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AD has become a disease of particular concern in the United States because the nation's older adult population is growing rapidly. By the United States will have approximately Prevalence the number of people with a disease at a given time is partially determined by the length of time people with AD survive. Even though the average survival is eight years after diagnosis, some AD patients have lived longer than twenty years with the disease.


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Therefore, improvements in AD care, as well as increased length of life of the older adult population in general, will increase the numbers of AD patients. AD is not a normal consequence of growing older, and scientists are continuing to seek its cause. Researchers find some promising genetic clues to the disease.

Table 5. Mutations in four genes, situated on chromosomes 1, 14, 19, and 21, are thought to be involved in the disease, and the best described are PS1 or AD3 on chromosome 14 and PS2 or AD4 on chromosome 1. The formation of lesions made of fragmented brain cells surrounded by amyloid-family proteins is characteristic of the disease. Interestingly, these lesions and their associated proteins are closely related to similar structures found in Down syndrome. Tangles of filaments largely made up of a protein associated with the cytoskeleton have also been observed in samples taken from AD brain tissue.

The first genetic breakthrough was reported in the February issue of the British journal Nature. Investigators reported that they had discovered that a mutation in a single gene could cause this progressive neurological illness. Scientists found the defect in the gene that directs cells to produce a substance called amyloid protein. Researchers at the Massachusetts Institute of Technology found that low levels of the brain chemical acetylcholine contribute to the formation of hard deposits of amyloid protein that accumulate in the brain tissue of AD patients.

In unaffected people the protein fragments are broken down and excreted by the body. Amyloid protein is found in cells throughout the body. Researchers do not know why it becomes a deadly substance in the brain cells of some people and not others. In three more genes linked to AD were identified. One gene appears to be related to the most devastating form of AD, which can strike people in their thirties. When defective, the gene may prevent brain cells from correctly processing a substance called beta amyloid precursor protein.

The second gene is linked to another early-onset form of AD that strikes before age sixty-five. This gene also appears to be involved in producing beta amyloid. Researchers believe that the discovery of these two genes will allow them to narrow their search for the proteins responsible for early-onset AD and give them clues to the causes of AD in older people.

Researchers have since found that the gene plays several roles. It regulates lipid metabolism within the organs and helps to redistribute cholesterol. In the brain apoE participates in repairing nerve tissue that has been injured. There are three forms alleles of the gene: apoE-2, apoE-3, and apoE Until recently, people with two copies of apoE-4, one from each parent, were thought to have a greatly increased risk of developing AD before age seventy. Between one-half and one-third of all AD patients have at least one apoE-4 gene, whereas only In , however, researchers discovered that the apoE-4 gene seems to affect when a person may develop AD, not whether the person will develop the disease.

Another newly discovered gene, A2M-2, appears to affect whether a person will develop AD. The discovery of A2M-2 opens up the possibility of developing a drug that mimics the A2M gene's normal function. This can protect susceptible people against brain damage or perhaps even reverse it. For many years the only sure way to diagnose the disease was to examine brain tissue under a microscope, which was not possible while the AD victim was still alive. An autopsy of someone who has died of AD reveals a characteristic pattern that is the hallmark of the disease: tangles of fibers neurofibrillary tangles and clusters of degenerated nerve endings neuritic plaques in areas of the brain that are crucial for memory and intellect.

Also, the cortex of the brain is shrunken. Diagnostic tests for AD have included analysis of blood and spinal fluid as well as the use of magnetic resonance imaging MRI to measure the volume of brain tissue in areas of the brain used for memory, organizational ability, and planning to accurately identify people with AD and predict who will develop AD in the future. Georganopoulou et al. The test is called a bio-barcode assay and is as much as a million times more sensitive than other tests.

First used to identify a marker for prostate cancer, the test is used to detect a protein in the brain called amyloid beta-derived diffusible ligand ADDL. To detect them, Georga-nopoulou and her colleagues use nanoscale particles that have antibodies specific to ADDL. Physicians and neuroscientists have been eager for a simple and accurate test that can distinguish people with AD from those with cognitive problems or dementias arising from other causes.

An accurate test would allow the detection of AD early enough for the use of experimental medications to slow the progression of the disease, as well as identify those at risk of developing AD. However, the availability of tests raises ethical and practical questions: Do patients really want to know their risks of developing AD? Will health insurers use genetic or other diagnostic test results to deny insurance coverage?

There is still no cure or prevention for AD, and treatment focuses on managing symptoms. Medication can lessen some of the symptoms, such as agitation, anxiety, unpredictable behavior, and depression. Physical exercise and good nutrition are important, as is a calm and highly structured environment. The object is to help the AD patient maintain as much comfort, normalcy, and dignity for as long as possible. By five prescription drugs were available to treat people who suffer from AD. Four of these — galantamine, rivastigmine, donepezil, and tacrine — are cholinesterase inhibitors and are prescribed for the treatment of mild to moderate AD.

These drugs produce some delay in the deterioration of memory and other cognitive skills in some patients. They offer mild benefits at best and may lose their effectiveness over time, but currently they are the only alternatives available to treat mild to moderate AD. The fifth approved medication, memantine, is prescribed for the treatment of moderate to severe AD.

It acts to delay progression of some symptoms of moderate to severe AD and may allow patients to maintain certain daily functions a little longer. It is thought to work by regulating glutamate, a chemical in the brain that, in excessive amounts, may lead to brain cell death. Other researchers are examining the roles of the hormones estrogen and progesterone on memory and cognitive function.

Because AD involves inflammatory processes in the brain, scientists are also studying the use of anti-inflammatory agents such as ibuprofen and prednisone to reduce the risk of developing AD. Researchers are also investigating the relationship between the various gene sites, particularly the mutation on chromosome 21, and environmental influences that may increase susceptibility to AD.

Furthermore, researchers are trying to determine whether antioxidants, such as vitamin E, can prevent people with mild memory impairment from progressing to AD. Cancer is a large group of diseases characterized by uncontrolled cell division and the growth and spread of abnormal cells. These cells may grow into masses of tissue called tumors. Tumors composed of cells that are not cancerous are called benign tumors. Tumors consisting of cancer cells are called malignant tumors. The dangerous aspect of cancer is that cancer cells invade and destroy normal tissue. The mechanisms of action that disrupt the cell cycle are impairment of a DNA repair pathway, transformation of a normal gene into an oncogene a hyperactive gene that stimulates cell growth , and the malfunction of a tumor-suppressor gene a gene that inhibits cell division.

The spread of cancer cells occurs either by local growth of the tumor or by some of the cells becoming detached and traveling through the blood and lymphatic system to seed additional tumors in other parts of the body. Metastasis the spread of cancer cells may be confined to a local region of the body, but if left untreated and often despite treatment , the cancer cells can spread throughout the entire body, eventually causing death.

It is perhaps the rapid, invasive, and destructive nature of cancer that makes it, arguably, the most feared of all diseases, even though it is second to heart disease as the leading cause of death in the United States. Cancer can be caused by both external environmental influences chemicals, radiation, and viruses and internal factors hormones, immune conditions, and inherited mutations. These factors may act together or in sequence to begin or promote cancer. There is consensus in the scientific community that several cancer-promoting influences accrue and interact before an individual will develop a malignant growth.

With only a few exceptions, no single factor or risk alone is sufficient to cause cancer. As with other disorders that arise in response to multiple factors, susceptibility to certain cancers is often attributed to a mutated gene. Scientists and physicians have known for some time that predisposition to some forms of breast cancer are inherited and have been searching for the gene or genes responsible so that they can test patients and provide more careful monitoring for those at risk.

Researchers also think that the two genes are linked to ovarian, prostate, and colon cancer and that BRCA2 likely plays some role in breast cancer in men. Scientists suspect that the two genes may also participate in some way in the development of breast cancer in women with no family history of the disease. Sung-Won Kim et al. According to Els M. Berns et al. ERBB2 often triggers an aggressive form of cancer that can cause death more quickly than other breast cancers, often within ten to eighteen months after the cancer spreads. The ERBB2 gene produces a protein on the surface of cells that serves as a receiving point for growth-stimulating hormones.

Stacey et al. Stacey and his coauthors studied 1, Icelandic women who had breast cancer and compared them to similar women without the disease. They found a specific mutation, BARD1, in 2. Another study Sheila Seal et al. Although BRIP1 increases a woman's breast cancer risk twofold, other gene mutations raise it much more. Individuals with faulty DNA-repair genes have an increased risk of cancer because their healthy cells are more likely to accumulate genetic damage that can trigger the cell to replicate uncontrollably.

Cystic fibrosis CF is the most common inherited fatal disease of children and young adults in the United States. An estimated 10 million Americans, almost all of whom are white, are symptomless carriers of the CF gene. Like sickle-cell disease, it is a recessive genetic disorder — to inherit this disease, a child must receive the CF gene from both parents.

In the CF gene was identified, and in it was cloned and sequenced. It is located on the long arm of chromosome 7 at position The gene was called cystic fibrosis transmembrane conductance regulator CFTR because it was discovered to encode a membrane protein that controls the transit of chloride ions across the plasma membrane of cells.

Nearly 1, mutations of the large gene — , nucleotides — have been identified. Though most are extremely rare, several account for more than two-thirds of all mutations. The most frequently occurring mutation causes faulty processing of the protein such that the protein is degraded before it reaches the cell membrane. The mutated versions of the gene found in people with CF were seen to cause relatively modest impairment of chloride transport in cells. However, this seemingly minor defect can result in a multisystem disease that affects organs and tissues throughout the body, provoking abnormal, thick secretions from glands and epithelial cells.

Ultimately, these secretions fill the lungs and cause affected children to die of respiratory failure. The progression from the defective gene and protein it encodes to life-threatening illness follows this complex path:. A simple sweat test is currently the standard diagnostic test for CF. The test measures the amount of salt in the sweat; abnormally high levels are the hallmark of cystic fibrosis. In August researchers isolated the specific gene that causes CF.

In scientists successfully corrected the biochemical defect by inserting a healthy gene into diseased cells grown in the laboratory, a major step toward developing new therapies for the disease. In they injected healthy genes into laboratory rats with a deactivated common cold virus as the delivery agent. The rats began to manufacture the missing protein, which regulates the chloride and sodium in the tissues, preventing the deadly buildup of mucus. Scientists were hopeful that within a few years CF would be eliminated as a fatal disease, giving many children the chance for healthy, normal lives.

In , however, optimism faded when the medical community discovered that the CF gene was more com-plicated than expected. Scientists found that the gene can be mutated at more than points, and more points are being recognized at an alarming rate. At the same time, they discovered that many people who have inherited mutated genes from both parents do not have cystic fibrosis. With so many possible mutations, the potential combinations in a person who inherits one gene from each parent are immeasurable. The combinations of different mutations create different effects. Some may result in crippling and fatal CF, whereas others may cause less serious disorders, such as infertility, asthma, or chronic bronchitis.

To further complicate the picture, other genes can alter the way different mutations of the CF gene affect the body. The Cystic Fibrosis Foundation supports clinical research studies in human gene therapy. One form of gene therapy uses a compacted DNA technology. This gene transfer system compacts single copies of the healthy CFTR gene so that they are small enough to pass through a cell membrane into the nucleus. Researchers are also finding that CF mutations may be much more common than previously thought. For example, Stephanie A. This finding may indicate that many more common diseases, such as asthma, may be caused by mutations of the CF gene.

Other scientists speculate that the frequency of CF carriers among people of European descent may have, at some point in time, conferred immunity to some other disorder, in much the same way that the sickle-cell carriers were protected from malaria. Diabetes is a disease that affects the body's use of food, causing blood glucose sugar levels in the blood to become too high. Normally, the body converts sugars, fats, starches, and proteins into a form of sugar called glucose. The blood then carries glucose to all the cells throughout the body. In the cells, with the help of the hormone insulin, which facilitates the entry of glucose into the cells, the glucose is either converted into energy for use immediately or stored for the future.

Beta cells of the pancreas, a small organ located behind the stomach, manufacture the insulin. The process of turning food into energy via glucose blood sugar is important because the body depends on glucose for its energy source. In a person with diabetes, food is converted to glucose, but there is a problem with insulin. In one type of diabetes the pancreas does not manufacture enough insulin, and in another type the body has insulin but cannot use the insulin effectively this latter condition is called insulin resistance.

When insulin is either absent or ineffective, glucose cannot get into the cells to be converted into energy. Instead, the unused glucose accumulates in the blood. If a person's blood-glucose level rises high enough, the excess glucose is excreted from the body via urine, causing frequent urination. This, in turn, leads to an increased feeling of thirst as the body tries to compensate for the fluid lost through urination. There are two distinct types of diabetes.

Type 1 diabetes also called juvenile diabetes occurs most often in children and young adults. The pancreas stops manufacturing insulin, so the hormone must be injected daily. Type 2 diabetes is most often seen in adults. In this type the pancreas produces insulin, but it is not used effectively and the body resists its effects.

Of these, approximately one-third had not been diagnosed. In diabetes was the sixth leading cause of death and in , 1. The individuals most at risk for Type 2 diabetes are usually overweight, over forty years old, and have a family history of diabetes. The causes of both Type 1 and Type 2 diabetes are unknown, but a family history of the disease increases the risk for both types, leading researchers to believe there is a genetic component. Some scientists believe that a flaw in the body's immune system may be a factor in Type 1 diabetes.

Poor cardiovascular fitness is another risk factor for developing diabetes. Mutations in several genes probably contribute to the origin and onset of Type 1 diabetes. For example, an insulin-dependent diabetes mellitus IDDM1 site on chromosome 6 may harbor at least one susceptibility gene for Type 1 diabetes.

The role of this mutation in increasing susceptibility is not yet known; however, because chromosome 6 also contains genes for antigens the molecules that normally tell the immune system not to attack itself , there may be some interaction between immunity and diabetes. In Type 1 diabetes the body's immune system mounts an immunological assault on its own insulin and the pancreatic cells that manufacture it.

Some ten sites in the human genome, including a gene at the locus IDDM2 on chromosome 11 and the gene for glucokinase, an enzyme that is crucial for glucose metabolism, on chromosome 7, appear to increase susceptibility to Type 1 diabetes. In Type 2 diabetes heredity may be a factor, but because the pancreas continues to produce insulin, the disease is considered a problem of insulin resistance, in which the body is not using the hormone efficiently.

In people prone to Type 2 diabetes, being overweight can set off the disease because excess fat prevents insulin from working correctly. Maintaining a healthy weight and keeping physically fit can usually prevent noninsulin-dependent diabetes. To date, insulin-dependent diabetes Type 1 cannot be prevented. Because diabetes deprives body cells of the glucose needed to function properly, complications can develop that threaten the lives of diabetics.

Complications of diabetes include higher risk and rates of heart disease; circulatory problems, especially in the legs, often severe enough to require surgery or even amputation; diabetic retinopathy, a condition that can cause blindness; kidney disease that may require dialysis; dental problems; impaired healing and increased risk of infection; and problems of pregnancy.

People who pay close attention to the roles of diet, exercise, weight management, and pharmacological control proper use of insulin and other medication to manage their disease suffer the fewest complications. Huntington's disease HD is an inherited, progressive brain disorder. It causes the degeneration of cells in the basal ganglia , a pair of nerve clusters deep in the brain that affect both the body and the mind. HD is caused by a single dominant gene that affects men and women of all races and ethnic groups. The gene mutation that produces HD was mapped to chromosome 4 in and cloned in The mutation is an expansion of a nucleotide triplet repeat in the DNA that codes for the protein huntingtin.

In unaffected people the gene has thirty or fewer of these triplets, but HD patients have forty or more. These increased multiples either destroy the gene's ability to make the necessary protein or cause it to produce a misshapen and malfunctioning protein.

Either way, the defect results in the death of brain cells. The number of repeated triplets is inversely related to the age when the individual first experiences symptoms — the more repeated triplets, the younger the age of onset of the disease. Like myotonic dystrophy, in which the symptoms of the disease often increase in severity from one generation to the next, the unstable triplet repeat sequence can lengthen from one generation to the next, with a resultant decrease in the age when symptoms first appear.

HD does not usually strike until mid-adulthood, between the ages thirty and fifty, although there is a juvenile form that can affect children and adolescents. Early symptoms, such as forgetfulness, a lack of muscle coordination, or a loss of balance, are often ignored, delaying the diagnosis. The disease gradually takes its toll over a ten- to twenty-five-year period. Within a few years characteristic involuntary movement chorea of the body, limbs, and facial muscles appears. As HD progresses, speech becomes slurred and swallowing becomes difficult.

The patients' cognitive abilities decline, and there are distinct personality changes — depression and withdrawal, sometimes countered with euphoria. Eventually, nearly all patients must be institutionalized, and they usually die as a result of choking or infections. HD, once considered rare, is now recognized as one of the more common hereditary diseases. HD appears to be less common in other populations, including people of Japanese, Chinese, and African descent. In researchers identified a DNA marker that made it possible to offer a test to determine whether an individual has inherited the HD gene before symptoms appear.

In some cases it is even possible to make a prenatal diagnosis on an unborn child. Many people, however, prefer not to know whether or not they carry the defective gene. Currently, researchers are trying to determine if the exact number of excess triplets indicates when in life a person will be affected by the disease. Some scientists fear that the ability to tell people that they are going to develop an incurable disease and pinpoint when they will develop it will make genetic testing, already a difficult decision, even more complicated. Muscular dystrophy MD is a term that applies to a group of more than thirty types of hereditary muscle-destroying disorders.

More than a million Americans are affected by one of the forms of MD. Each variant of the disease is caused by defects in the genes that play important roles in the growth and development of muscles. Duchenne muscular dystrophy DMD is one of the most frequently occurring types of MD and is characterized by rapid progression of muscle degeneration that occurs early in life. In all forms of MD the proteins produced by the defective genes are abnormal, causing the muscles to waste away.

Unable to function properly, the muscle cells die and are replaced by fat and connective tissue. The gene for DMD is located on the X chromosome and encodes a large protein called dystrophin. Dystrophin provides structural support for muscle cells and without it the cell membrane becomes penetrable, allowing extracellular components into the cell. These additional components increase the intracellular pressure, causing the muscle cell to die. With myotonic dystrophy the muscles contract but have diminishing ability to relax, and there is muscle weakening and wasting.

Typically, the initial complaints are the loss of hand strength or tripping while walking or climbing stairs. Along with decreased muscle strength, myotonic dystrophy may cause mental deficiency, hair loss, and cataracts. According to HealthAtoZ. The myotonic dystrophy gene is a protein kinase gene found on the long arm of chromosome The defect is a repeated set of three nucleotides — cytosine C , thymine T , and guanine G — in the gene. Unaffected individuals have CTG repeats with between three and thirty-seven iterations repetitions of the triplet.

In contrast, people with the mild phenotype of myotonic dystrophy have between 40 and , and those with more serious forms of the disease have between and 1, iterations. All the various disorders labeled MD cause progressive weakening and wasting of muscle tissues. They vary, however, in terms of the usual age at the onset of symptoms, rate of progression, and initial group of muscles affected.

The most common type, DMD, affects young boys, who show symptoms in early childhood and usually die from respiratory weakness or damage to the heart before adulthood. The gene is passed from the mother to her children. Other forms of MD appear later in life and are usually not fatal. In scientists discovered the defect in the gene that causes myotonic dystrophy.

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In people with this disorder, a segment of the gene is enlarged and unstable. This finding helps physicians more accurately diagnose myotonic dystrophy. In Duygu Selcen and Andrew G. Selcen and Engel detected ZASP mutations in eleven patients; in seven of these, they observed a dominant pattern of inheritance. There is no known cure for MD, but patients can be made more comfortable and functional by a combination of physical therapy , exercise programs, and orthopedic devices special shoes, braces, or powered wheelchairs that help them to maintain mobility and independence as long as possible.

Genetic research offers hope of finding effective treatments, and even cures, for these diseases. Gene therapy experiments designed to find a cure or a treatment for one or more of these types of MD are ongoing. Research teams have identified the crucial proteins produced by these genes, such as dystrophin, beta sarcoglycan, gamma sarcoglycan, and adhalin. One experimental treatment approach involves substituting a protein of comparable size, such as utrophin for dystrophin, to compensate for the loss of dystrophin.

The ontology of craniofacial development and malformation for translational craniofacial research

Because defective or absent proteins cause MD, researchers hope that experimental treatments to transplant normal muscle cells into wasting muscles will replace the diseased cells. Muscle cells, unlike other cells in the body, fuse together to become giant cells. Scientists hope that if cells with healthy genes can be introduced into the muscles and accepted by the body's immune system, the muscle cells will then begin to produce the missing proteins. New delivery methods called vectors are also being tested, such as implanting a healthy gene into a virus that has been stripped of all of its harmful properties and then injecting the modified virus into a patient.

Researchers hope this will reduce the amount of rejection by the patient's immune system, allowing the healthy gene to restore the missing muscle protein. Phenylketonuria PKU is an example of a disorder caused by a gene-environment interaction. As a result of the defect, the affected individual is unable to convert phenylalanine into tyrosine. Phenylalanine in the body accumulates in the blood and can reach toxic levels. This toxicity may impair brain and nerve development and result in mental retardation, organ damage, and unusual posture.

When it occurs during pregnancy, it may jeopardize the health and viability of the unborn child. Originally, PKU was considered simply an autosomal recessive inherited error of metabolism that occurred when an individual received two defective copies, caused by mutations in both alleles of the phenylalanine hydrox-ylase gene found on chromosome The environmental trigger — dietary phenylalanine — was not identified at first because phenylalanine is so prevalent in the diet, occurring in common foods such as milk and eggs and in the artificial sweetener aspartame.

Recognition of dietary phenylalanine as a critical environmental trigger has enabled children born with PKU to lead normal lives when they are placed on low-phenylalanine diets, and mothers with the disease can bear healthy children. After a second screening is done for those with elevated blood levels, approximately 1 out of 10, infants is diagnosed with PKU and, with proper diet, is likely to lead a healthy, normal life.

Sickle-cell disease SCD is a group of hereditary diseases, including sickle-cell anemia SCA and sickle B-thalassemia, in which the red blood cells contain an abnormal hemoglobin, called hemoglobin S HbS. HbS is responsible for the premature destruction of red blood cells, or hemolysis. In addition, it causes the red cells to become deformed, actually taking on a sickle shape, particularly in parts of the body where the amount of oxygen is relatively low. These abnormally shaped cells cannot travel smoothly through the smaller blood vessels and capillaries.

They tend to clog the vessels and prevent blood from reaching vital tissues. This blockage produces anoxia lack of oxygen , which in turn causes more sick-ling and more damage. SCA is an autosomal recessive disease caused by a point mutation in the hemoglobin beta gene HBB found on chromosome 11p A mutation in HBB results in the production of hemoglobin with an abnormal structure.

It also shows how when red blood cells with HbS are oxygen-deprived they become sickle shaped and may cause blockages that result in tissue death. People with SCA have symptoms of anemia, including fatigue, weakness, fainting, and palpitations or an increased awareness of their heartbeat.

These palpitations result from the heart's attempts to compensate for the anemia by pumping blood faster than normal. In addition, patients experience occasional sickle-cell crises — attacks of pain in the bones and abdomen. Blood clots may also develop in the lungs, kidneys, brain, and other organs. A severe crisis or several acute crises can permanently damage various organs of the body.

This damage can lead to death from heart failure, kidney failure, or stroke. The frequency of these crises varies from patient to patient. A sickle-cell crisis, however, occurs more often during infections and after an accident or an injury. Both the sickle-cell trait and the disease exist almost exclusively in people of African, Native American, and Hispanic descent and in those from parts of Italy, Greece , Middle Eastern countries, and India. If one parent has the sickle-cell gene, then the couple's offspring will carry the trait; if both the mother and the father have the trait, then their children may be born with SCA.

This trait is relatively common among African-Americans. People of African descent are advised to seek genetic counseling and testing for the trait before starting a family. SCD is the most common inherited blood disorder in the United States, affecting 72, Americans, most of whom have African ancestry. SCA occurs in approximately 1 out of African-American births and in 1 out of 1, to 1, Hispanic births.

The occurrence of SCA in other groups is much lower. There is no universal cure for SCD, but the symptoms can be treated. Crises accompanied by extreme pain are the most common problems and can usually be treated with painkillers. Maintaining healthy eating and behavior and prompt treatment for any type of infection or injury is important.

Special precautions are often necessary before any type of surgery, and for major surgery some patients receive transfusions to boost their levels of hemoglobin the oxygen-bearing, iron-containing protein in red blood cells. In early a medication that prevented the cells from clogging vessels and cutting off oxygen was approved by the Food and Drug Administration. Many adults with SCD now take hydroxyurea, an anticancer drug that causes the body to produce red blood cells that resist sickling.

In Martin H. Steinberg et al. It is a fatal genetic disorder in children that causes the progressive destruction of the central nervous system. It is caused by the absence of an important enzyme called hexosaminidase A hex-A. Without hex-A, a fatty substance called GM2 ganglioside builds up abnormally in the cells, particularly the brain's nerve cells. Eventually, these cells degenerate and die.

This destructive process begins early in the development of a fetus, but the disease is not usually diagnosed until the baby is several months old. By the time a child with TSD is four or five years old, the nervous system is so badly damaged that the child dies. Both the mother and the father must be carriers of the defective TSD gene to produce a child with the disease. People who carry the gene for TSD are entirely unaffected and usually unaware that they have the potential to pass this disease to their offspring.

A blood test distinguishes Tay-Sachs carriers from noncarriers. Blood samples may be analyzed by enzyme assay or DNA studies. Enzyme assay measures the level of hex-A in blood. Carriers have less hex-A than noncarriers. When only one parent is a carrier, the couple will not have a child with TSD. When both parents carry the recessive TSD gene, they have a one in four chance in every pregnancy of having a child with the disease.

Prenatal diagnosis early in pregnancy can predict if the unborn child has TSD. If the fetus has the disease, the couple may choose to terminate the pregnancy. Some genetic diseases, such as TSD, occur most frequently in a specific population. French-Canadians and Cajuns also have the same carrier rate as Ashkenazi Jews.

In the general population the carrier rate is 1 out of Cite this article Pick a style below, and copy the text for your bibliography. September 24, Retrieved September 24, from Encyclopedia. Then, copy and paste the text into your bibliography or works cited list.

Because each style has its own formatting nuances that evolve over time and not all information is available for every reference entry or article, Encyclopedia. It also has a role in infectious diseases once believed to be entirely environmentally caused such as human immunodeficiency virus HIV, which is the virus that causes acquired immune deficiency syndrome [AIDS] infection and tuberculosis. Like most diseases, these frequently occurring disorders are due to the interactions of multiple genes and environmental factors. It is commonly accepted that diseases fall into one of three broad categories: those few that are primarily genetic in origin; those that are largely attributable to environmental causes; and those—the majority of conditions—in which genetics and environmental factors make comparable, though not necessarily equal, contributions.

As understanding in genomics advances and scientists identify genes involved in more diseases, the distinctions between these three classes of disorders is diminishing. Since genes code for proteins, when a gene is mutated so that its protein product can no longer carry out its normal function, it may produce a disorder.

There are more than 6, known single-gene disorders, which occur in about one in every births. Down's syndrome or trisomy 21 is a chromosomal disorder that results when an individual has an extra copy, or a total of three copies, of chromosome Compared with the three other patterns of inheritance, mitochondrial disorders occur infrequently. Genomic medicine predicts the risk of disease in the individual, whether highly probable, as in the case of some of the well-established single-gene disorders, or in terms of an increased susceptibility likely to be influenced by environmental factors.

Although many diseases, disorders, and conditions are termed "genetic," classifying a disease as genetic simply means that there is an identified genetic component to either its origin or its expression. Many medical geneticists contend that the majority of diseases cannot be classified as strictly genetic or environmental.

It is the fourth leading cause of death in adults, and the incidence of the disease rises with age.


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The U. The disease was first described by the German physician Alois Alzheimer — in after he had cared for a patient with an unusual mental illness. Alzheimer observed anatomical changes in his patient's brain and described them as abnormal clumps and tangled bundles of fibers.

Nearly a century later, these abnormal findings, now described as amyloid plaques and neurofibrillary tangles, along with abnormal clusters of proteins in the brain, are the characteristic markers of AD. The disease knows no social or economic boundaries and affects men and women almost equally. Most patients are cared for at home as long as possible, a situation that can be emotionally and physically devastating for the affected individuals and their families.

While average survival is eight years after diagnosis, some AD patients have lived longer than twenty years with the disease. In November former president Ronald Reagan, at age eighty-three, announced that he had been diagnosed with AD and wanted to make Americans more aware of the disease.

Some observers believe that it is theoretically possible that AD had affected Reagan before he left the White House in January In former president Reagan died as a result of the disease. In August another American legend, actor and activist Charlton Heston, announced that he, too, had been diagnosed with AD. Researchers have found some promising genetic clues to the disease.

Interestingly, these lesions and their associated proteins are closely related to similar structures found in Down's syndrome. In normal people the protein fragments are broken down and excreted by the body. Researchers do not know how it becomes a deadly substance in the brain cells of some people and not others. The third gene, known as apolipoprotein E apoE , was actually reported as associated with AD in , but its role in the body was not known at that time.

Within the body, it regulates lipid metabolism within the organs and helps to redistribute cholesterol. This has the potential to. AD begins slowly. The symptoms include difficulty with memory and a loss of cognitive function intellectual abilities. The AD patient may also experience confusion; language problems, such as trouble finding words; impaired judgment; disorientation in place and time; and changes in mood, behavior, and personality.

How quickly these changes occur varies from person to person, but eventually the disease leaves its victims unable to care for themselves. In their terminal stages AD victims require care twenty-four hours a day. They no longer recognize family members or themselves, and they need help with such daily activities as eating, dressing, bathing, and using the toilet. Eventually, they may become incontinent, blind, and unable to communicate. Finally, their bodies may "forget" how to breathe or make the heart beat. Many patients die from pneumonia.

For many years, the only sure way to diagnose the disease was to examine brain tissue under a microscope, which was not possible while the AD victim was still alive. An autopsy of someone who has died of AD reveals a characteristic pattern that is the hallmark of the disease—tangles of fibers neurofibrillary tangles and clusters of degenerated nerve endings neuritic plaques in areas of the brain that are crucial for memory and intellect.

In a San Francisco biotechnology firm developed a diagnostic test for AD. In researchers at Brigham and Women's Hospital in Boston found that by using magnetic resonance imaging MRI they could measure the volume of brain tissue in areas of the brain used for memory, organizational ability, and planning, and using these measurements could accurately identify people with AD and predict who would develop AD in the future. In early researchers Chad Mirkin and William Klein at Northwestern University announced development of yet another diagnostic test that detects small amounts of protein in spinal fluid.

First used to identify a marker for prostate cancer, the test is used to detect a protein in the brain called amyloid-beta-derived diffusible ligand ADDL. ADDLs are small soluble proteins that may be indicative of Alzheimer's disease. To detect them the researchers used nanoscale particles that had antibodies specific to ADDL.

The researchers' findings were reported in the February 9, , issue of the Proceedings of the National Academy of Science. Investigators continue to look at other biological markers, such as blood tests, for AD and at neuropsychological tests, which measure memory, orientation, judgment, and problem solving, to see if they can accurately predict whether healthy, unaffected older adults will develop AD or whether those with mild cognitive impairment will go on to develop AD. Physicians and neuroscientists have long been eager for a simple and accurate test that can distinguish people with AD from those with cognitive problems or dementias arising from other causes.

But the availability of tests raises ethical and practical questions: Do patients really want to know their risks of developing AD? But in early the Food and Drug Administration approved a new drug, donepezil, to be marketed under the trade name Aricept. Both drugs are cholinesterase inhibitors, which produce some delay in the deterioration of memory and other cognitive skills. They offer only mild benefits at best, but currently they are the only alternatives available to AD patients.

All of the drugs being tested are intended to improve the symptoms of AD and slow its progression, but none is expected to "cure" AD. The investigational drugs aim to address three aspects of AD: to improve cognitive function in persons with early AD, slow or postpone the progression of the disease, and control behavioral problems such as wandering, aggression, and agitation of patients with AD. They offer mild benefits at best, and may lose their effectiveness over time, but currently they are the only alternatives available to treat mild to moderate AD.

It is thought to act by regulating glutamate, a chemical in the brain that, in excessive amounts, may lead to brain cell death. Since AD involves inflammatory processes in the brain, scientists are also studying the use of anti-inflammatory agents such as ibuprofen or prednisone to reduce the risk of developing AD. Another NIA-funded study is trying to find out whether antioxidants, such as vitamin E, can prevent people with mild memory impairment from progressing to AD.

They hope to compare the genes of the afflicted siblings with those from another family member who does not have AD in an effort to find the genes that contribute to AD. The mechanisms of action that disrupt the cell cycle are: impairment of a DNA repair pathway, transformation of a normal gene into an oncogene a hyperactive gene that stimulates cell growth , and the malfunction of a tumor suppressor gene a gene that inhibits cell division. The spread of cancer cells occurs either by local growth of the tumor or by some of the cells becoming detached and traveling through the blood and lymphatic system to develop additional tumors in other parts of the body.

Metastasis the spread of cancer cells may be confined to a local region of the body, but if left untreated and often despite treatment , the cancer cells can spread throughout the entire body, causing death. Researchers also think that the two genes are linked to ovarian, prostate, and colon cancer, and BRCA2 likely plays some role in breast cancer in men.

A November study headed by Stephen C. Rubin, a professor and chief of gynecological oncology cancers of the female reproductive organs at the University of Pennsylvania , reported a result that was totally unexpected. The study found that women with defective BRCA1 genes who developed ovarian cancer survived longer than those without the mutated gene who developed ovarian cancer. Women with the defective gene lived an average of seventy-seven months after diagnosis, while those without the mutated gene averaged only a twenty-nine-month survival.

Researchers do not know if those with the defective gene had less deadly types of cancers or if their cancers responded better to treatment. Herceptin, a genetically engineered antibody, increases the benefits of chemotherapy by shrinking tumors and slowing the progression of ERBB2. Herceptin became available in late It occurs in about one in every 3, Caucasian births, one in 15, African-Americans and one in 31, Asian-Americans.

An estimated twelve million Americans one in twenty-five , almost all of whom are white, are symptomless carriers of the CF gene. Like sickle-cell disease, it is a recessive genetic disorder—in order to inherit this disease, a child must receive the CF gene from both parents. Nearly 1, mutations of the large gene—, nucleotides—have been identified. But this seemingly minor defect can result in a multisystem disease that affects organs and tissues throughout the body, provoking abnormal, thick secretions from glands and epithelial cells.

At first, a child with CF does not appear to be suffering from a serious illness, but the diagnosis is usually made by the age of three. Often, the only signs are a persistent cough, a large appetite but poor weight gain, an extremely salty taste to the skin, and large, foul-smelling bowel movements. A simple "sweat test" is currently the standard diagnostic test for CF. Over time children with CF develop great difficulty in breathing. The CF gene causes the body to produce thick, sticky mucus in the lungs and pancreas, causing difficulty in breathing and interference with digestion.

In they injected healthy genes into laboratory rats by using a deactivated common cold virus as the delivery agent. In , however, optimism faded when the medical community discovered that the CF gene was more complicated than expected. Scientists found that the gene can be mutated at more than points, and more points are appearing at an alarming rate. Some may result in crippling and fatal CF, while others may cause less serious disorders, such as infertility, asthma, or chronic bronchitis.

Osteoglophonic dysplasia

In the Cystic Fibrosis Foundation continued to support clinical research studies in human gene therapy. Several studies used the adenovirus rather than the common cold virus as the vehicle for delivering healthy genes to lung or nasal tissue. Another study is using liposomes fat cells as a delivery vehicle. Still another form of gene therapy uses a compacted DNA technology. The nonviral gene transfer system compacts single copies of the healthy CFTR gene so that they are small enough to pass through a cell membrane into the nucleus.

Other scientists have speculated that the frequency of CF carriers among people of European descent may have, at some point in time, conferred immunity to some other disorder, in much the same way that the sickle-cell carriers were protected from malaria. Since there is a relatively high frequency of carriers of the defective gene in the general population, in the NIH, the American College of Medical Genetics, and the American College of Obstetricians and Gynecologists issued a recommendation that CF screening be offered to every white woman who is pregnant or considering having a baby.

However, the same year the results of a research study conducted at Northwestern University Medical School in Chicago found that many people who carry the CF gene fail to inform family members about their risk. The investigators and other health educators believe that if carriers were better informed about their risks they might be more likely to disclose them.

Pretest education and counseling were seen as key to increasing carriers' understanding of the significance of findings and their family planning options. For example, when both parents are carriers, the risk of their child having CF is one in four, and the risk of their child being a carrier is one in two. In this case parents may choose to have prenatal diagnosis using chorionic villus sampling CVS or amniocentesis to find out whether their unborn child will have the disease.

Alternatively, they may choose to use assisted reproductive technology such as in vitro fertilization in which the egg and sperm are united outside of the body because it offers the option of preimplantation diagnosis. This is a genetic test that enables parents undergoing in vitro fertilization to screen an embryo for CF genetic mutations before it is implanted in the uterus to grow and develop.

In a body with diabetes, food is converted to glucose, but there is a problem with insulin. If a person's blood-glucose level rises high enough, the excess glucose "spills over" into the urine, causing frequent urination. Insulin-dependent diabetes also called Type 1 or juvenile diabetes , the most severe form of the disease, occurs most often in children and young adults.

The pancreas stops manufacturing insulin, and the hormone must be injected daily. Non-insulin-dependent diabetes also known as Type 2 is most often seen in adults. The role of this mutation in increasing susceptibility is not yet known; however, since chromosome 6 also contains genes for antigens the molecules that normally tell the immune system not to attack itself , there may be some interaction between immunity and diabetes. In noninsulin-dependent diabetes, heredity may be a factor, but since the pancreas continues to produce insulin, the disease is considered a problem of insulin resistance, in which the body is not using the hormone efficiently.

Blacks are somewhat more likely to develop Type 2 diabetes than whites, while Hispanic Americans are much more likely to develop this type of the disease than the general population. Diabetes is also prevalent among many Native Americans. Because diabetes deprives body cells of the glucose needed to function properly, several complications can develop to further threaten the lives of victims. The de novo mutation was confirmed with Sanger sequencing in the patient and her parents.

She showed occipital plagiocephaly with frontal bossing Figure A and B. Skull frontal and lateral radiography revealed fusion of most of the sutures except coronal suture, with convolutional markings Figure D and E. She had complete cleft palate Figure C. Cholangiocarcinoma is a highly lethal cancer with limited therapeutic options.

FGFR fusions have been identified as a novel oncogenic and druggable target in a number of cancers. In addition, BGJ appeared to be superior in potency to ponatinib and dovitinib in this model. Purpose The etiology of intestinal atresia remains elusive but has been ascribed to a number of possible events including in utero vascular accidents, failure of recanalization of the intestinal lumen and mechanical compression. Another such event that has been postulated to be a cause in atresia formation is disruption in notochord development.

This hypothesis arose from clinical observations of notochord abnormalities in patients with intestinal atresias as well as abnormal notochord development observed in a pharmacological animal model of intestinal atresia. Embryos with notochord abnormalities were observed to have ectopic expression of Sonic Hedgehog Shh which in turn was postulated to be causative in atresia formation. Whole mount in situ hybridization was performed on E Sections were photographed specifically for the notochord and resulting images reconstructed in 3-D using Amira software.

Explants were harvested, fixed in formalin and photographed. The etiology of intestinal atresia remains elusive but has been ascribed to a number of possible events including in utero vascular accidents, failure of recanalization of the intestinal lumen, and mechanical compression. This hypothesis arose from clinical observations of notochord abnormalities in patients with intestinal atresias as well as abnormal notochord development observed in a pharmacologic animal model of intestinal atresia. Embryos with notochord abnormalities were observed to have ectopic expression of Sonic Hedgehog Shh , which in turn was postulated to be causative in atresia formation.

Whole-mount in situ hybridization was performed on E Embryos at each time point were harvested and sectioned for hematoxylin-eosin staining. Explants were harvested, fixed in formalin, and photographed. The epicardium serves as a source of growth factors that regulate myocardial proliferation and as a source of epicardial-derived cells EPDC , which give rise to interstitial cardiac fibroblasts and perivascular cells. These progenitors populate the compact myocardium to become part of the mature coronary vasculature and fibrous skeleton of the heart.

Little is known about the mechanisms that regulate EPDC migration into the myocardium or the functions carried out by these cells once they enter the myocardium. However, it has been proposed that cardiac fibroblasts are important for growth of the heart during late gestation and are a source of homeostatic factors in the adult. Here, we identify a myocardial to epicardial fibroblast growth factor FGF signal, mediated by FGF10 and FGFR 2 b, that is essential for movement of cardiac fibroblasts into the compact myocardium.

Inactivation of this signaling pathway results in fewer epicardial derived cells within the compact myocardium, decreased myocardial proliferation and a resulting smaller thin-walled heart. However, the functions of these molecules in trophectoderm cells TEs that lead to the formation of the blastocyst as well as the underlying mechanism have not been elucidated. The present study has demonstrated for the first time that endogenous FGF2 secreted by TEs can regulate protein expression and distribution in TEs via the FGFR 2 -mediated activation of PKC and p38, which are important for the development of expanded blastocysts.

This finding provides the first explanation for the long-observed phenomenon that only high concentrations of exogenous FGFs have effects on embryonic development, but in vivo the amount of endogenous FGFs are trace. Accordingly, inhibition of type 1 receptors for activin in neonatal mice induced uterine differentiation in vaginal epithelium by down-regulating RUNX1, whereas conditional deletion of Smad2 and Smad3 had no effect on vaginal epithelial differentiation.

The development of benign prostatic hyperplasia BPH is an androgen-dependent process which may be mediated by a number of locally produced growth factors. Finasteride, a 5alpha-reductase inhibitor, is an effective drug in the treatment of BPH, inducing regressive changes in the prostate of treated patients, even though its mechanisms of action are not yet completely elucidated. Immunohistochemistry showed strong bFGF immunoreactivity in the prostatic stroma of untreated patients, this being somewhat weaker in the epithelium.

In treated patients, epithelial immunoreactivity was practically negative, and a considerable reduction in stromal immunoreactivity was seen. FGFR1 showed a weak immunoreactivity in the stroma and in basal epithelial cells. FGFR 2 exhibited strong stromal immunoreactivity, becoming weaker in the basal epithelium. No differences were seen in the expression of both receptors between the groups of treated and untreated patients. In our opinion, finasteride may act as a negative regulator of b. SerTrp and p. Apert syndrome AS is a rare autosomal dominant disorder characterised by craniosynostosis and limb malformations, and is associated with congenital heart disease and other systemic malformations, including intellectual disability.

We report two Indonesian patients with AS, in whom molecular analysis detected p. SerTrp c. ProArg c. Although the syndrome has been frequently described, this is the first clinical report of AS confirmed by molecular analysis in Indonesia. The difference in severity of clinical features in the two patients may be consistent with a genotype-phenotype correlation of the FGFR 2 mutation.

The management of individuals with AS is best achieved within a multidisciplinary setting. However, in most developing countries, early intervention may be delayed due to late diagnosis, a lack of facilities and financial constraints. This report underpins the benefits of early diagnosis for AS management. There are several factors like angiogenesis, lymphangiogenesis, genetic alterations, mutational factors that are involved in malignant transformation of potentially malignant oral lesions PMOLs to oral squamous cell carcinoma OSCC.

Fibroblast growth factor-2 FGF-2 is one of the prototypes of the large family of growth factors that bind heparin. FGF-2 induces angiogenesis and its receptors may play a role in synthesis of collagen. FGFs are involved in transmission of signals between the epithelium and connective tissue, and influence growth and differentiation of a wide variety of tissue including epithelia. Icotinib hydrochloride, a novel inhibitor of epidermal growth factor receptor tyrosine kinase, has been approved by the State Food and Drug Administration for the treatment of advanced non-small-cell lung cancer.

Up to date, cutaneous response to icotinib is largely unknown. Here we report an uncommon lesional phenomenon in a year-old Chinese male with non-small-cell lung cancer, who received icotinib as a second-line treatment. Characteristic papulopustular rash on the chest and back was observed 4 days later. Interestingly, the rash completely spares a pre-irradiated area. Thus, the present case indicated that loss of the basal layer of proliferative cells and antigen-presenting cells Langerhans cell , as well as the down-regulation of FGFR 2 signaling in the pre-irradiated skin area, may join forces in inhibiting icotinib-associated cutaneous reactions.

To our knowledge, this is the first report of both lesional area and lesion-spared area in a Chinese male receiving treatment with a new epidermal growth factor receptor-tyrosine kinase inhibitor icotinib. The immunohistochemical reactions described here also provide new insight into the pathogenesis of epidermal growth factor receptor-tyrosine kinase inhibitor-related skin toxicities, and the role that other tyrosine kinase receptors including FGFR played in non-small-cell lung cancer. Apert syndrome AS is a common genetic syndrome in humans characterized with craniosynostosis.

Apert patients and mouse models showed abnormalities in sutures, cranial base and brain, that may all be involved in the pathogenesis of skull malformation of Apert syndrome. Our study indicates that the abnormal skull morphology of AS is caused by the combined effects of the maldevelopment in calvarias, cranial base, and brain tissue. These findings further deepen our knowledge about the pathogenesis of the abnormal skull morphology of AS, and provide new clues for the further analyses of skull phenotypes and clinical management of AS. Objectives Craniosynostosis, the premature fusion of cranial bones, has traditionally been described as a disease of increased bone mineralization.

We propose an alternative hypothesis that craniosynostosis results from abnormal tissue mineralization through the downregulation of tissue-nonspecific alkaline phosphatase TNAP enzyme downstream of activating mutations in FGFRs. Mice were sacrificed at four weeks post-natal. Serum was collected to test for alkaline phosphatase AP , phosphorus, and calcium levels. Craniofacial bone fusion and morphology was assessed by micro-computed tomography. Results Injection with the TNAP lentivirus significantly increased serum AP levels increased serum AP levels are indicative of efficient transduction and production of the recombinant protein , but results were variable and dependent upon viral lot and the litter of mice injected.

With each unit increase in AP level, the odds of lambdoid suture fusion decreased by Future studies should incorporate injection of recombinant TNAP protein, to avoid potential side effects and variable efficacy of lentiviral gene delivery. Craniosynostosis, the premature fusion of cranial bones, has traditionally been described as a disease of increased bone mineralization. We propose an alternative hypothesis that craniosynostosis results from abnormal tissue mineralization through the downregulation of tissue-non-specific alkaline phosphatase TNAP enzyme downstream of activating mutations in FGFRs.

potocki-shaffer syndrome comprehensive: Topics by gyqacyxaja.cf

Mice were sacrificed at 4 weeks postnatal. Craniofacial bone fusion and morphology were assessed by micro-computed tomography. Injection with the TNAP lentivirus significantly increased serum AP levels increased serum AP levels are indicative of efficient transduction and production of the recombinant protein , but results were variable and dependent upon viral lot and the litter of mice injected. Fibroblast growth factors FGF play a critical role in bone growth and development affecting both chondrogenesis and osteogenesis. During the process of intramembranous ossification, which leads to the formation of the flat bones of the skull, unregulated FGF signaling can produce premature suture closure or craniosynostosis and other craniofacial deformities.

Indeed, many human craniosynostosis disorders have been linked to activating mutations in FGF receptors FGFR 1 and 2, but the precise effects of FGF on the proliferation, maturation and differentiation of the target osteoblastic cells are still unclear. In this report, we studied the effects of FGF treatment on primary murine calvarial osteoblast, and on OB1, a newly established osteoblastic cell line.

We show that FGF signaling has a dual effect on osteoblast proliferation and differentiation. However, immature osteoblasts respond to FGF treatment with increased proliferation, whereas in differentiating cells FGF does not induce DNA synthesis but causes apoptosis.

When either primary or OB1 osteoblasts are induced to differentiate, FGF signaling inhibits expression of alkaline phosphatase, and blocks mineralization. Both mutations inhibited differentiation, while dramatically inducing apoptosis. Furthermore, we could also show that overexpression of FGF2 in transgenic mice leads to increased apoptosis in their calvaria.

These data provide the first biochemical analysis of FGF signaling in osteoblasts, and show that FGF can act as a cell death inducer with distinct effects in proliferating and differentiating osteoblasts. Genome-wide association study identifies novel breast cancer susceptibility loci. Easton, Douglas F. Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4, breast cancer cases and 4, controls, followed by a third stage in which 30 single nucleotide polymorphisms SNPs were tested for confirmation in 21, cases and 22, controls from 22 studies.

At the second stage, 1, SNPs were significant at the P Variants in human papillomavirus receptor and associated genes are associated with type-specific HPV infection and lesion progression of the cervix. Human papillomavirus HPV infects cervical epithelial cells through cellular membrane receptors, and then induces the initiation and progression of cervical cancer. Single nucleotide polymorphisms SNPs may impact the susceptibility and outcome of diseases, but it's still unknown whether variant in HPV receptor and associated genes is associated with type-specific HPV infection and cervical lesion progression.

Our findings suggest that HPV receptor and associated gene variants may influence the susceptibilities to HPV type-specific infection and cervical lesion progression, which might have a potential application value in cervical cancer screening and therapy. Genome-wide association studies GWAS have identified several loci as being associated with breast cancer in mostly European populations.

The polymorphism on 2q35 was associated with a statistically significant increased risk among Hispanic women OR 1. Our data replicated some of the previously reported GWAS findings. Cellulase variants. In certain embodiments the glycoside hydrolase is a variant of a family 9 glycoside hydrolase.

In certain embodiments the glycoside hydrolase is a variant of a theme B family 9 glycoside hydrolase. Expanding the mutation spectrum in Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants. Craniosynostosis, caused by the premature fusion of one or more of the cranial sutures, can be classified into non-syndromic or syndromic and by which sutures are affected.

Clinical assignment is a difficult challenge due to the high phenotypic variability observed between syndromes. We subsequently screened additional genes in the probands with no detected mutation: one duplication of the IHH regulatory region was identified in a patient with craniosynostosis Philadelphia type and five variants , four novel, were identified in the recently described TCF12, in probands with coronal or multisuture affectation. Public variant databases: liability?

Public variant databases support the curation, clinical interpretation, and sharing of genomic data, thus reducing harmful errors or delays in diagnosis. As variant databases are increasingly relied on in the clinical context, there is concern that negligent variant interpretation will harm patients and attract liability. This article explores the evolving legal duties of laboratories, public variant databases, and physicians in clinical genomics and recommends a governance framework for databases to promote responsible data sharing. Genet Med advance online publication 15 December CDKL5 variants.

Kalscheuer, Vera M. Objective: To provide new insights into the interpretation of genetic variants in a rare neurologic disorder, CDKL5 deficiency, in the contexts of population sequencing data and an updated characterization of the CDKL5 gene. Methods: We analyzed all known potentially pathogenic CDKL5 variants by combining data from large-scale population sequencing studies with CDKL5 variants from new and all available clinical cohorts and combined this with computational methods to predict pathogenicity.

Results: The study has identified several variants that can be reclassified as benign or likely benign. With the addition of novel CDKL5 variants , we confirm that pathogenic missense variants cluster in the catalytic domain of CDKL5 and reclassify a purported missense variant as having a splicing consequence. We provide further evidence that missense variants in the final 3 exons are likely to be benign and not important to disease pathology. We also use the available data to make a preliminary estimate of minimum incidence of CDKL5 deficiency. Conclusions: These findings have implications for genetic diagnosis, providing evidence for the reclassification of specific variants previously thought to result in CDKL5 deficiency.

The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6. The chromosome 10 locus was in ZNF, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1, cases and 1, controls.

The combined per allele HR of the minor allele for the novel loci rs was 0. Variants of cellobiohydrolases. Bott, Richard R. Disclosed are a number of homologs and variants of Hypocrea jecorina Ce17A formerly Trichoderma reesei cellobiohydrolase I or CBH1 , nucleic acids encoding the same and methods for producing the same.

Although causative alterations in key genes controlling gonad development have been identified, the majority of DSD cases remain unexplained. To improve the diagnosis, we screened children born with idiopathic DSD using a clinically validated array-based comparative genomic hybridization platform. Clinically relevant imbalances were found in Most anomalies Among these defects, confirmed de novo duplication and deletion events were noted on 1p The causality of defects observed in 5p The identification of risk germline rearrangements for urogenital birth defects may impact diagnosis and genetic counseling and contribute to the elucidation of the molecular mechanisms underlying the pathogenesis of human sexual development.

Chapter 4: Variant descriptions. This report documents differences between geographic variants of the FFE. Comparability of Essay Question Variants. Writing task variants can increase test security in high-stakes essay assessments by substantially increasing the pool of available writing stimuli and by making the specific writing task less predictable. A given prompt parent may be used as the basis for one or more different variants. Six variant types based on argument essay prompts from a…. Variants of glycoside hydrolases.

The present invention relates to variants of a parent glycoside hydrolase, comprising a substitution at one or more positions corresponding to positions 21, 94, , , , , , , , , , , , and of amino acids 1 to of SEQ ID NO: 2, and optionally further comprising a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, , , , , , , , , , , , , , and of amino acids 1 to of SEQ ID NO: 2 a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, , , , , , , , , , , , , , and of amino acids 1 to of SEQ ID NO: 2, wherein the variants have glycoside hydrolase activity.

The present invention also relates to nucleotide sequences encoding the variant glycoside hydrolases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences. Variants of windmill nystagmus. We report oculographic characteristics in three patients with variants of windmill nystagmus in whom the common denominator was profound visual loss due to retinal diseases. We hypothesize that windmill nystagmus is a unique manifestation of "eye movements of the blind. Assessing interactions between the associations of common genetic susceptibility variants , reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study.

Introduction Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium. Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects.

Results These analyses were applied to data for up to 26, invasive breast cancer cases and up to 32, controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar.

Conclusions The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index BMI. The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified. Cellobiohydrolase variants and polynucleotides encoding same. The present invention relates to variants of a parent cellobiohydrolase II. The present invention also relates to polynucleotides encoding the variants ; nucleic acid constructs, vectors, and host cells comprising the polynucleotides; and methods of using the variants.

Cellobiohydrolase variants and polynucleotides encoding the same. The present invention relates to variants of a parent cellobiohydrolase. The present invention also relates to polynucleotides encoding the cellobiohydrolase variants ; nucleic acid constructs, vectors, and host cells comprising the polynucleotides; and methods of using the cellobiohydrolase variants.

Variants of beta-glucosidase. The present invention relates to variants of a parent beta-glucosidase, comprising a substitution at one or more positions corresponding to positions , , , and of amino acids 1 to of SEQ ID NO: 2 or corresponding to positions , , , and of amino acids 1 to of SEQ ID NO: 70, wherein the variant has beta-glucosidase activity. The present invention also relates to nucleotide sequences encoding the variant beta-glucosidases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences. Variants of beta-glucosidases. Rare variants and cardiovascular disease.

Cardiovascular disease CVD is a leading cause of mortality and morbidity in the Western world. Large genome-wide association studies GWASs of coronary artery disease, myocardial infarction, stroke and dilated cardiomyopathy have identified a number of common genetic variants with modest effects on disease risk. Similarly, studies of important modifiable risk factors of CVD have identified a large number of predominantly common variant associations, for example, with blood pressure and blood lipid levels.

In each case, despite the often large numbers of loci identified, only a small proportion of the phenotypic variance is explained. It has been hypothesised that rare variants with large effects may account for some of the missing variance but large-scale studies of rare variation are in their infancy for cardiovascular traits and have yet to produce fruitful results. Studies of monogenic CVDs, inherited disorders believed to be entirely driven by individual rare mutations, have highlighted genes that play a key role in disease aetiology.

In this review, we discuss how findings from studies of rare variants in monogenic disease and GWAS of predominantly common variants are converging to provide further insight into biological disease mechanisms. Published by Oxford University Press. For permissions, please email: journals. Odontogenic keratocyst: a peripheral variant. Odontogenic keratocyst, which is developmental in nature, is an intraosseous lesion though on rare occasions it may occur in an extraosseous location.

The extraosseous variant is referred to as peripheral odontogenic keratocyst. Though, clinically, peripheral odontogenic keratocyst resembles the gingival cyst of adults, it has histologic features that are pathognomonic of odontogenic keratocyst. This article presents a case of this uncommon entity. Rare variants and autoimmune disease. The study of rare variants in monogenic forms of autoimmune disease has offered insight into the aetiology of more complex pathologies.

Research in complex autoimmune disease initially focused on sequencing candidate genes, with some early successes, notably in uncovering low-frequency variation associated with Type 1 diabetes mellitus. However, other early examples have proved difficult to replicate, and a recent study across six autoimmune diseases, re-sequencing 25 autoimmune disease-associated genes in large sample sizes, failed to find any associated rare variants.

The study of rare and low-frequency variation in autoimmune diseases has been made accessible by the inclusion of such variants on custom genotyping arrays e. Immunochip and Exome arrays. Whole-exome sequencing approaches are now also being utilised to uncover the contribution of rare coding variants to disease susceptibility, severity and treatment response.

Other sequencing strategies are starting to uncover the role of regulatory rare variation. Address What's this? Submit What's this? Gilbert, Rebecca; Martin, Richard M. Athene; Hamdy, Freddie C. Introduction Prostate-specific antigen PSA testing is a widely accepted screening method for prostate cancer, but with low specificity at thresholds giving good sensitivity. Removing the genetic contribution to PSA levels may improve the ability of the remaining biologically-determined variation in PSA to discriminate between high and low risk of progression within men with identified prostate cancer.

We calculated the Area under the Curve AUC to determine how well genetically corrected PSA risk scores distinguished men at high risk of progression from low risk men. Results The analysis includes men with prostate cancer Low risk: Variant Humicola grisea CBH1. The variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted.

Variant humicola grisea CBH1. DHAD variants and methods of screening. Such enzymes can result in increased production of compounds from DHAD requiring biosynthetic pathways. Also disclosed are isolated nucleic acids encoding the DHAD variants , recombinant host cells comprising the isolated nucleic acid molecules, and methods of producing butanol. Variant myopia: A new presentation? The purpose of this study is to create a clinical profile of VM.

Fourteen eyes of 14 age- and refractive error-matched participants served as controls. Potential participants underwent a comprehensive orthoptic examination followed by retinoscopy Ret , closed-field autorefractor CA , subjective acceptance SA , choroidal and retinal thickness, ocular biometry, and higher order spherical aberrations measurements. Results: In the VM eyes, a statistically and clinically significant difference was noted between the Ret and CA and Ret and SA under both cycloplegic and noncycloplegic conditions multivariate repeated measures analysis of variance, P variant myopic presentation.

These individuals have thinner choroids in the eye with variant myopic presentation compared to the fellow eyes and controls. Hypotheses and clinical implications of variant myopia are discussed. Characterization of form variants of Xenorhabdus luminescens. From Xenorhabdus luminescens XE One, which produced a red pigment and antibiotics, was luminescent, and could take up dye from culture media, was considered the primary form XE-red.

A pink-pigmented variant XE-pink differed from the primary form only in pigmentation and uptake of dye. Of the two other variants , one produced a yellow pigment and fewer antibiotics XE-yellow , while the other did not produce a pigment or antibiotics XE-white. Both were less luminescent, did not take up dye, and had small cell and colony sizes. These two variants were very unstable and shifted to the primary form after 3 to 5 days.

It was not possible to separate the primary form and the white variant completely; subcultures of one colony always contained a few colonies of the other variant. The white variant was also found in several other X. DNA fingerprints showed that all four variants are genetically identical and are therefore derivatives of the same parent. Protein patterns revealed a few differences among the four variants. None of the variants could be considered the secondary form.

The mechanism and function of this variability are discussed. Images PMID Variant Interpretation: Functional Assays to the Rescue. Classical genetic approaches for interpreting variants , such as case-control or co-segregation studies, require finding many individuals with each variant. Because the overwhelming majority of variants are present in only a few living humans, this strategy has clear limits. Fully realizing the clinical potential of genetics requires that we accurately infer pathogenicity even for rare or private variation. Many computational approaches to predicting variant effects have been developed, but they can identify only a small fraction of pathogenic variants with the high confidence that is required in the clinic.

Experimentally measuring a variant 's functional consequences can provide clearer guidance, but individual assays performed only after the discovery of the variant are both time and resource intensive. Here, we discuss how multiplex assays of variant effect MAVEs can be used to measure the functional consequences of all possible variants in disease-relevant loci for a variety of molecular and cellular phenotypes. The resulting large-scale functional data can be combined with machine learning and clinical knowledge for the development of "lookup tables" of accurate pathogenicity predictions.

A coordinated effort to produce, analyze, and disseminate large-scale functional data generated by multiplex assays could be essential to addressing the variant -interpretation crisis. Two cases of scimitar variant. The scimitar sign is characteristic of partial anomalous pulmonary venous drainage into the inferior vena cava IVC. We encountered two variant cases of scimitar sign. In one case, the scimitar vein entered both the IVC and the left atrium LA without any intracardiac shunts. Surgical repair was made by simple ligation of the scimitar vein to correct the left to right shunt.

Retrograde balloon occlusion angiography of the scimitar vein was diagnostic. In the other case, the scimitar vein showed a meandering course, and then drained into the LA without any connection with the IVC, and surgical intervention was not required. Mitochondrial DNA variants in obesity. Heritability estimates for body mass index BMI variation are high. For mothers and their offspring higher BMI correlations have been described than for fathers.

For discovery, we analyzed association in a case-control CC sample of 1, extremely obese children and adolescents and lean adult controls. For discovery, nominal association with obesity was found for the frequent allele G of m. These findings could not be confirmed independently. For two of the identified D-loop variants nominal association was detected m. Only eight controls carried the m. Though follow-up of some D-loop variants still is conceivable, our hypothesis of a contribution of variation in the exclusively maternally inherited mtDNA to the observed larger correlations for BMI between mothers and their.

Rare high-impact disease variants : properties and identifications. Although many genome-wide association studies have been performed, the identification of disease polymorphisms remains important. It is now suspected that many rare disease variants induce the association signal of common variants in linkage disequilibrium LD.

Based on recent development of genetic models, the current study provides explanations of the existence of rare variants with high impacts and common variants with low impacts. Disease variants are neither necessary nor sufficient due to gene-gene or gene-environment interactions. A new method was developed based on theoretical aspects to identify both rare and common disease variants by their genotypes. Common disease variants were identified with relatively small odds ratios and relatively small sample sizes, except for specific situations in which the disease variants were in strong LD with a variant with a higher frequency.

Rare disease variants with small impacts were difficult to identify without increasing sample sizes; however, the method was reasonably accurate for rare disease variants with high impacts. For rare variants , dominant variants generally showed better Type II error rates than recessive variants ; however, the trend was reversed for common variants.

Type II error rates increased in gene regions containing more than two disease variants because the more common variant , rather than both disease variants , was usually identified. The proposed method would be useful for identifying common disease variants with small impacts and rare disease variants with large impacts when disease variants have the same effects on disease presentation. Fibrolamellar variant of hepatocellular carcinoma. The fibrolamellar variant of hepatocellular carcinoma is a rare primary liver cancer occurring in adolescents and young adults without chronic liver disease or known risk factors.

Histologically, it is defined by lamellar bands of fibrosis surrounding well-differentiated tumor cells. Radiologic imaging typically demonstrates a large, solitary mass with calcifications and a central scar. Lymph node metastases in the porta hepatis are frequently diagnosed upon presentation. More patients with fibrolamellar carcinoma are candidates for surgical resection than those with conventional hepatocellular carcinoma, owing to their young age and absence of cirrhosis. Despite complete surgical resection, relapse rates are high, and novel therapies are needed to prevent and treat recurrent disease.

Beta-glucosidase I variants with improved properties. The present disclosure is generally directed to enzymes and in particular beta-glucosidase variants. Also described are nucleic acids encoding beta-glucosidase variants , compositions comprising beta-glucosidase variants , methods of using beta-glucosidase variants , and methods of identifying additional useful beta-glucosidase variants.

Variant Review with the Integrative Genomics Viewer. Manual review of aligned reads for confirmation and interpretation of variant calls is an important step in many variant calling pipelines for next-generation sequencing NGS data. Visual inspection can greatly increase the confidence in calls, reduce the risk of false positives, and help characterize complex events.

The Integrative Genomics Viewer IGV was one of the first tools to provide NGS data visualization, and it currently provides a rich set of tools for inspection, validation, and interpretation of NGS datasets, as well as other types of genomic data. Here, we present a short overview of IGV's variant review features for both single-nucleotide variants and structural variants , with examples from both cancer and germline datasets.

Systematic comparison of variant calling pipelines using gold standard personal exome variants. The success of clinical genomics using next generation sequencing NGS requires the accurate and consistent identification of personal genome variants. Assorted variant calling methods have been developed, which show low concordance between their calls. Hence, a systematic comparison of the variant callers could give important guidance to NGS-based clinical genomics. Recently, a set of high-confident variant calls for one individual NA has been published by the Genome in a Bottle GIAB consortium, enabling performance benchmarking of different variant calling pipelines.

We observed different biases toward specific types of SNP genotyping errors by the different variant callers. The results of our study provide useful guidelines for reliable variant identification from deep sequencing of personal genomes. Variability extraction and modeling for product variants. Fast-changing hardware and software technologies in addition to larger and more specialized customer bases demand software tailored to meet very diverse requirements.

Software development approaches that aim at capturing this diversity on a single consolidated platform often require large upfront investments, e. Alternatively, companies resort to developing one variant of a software product at a time by reusing as much as possible from already-existing product variants. However, identifying and extracting the parts to reuse is an error-prone and inefficient task compounded by the typically large number of product variants. Hence, more disciplined and systematic approaches are needed to cope with the complexity of developing and maintaining sets of product variants.

Such approaches require detailed information about the product variants , the features they provide and their relations. In this paper, we present an approach to extract such variability information from product variants. It identifies traces from features and feature interactions to their implementation artifacts, and computes their dependencies.

This work can be useful in many scenarios ranging from ad hoc development approaches such as clone-and-own to systematic reuse approaches such as software product lines. We applied our variability extraction approach to six case studies and provide a detailed evaluation. The results show that the extracted variability information is consistent with the variability in our six case study systems given by their variability models and available product variants. Synthesis of spatially variant lattices. A straightforward procedure is described here that allows many properties of the lattice to be spatially varied at the same time while producing a final lattice that is still smooth and continuous.

Properties include unit cell orientation, lattice spacing, fill fraction, and more.

Crouzon Syndrome

This adds many degrees of freedom to a design such as spatially varying the orientation to exploit directional phenomena. The method is not a coordinate transformation technique so it can more easily produce complicated and arbitrary spatial variance. The performance of the structure was confirmed through simulation and it showed virtually no scattering around the bend that would have arisen if the lattice had defects or discontinuities. The advent of next generation sequencing technology has allowed rare variant detection and association with common traits, often by investigating specific genomic regions for rare variant effects on a trait.

Although multiply correlated phenotypes are often concurrently observed in GWAS, most studies analyze only single phenotypes, which may lessen statistical power. To increase power, multivariate analyses, which consider correlations between multiple phenotypes, can be used.

However, few existing multi- variant analyses can identify rare variants for assessing multiple phenotypes. We then assessed validation of those genes by a replication study, using an independent dataset of 3, individuals. Notably, we detected the gene ZNF among five significant genes.

Overall, MAAUSS successfully conserved type 1 error rates and in many cases, had a higher power than the existing methods. This study illustrates a feasible and straightforward approach for identifying rare variants correlated with multiple phenotypes, with likely relevance to missing heritability. Histone H3 Variants in Trichomonas vaginalis. The parabasalid protist Trichomonas vaginalis is a widespread parasite that affects humans, frequently causing vaginitis in infected women.

Trichomonad mitosis is marked by the persistence of the nuclear membrane and the presence of an asymmetric extranuclear spindle with no obvious direct connection to the chromosomes. No centromeric markers have been described in T. In other eukaryotes, nucleosomes of centromeric chromatin contain the histone H3 variant CenH3. The principal aim of this work was to identify a CenH3 homolog in T. We performed a screen of the T. Three variant histone H3 proteins were identified, and the subcellular localization of their epitope-tagged variants was determined.

We propose that this variant represents the centromeric marker CenH3 and thus can be employed as a tool to study mitosis in T. Furthermore, we suggest that the peripheral distribution of CenH3 within the nucleus results from the association of centromeres with the nuclear envelope throughout the cell cycle. Histological variants of cutaneous Kaposi sarcoma. This review provides a comprehensive overview of the broad clinicopathologic spectrum of cutaneous Kaposi sarcoma KS lesions. Variants discussed include: usual KS lesions associated with disease progression i.

Involuting lesions as a result of treatment related regression are also presented. The variant call format and VCFtools. The variant call format VCF is a generic format for storing DNA polymorphism data such as SNPs, insertions, deletions and structural variants , together with rich annotations. VCF is usually stored in a compressed manner and can be indexed for fast data retrieval of variants from a range of positions on the reference genome. RAGE splicing variants in mammals. These naturally occurring isoforms are characterized by either N-terminally or C-terminally truncations and are discussed as possible regulators of the full-length RAGE receptor either by competitive ligand binding or by displacing the full-length protein in the membrane.

Accordingly, expression deregulations of the naturally occurring isoforms were supposed to have significant effect on RAGE-mediated disorders. Thereby the soluble C-truncated RAGE isoforms present in plasma and tissues are the mostly focused isoforms in research and clinics. Deregulations of the circulating levels of soluble RAGE forms were reported in several RAGE-associated pathological disorders including for example atherosclerosis, diabetes, renal failure, Alzheimer's disease, and several cancer types.

Regarding other mammalian species, the canine RAGE gene showed high similarities to the corresponding human structures indicating RAGE to be evolutionary highly conserved between both species. Due to the similarities seen in several canine and human diseases-including cancer-comparative structural and functional analyses allow the development of RAGE and ligand-specific therapeutic approaches beneficial for human and veterinary medicine. Genetic variants of ghrelin in metabolic disorders. An increasing understanding of the role of genes in the development of obesity may reveal genetic variants that, in combination with conventional risk factors, may help to predict an individual's risk for developing metabolic disorders.

Accumulating evidence indicates that ghrelin plays a role in regulating food intake and energy homeostasis and it is a reasonable candidate gene for obesity-related co-morbidities. In cross-sectional studies low total ghrelin concentrations and some genetic polymorphisms of ghrelin have been associated with obesity-associated diseases. The present review highlights many of the important problems in association studies of genetic variants and complex diseases. It is known that population-specific differences in reported associations exist. We therefore conclude that more studies on variants of ghrelin gene are needed to perform in different populations to get deeper understanding on the relationship of ghrelin gene and its variants to obesity.

Isolation of a variant of Candida albicans. During the course of Candida albicans antigen production, a variant of this organism was encountered which did not produce hyphae at 37 degrees C. Presented here are some of the characteristics of this variant. It produces hyphae at 25 degrees C on cornmeal agar and synthetic medium plus N-acetylglucosamine and Tween At 37 degrees C, it does not produce hyphae on these media, although C.

In liquid synthetic medium, this variant does not produce hyphae at 37 degrees C. After 50 to 70 h in balanced exponential-phase growth, particle size distribution was narrow, and there were no differences in the DNA, RNA, or protein content per particle in the two strains. When balanced exponential-phase cultures were brought into stationary phase, both strains contained the same amount of DNA per cell. We then performed a meta-analysis on imputed data for the TREM2 variant rs predicted to cause a R47H substitution from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease.

We genotyped the R47H variant in an additional cases and controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. There were 22 variant alleles in patients with Alzheimer's disease and 5 variant alleles in controls P variant , rs encoding R47H , showed highly significant association with Alzheimer's disease P variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease.

Funded by Alzheimer's Research UK and others. Brain calcifications and PCDH12 variants. Objective: To assess the potential connection between PCDH12 and brain calcifications in a patient carrying a homozygous nonsense variant in PCDH12 and in adult patients with brain calcifications. Results: We identified brain calcifications in subcortical and perithalamic regions in the patient with a homozygous PCDH12 nonsense variant. The calcification pattern was different from what has been observed in PFBC and more similar to what is described in in utero infections.

In patients with PFBC or BCUC, we found no protein-truncating variant and 3 rare minor allele frequency variants in 3 unrelated patients, albeit with no segregation data available. Conclusions: Brain calcifications should be added to the phenotypic spectrum associated with PCDH12 biallelic loss of function, in the context of severe cerebral developmental abnormalities. Variants modulating expression of the prostaglandin receptor 4 PTGER4 have been reported to be associated with Cohn's disease CD , but the clinical impact remains to be elucidated. We analyzed these variants in a large German inflammatory bowel disease IBD cohort and searched for a potential phenotype association.

Data were correlated to results from NOD2 genotyping and to clinical characteristics. Interestingly, the chance for developing stricturing disease behavior was enhanced if mutant alleles in both rs and NOD2 were present OR 2. No overall association to CD or UC was found for the rs variant. The PTGER4 modulating variant rs increases susceptibility for CD and might resemble a risk factor for stricturing disease behavior.

Apert Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

Beta-glucosidase variants and polynucleotides encoding same. The present invention relates to beta-glucosidase variants , e. The present invention also relates to polynucleotides encoding the beta-glucosidase variants ; nucleic acid constructs, vectors, and host cells comprising the polynucleotides; and methods of using the beta-glucosidase variants. Antoniou, Antonis C. Mateus; Greene, Mark H. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families.

These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. Visualizing the geography of genetic variants. One of the key characteristics of any genetic variant is its geographic distribution. The geographic distribution can shed light on where an allele first arose, what populations it has spread to, and in turn on how migration, genetic drift, and natural selection have acted.

Here we develop an interactive visualization tool for rapidly displaying the geographic distribution of genetic variants. Supplementary data are available at Bioinformatics online. Diseases affecting hemoglobin synthesis and function are extremely common worldwide. These variants alter hemoglobin structure and biochemical properties with physiological effects ranging from insignificant to severe.

Studies of these mutations in patients and in the laboratory have produced a wealth of information on hemoglobin biochemistry and biology with significant implications for hematology practice. More generally, landmark studies of hemoglobin performed over the past 60 years have established important paradigms for the disciplines of structural biology, genetics, biochemistry, and medicine. Here we review the major classes of hemoglobin variants , emphasizing general concepts and illustrative examples.