n\n#### Normal\n\nAn _FMR1_ gene with 5 to 44 CGG repeats is considered normal. Individuals with this number of _FMR1_ CGG repeats do not have an increased chance of having a child with fragile X syndrome. CGG repeats in this range are considered stable because they usually pass from parent to child with the same number of repeats. For example, if a parent\'s gene has 30 CGG repeats, their child will likely have a gene with 30 CGG repeats.\n\n#### Intermediate\n\nAn individual with 45 to 54 repeats is not expected to have an increased chance of passing on fragile X syndrome to their child, but the number of repeats transmitted to the next generation may increase slightly. \n\n#### Premutation\n\nIndividuals with 55 to 200 CGG repeats have a premutation. They do not have symptoms of fragile X syndrome. However, they are at increased risk for FXTAS, FXPOI, and FXAND. Depending on which parent has the premutation, future children may be at risk of having fragile X syndrome.\n\n#### Full mutation\n\nIndividuals with more than 200 CGG repeats have a non-functioning _FMR1_ gene (also known as a full mutation). Males with more than 200 CGG repeats usually have symptoms of fragile X syndrome. Females with more than 200 CGG repeats may also have symptoms of fragile X syndrome and are at risk of passing the condition on to their children.\n\n### What does it mean to have an intermediate result? \n\nAn FMR1 gene that has 45-54 repeats is considered intermediate. The number of CGG repeats is higher than normal but not large enough to be considered a premutation. Sometimes CGG repeats in the intermediate range are referred to as "gray zone" results. Individuals with an intermediate repeat do not have an increased chance of having a child with fragile X syndrome. Most intermediate genes are stable and do not significantly expand when passed on. However, repeats in the intermediate range may slightly expand when passed on to the next generation in some cases. For example, a parent with 45 CGG repeats could have a child with 50 CGG repeats. If the number of repeats continues to increase, future generations (i.e., grandchildren or great-grandchildren) may have a chance of inheriting fragile X. Expansion to a full mutation in one generation from a maternal gene with fewer than 56 repeats has not been reported. Children of individuals with an intermediate result may consider fragile X testing to determine their CGG repeat sizes once they are adults for reproductive planning purposes.\n\nApproximately 3% of patients undergoing fragile X carrier screening will have an intermediate result. Individuals with an intermediate repeat do NOT have an increased chance of having the physical symptoms affecting premutation carriers such as FXTAS, FXPOI, and FXAND.\n\n### What does it mean to have a premutation or full mutation? What is the chance that a child will have fragile X syndrome?\n\nFor females with a full mutation, 50% of their children will also inherit the full mutation and be at risk for symptoms of fragile X syndrome. Males who have full mutations typically do not reproduce.\n\nPremutations are more complicated. When the parent has a premutation, the risk of a child developing fragile X syndrome depends on the answers to the following questions:\n\n1. Which parent has the premutation?\n2. Will the child inherit the premutation?\n3. Will the premutation expand to a full mutation?\n\n#### Which parent has the premutation?\n\nFemales that are premutation carriers are at risk of having children with fragile X syndrome. Premutations inherited from a female can be unstable and may expand to become full mutations in the child. This risk can be modified by AGG interruptions, which reduce the likelihood of expansion.\n\nPremutations passed from a male parent may change the CGG repeat number. However, premutations do not expand to full mutations when passed from a male parent. Therefore, males with premutations are not at risk of having children with fragile X syndrome.\n\n#### Will the child inherit the premutation?\n\nPremutations are not thought to expand to full mutations when passed from a male parent to a female child. However, there can be a change in the number of CGG repeats. These female children are generally not at risk of having fragile X syndrome, but their future children (the grandchildren of the original premutation carrier) will be at risk. Male parents pass a Y chromosome to their male children instead of an X, so fragile X premutations are not passed from a male parent to a male child.\n\nIf a female parent has a premutation on one of their X chromosomes, there is a 50% chance in each pregnancy that their child will inherit the X chromosome with the premutation and a 50% chance that they will not. Only children who inherit the X chromosome with the premutation would be at risk for fragile X syndrome if it expands.\n\n\n#### Will the premutation expand to a full mutation?\n\nIf a female parent has a gene with a premutation that gets passed to their children, there are two possibilities:\n\n1. The premutation does not expand beyond 200 repeats and remains a premutation in the child. That child has no symptoms of fragile X syndrome but may experience FXAND and FXTAS or FXPOI as adults.\n2. The premutation expands into a full mutation, causing fragile X syndrome in males and risk for fragile X syndrome in females.\n\nRarely, a CGG repeat may contract (or reduce in number). Therefore, there is a small possibility that a premutation could be passed on as an intermediate or normal repeat to the child.\n\nThe greater the number of CGG repeats a female has, the more unstable the gene is and the more likely it will expand to a full mutation in their children. The smallest premutation observed to expand to a full mutation in a single generation is 56 repeats.\n\n| Number of Maternal Premutation CGG Repeats | Percentage (Total Females) Which Expanded to Full Mutations |\n| ------------- | ------------- |\n| 55-59 | <1% (1/197) |\n| 60-64 | 2% (2/115) |\n| 65-69 | 7% (6/85) |\n| 70-74 | 21% (18/84) |\n| 75-79 | 47% (47/99) |\n| 80-84 | 62% (60/96) |\n| 85-90 | 81% (34/42) |\n\nMore than 94% of genes with >90 CGGs expand to a full mutation.\n\nAdapted from [Nolin et al. (2015)](https://www.ncbi.nlm.nih.gov/pubmed/25210937) and [Nolin et al. (2011)](http://www.ncbi.nlm.nih.gov/pubmed/21717484). These percentages typically exclude families with a family history of fragile X syndrome.\n\n## How Common Is Fragile X Syndrome?\n\nThe incidence of fragile X syndrome is estimated to be 1 in 4,000 males and 1 in 8,000 females.\n\n## How Is Fragile X Syndrome Treated?\n\nThere is no cure for fragile X syndrome, but children with the condition can be treated and supported in many ways depending on their particular symptoms and the severity of those symptoms. They may benefit from educational support like early developmental intervention, special education classes in school, speech therapy, occupational therapy, and behavioral therapies. A physician may prescribe medication for behavioral issues such as aggression, anxiety, or hyperactivity.\n\nA small number of these children experience seizures which can be controlled with medication. While some have a heart murmur, it is usually harmless and may not require treatment.\n\n## What Is the Prognosis for an Individual with Fragile X Syndrome?\n\nWhile many of the children with fragile X syndrome have learning and behavioral problems, they generally do not have major medical problems and can live a normal lifespan., Fragile X syndrome causes serious intellectual impairment and behavioral problems. It is the most common form of inherited intellectual disability. Due to the X-linked pattern of inheritance, fragile X syndrome is more common and more severe in males than females. |
Subjects' offspring are at increased risk for inheriting the following genetic diseases: HFE-associated hereditary hemochromatosis, factor XI deficiency, and fragile X syndrome
Coded Conclusions: