Genomic resource centre

Genes and human disease


Monogenic diseases

Monogenic diseases result from modifications in a single gene occurring in all cells of the body. Though relatively rare, they affect millions of people worldwide. Scientists currently estimate that over 10,000 of human diseases are known to be monogenic. Pure genetic diseases are caused by a single error in a single gene in the human DNA. The nature of disease depends on the functions performed by the modified gene. The single-gene or monogenic diseases can be classified into three main categories:

  • Dominant
  • Recessive
  • X-linked

All human beings have two sets or copies of each gene called “allele”; one copy on each side of the chromosome pair. Recessive diseases are monogenic disorders that occur due to damages in both copies or allele. Dominant diseases are monogenic disorders that involve damage to only one gene copy. X linked diseases are monogenic disorders that are linked to defective genes on the X chromosome which is the sex chromosome. The X linked alleles can also be dominant or recessive. These alleles are expressed equally in men and women, more so in men as they carry only one copy of X chromosome (XY) whereas women carry two (XX).

Monogenic diseases are responsible for a heavy loss of life. The global prevalence of all single gene diseases at birth is approximately 10/1000. In Canada, it has been estimated that taken together, monogenic diseases may account for upto 40% of the work of hospital based paediatric practice (Scriver, 1995).

Thalassaemia
Sickle cell anemia
Haemophilia
Cystic Fibrosis
Tay sachs disease
Fragile X syndrome
Huntington's disease


Thalassaemia

Thalassaemia is a blood related genetic disorder which involves the absence of or errors in genes responsible for production of haemoglobin, a protein present in the red blood cells. Each red blood cell can contain between 240 and 300 million molecules of haemoglobin. The severity of the disease depends on the mutations involved in the genes, and their interplay.

A haemoglobin molecule has sub-units commonly referred to as alpha and beta. Both sub-units are necessary to bind oxygen in the lungs properly and deliver it to tissues in other parts of the body. Genes on chromosome 16 are responsible for alpha subunits, while genes on chromosome 11 control the production of beta subunits. A lack of a particular subunit determines the type of thalassaemia (eg. a lack of alpha subunits results in alpha-thalassemia). The lack of subunits thus corresponds to errors in the genes on the appropriate chromosomes.

There can be various gradations of the disease depending on the gene and the type of mutations.

Prevalence:

The alpha and beta thalassaemias are the most common inherited single-gene disorders in the world with the highest prevalence in areas where malaria was or still is endemic. The burden of this disorder in many regions is of such a magnitude that it represents a major public health concern. For example in Iran, it is estimated that about 8,000 pregnancies are at risk each year. In some endemic countries in the Mediterranean region, long-established control programs have achieved 80-100% prevention of newly affected births.

Diagnosis/ prognosis:

Diagnosis of thalassaemia can be made as early as 10-11 weeks in pregnancy using procedures such as amniocentesis and chorionic villi sampling. Individuals can also be tested for thalassaemia through routine blood counts. Thalassaemic patients may have reduced fertility or even infertility. Early treatment of thalessaemia has proved to be very effective in improving the quality of life of patients. Currently, genetic testing and counselling, and prenatal diagnosis play an increasingly important role in informing individual as well as professional decisions around the prevention, management and treatment of this disease.

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Sickle cell anemia

Sickle-cell anemia is a blood related disorder that affects the haemoglobin molecule, and causes the entire blood cell to change shape under stressed conditions. In sickle cell anaemia, the haemoglobin molecule is defective. After haemoglobin molecules give up their oxygen, some may cluster together and form long, rod-like structures which become stiff and assume sickle shape.

Unlike healthy red blood cells, which are usually smooth and donut-shaped, sickled red blood cells cannot squeeze through small blood vessels. Instead, they stack up and cause blockages that deprive organs and tissues of oxygen-carrying blood. This process produces periodic episodes of pain and ultimately can damage tissues and vital organs and lead to other serious medical problems. Normal red blood cells live about 120 days in the bloodstream, but sickled red cells die after about 10 to 20 days. Because they cannot be replaced fast enough, the blood is chronically short of red blood cells, leading to a condition commonly referred to as anemia.

Prevalence:

Sickle cell anemia affects millions throughout the world. It is particularly common among people whose ancestors come from Sub-Saharan Africa, South America, Cuba, Central America, Saudi Arabia, India, and Mediterranean countries such as Turkey, Greece, and Italy. In the Unites States, it affects around 72,000 people, most of whose ancestors come from Africa. The disease occurs in about 1 in every 500 African-American births and 1 in every 1000 to 1400 Hispanic-American births. About 2 million Americans, or 1 in 12 African Americans, carry the sickle cell allele.

Diagnosis/ prognosis:

The sickle cell disease can be diagnosed in a simple blood test. In many cases, sickle-cell anemia is diagnosed when new-borns are screened. Vaccines, antibiotics, and folic acid supplements are administered, in addition to pain killers. Blood transfusions and surgery are used in severe cases. The only known cure at present is a bone marrow transplant.

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Haemophilia

Haemophilia is a hereditary bleeding disorder, in which there is a partial or total lack of an essential blood clotting factor. It is a lifelong disorder, that results in excessive bleeding, and many times spontaneous bleeding, which, very often , is internal. Haemophilia A is the most common form, referred to as classical haemophilia. It is the result of a deficiency in clotting factor 8, while haemophilia B (Christmas Disease) is a deficiency in clotting factor 9. This illness is a sex-linked recessive disorder.

Prevalence:

Due to the sex-linkage of the disorder, there is a greater prominence in males than in females. About a third of new diagnoses are where there is no previous family history. It appears world-wide and occurs in all racial groups. About 6,000 people are affected with haemophilia in the UK. There are about 5400 people in the UK with haemophilia A and about 1100 with haemophilia B.

Diagnosis/ prognosis:

Blood tests can determine the presence of the haemophilia condition, and more specifically whether it is a type A or a type B disease. Usually, infants do not show signs before 9 months of age. Administration of clotting factors help affected individuals to live with the disease. There are various lifestyle changes that one can make as a haemophiliac, and though a serious disease, it can be tolerable with proper precautions and therapy. The prospects for youngster with haemophilia are excellent. Only a few decades ago, children with haemophilia had a significantly reduced life expectancy. They were often crippled with arthritis and joint deformity by their teens and had to attend special schools for disabled people. Many recent studies have documented a greatly increased life-expectancy among people suffering from haemophilia in developed countries over the last few decades. Children with haemophilia now face few limitations. They certainly attend normal schools, most jobs are open to them, and full participation in society through employment, marriage and having children is now the norm. It is anticipated, however, that the number of people with haemophilia in developed countries will increase steadily over the next few decades

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Cystic Fibrosis

Cystic Fibrosis is a genetic disorder that affects the respiratory, digestive and reproductive systems involving the production of abnormally thick mucus linings in the lungs and can lead to fatal lung infections. The disease can also result in various obstructions of the pancreas, hindering digestion. An individual must inherit two defective cystic fibrosis genes, one from each parent, to have the disease. Each time two carriers of the disease conceive, there is a 25 percent chance of passing cystic fibrosis to their children ; a 50 percent chance that the child will be a carrier of the cystic fibrosis gene; and a 25 percent chance that the child will be a non-carrier.

Prevalence:

The incidence of CF varies across the globe. Although it is severely underdiagnosed in Asia, existing evidence indicates that the prevelance of CF is rare. In the European Union 1 in 2000-3000 new borns is found to be affected by CF . In the United States of America the incidence of CF is reported to be 1 in every 3500 births.

Diagnosis/ prognosis:

People with CF have a variety of symptoms including: very salty-tasting skin; persistent coughing, at times with phlegm; wheezing or shortness of breath; an excessive appetite but poor weight gain; and greasy, bulky stools. Symptoms vary from person to person, in part, due to the more than 1,000 mutations of the CF gene, several of which have been identified and sequenced by researchers.The sweat test is the standard diagnostic test for CF. This simple and painless procedure measures the amount of salt in the sweat. A high salt level indicates CF. Although the results of this test are valid any time after a baby is 24 hours old, collecting a large enough sweat sample from a baby younger than 3 or 4 weeks old may be difficult. The sweat test can also confirm the diagnosis in older children and adults. If pancreatic enzyme levels are reduced, an analysis of the person's stool may reveal decreased or absent levels of the digestive enzymes (trypsin and chymotrypsin) or high levels of fat. If insulin secretion is reduced, blood sugar levels are high. Pulmonary function tests may show that breathing is compromised. Also, a chest x-ray may suggest the diagnosis. Relatives other than the parents of a child with cystic fibrosis may want to know if they're likely to have children with the disease. Genetic testing on a small blood sample can help determine who has a defective cystic fibrosis gene. Unless both parents have at least one such gene, their children will not have cystic fibrosis. If both parents carry a defective cystic fibrosis gene, each pregnancy has a 25 percent chance of producing a child with cystic fibrosis. During pregnancy, an accurate diagnosis of cystic fibrosis in the fetus is usually possible.

The severity of cystic fibrosis varies greatly from person to person regardless of age; the severity is determined largely by how much the lungs are affected. However, deterioration is inevitable, leading to debility and eventually death. Nonetheless, the outlook has improved steadily over the past 25 years, mainly because treatments can now postpone some of the changes that occur in the lungs. Half of the people with cystic fibrosis live longer than 28 years. Long-term survival is somewhat better in males, people who don't have pancreatic problems, and people whose initial symptoms are restricted to the digestive system. Despite their many problems, people with cystic fibrosis usually attend school or work until shortly before death. Gene therapy holds great promise for treating cystic fibrosis.

According to the CF Foundation's National Patient Registry, the median age of survival for a person with CF is currently 33.4 years. Only thirty years ago, a CF patient was not expected to reach adulthood. Many people even live into their fifties and sixties.

As more advances have been made in the treatment of CF, the number of adults with CF has steadily grown. Today, nearly 40 percent of the CF population is age 18 and older. Adults, however, may experience additional health challenges including CF-related diabetes and osteoporosis. CF also can cause reproductive problems - more than 95 percent of men with CF are sterile. But, with new technologies, some are becoming fathers. Although many women with CF are able to conceive, limited lung function and other health factors may make it difficult to carry a child to term.

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Tay sachs disease

Tay-Sachs disease is a fatal genetic disorder in which harmful quantities of a fatty substance called Ganglioside GM2 accumulate in the nerve cells in the brain. This is caused by a decrease in the functioning of the Hexosaminidase A enzyme. Abnormal Hexosaminidase A enzyme activity causes an accumulation of fat in nerve cells, leading to paralysis, dementia, blindness, psychoses, and even death. Though the degradation of the central nervous system begins at the fetal stage, observations such as loss of peripheral vision and motor co-ordination are not seen until about 6 months of age. This disease is autosomal recessive which means that an individual must inherit two defective genes, one from each parent, to inherit this disease. According to the age of onset there are two existing forms of Tay-Sachs disease.

  • Infantile Tay-Sachs disease
  • Late onset Tay-Sachs disease ( chronic GM2-gangliosidosis)

Prevalence:

The frequency of the condition is much higher in in Ashkenazi Jews of Eastern European origin than in others.

Approximately one in every 27 Jews in the United States of America is a carrier of the TSD gene. There is also a noticeable incidence of TSD in non-Jewish French Canadians living near the St. Lawrence River and in the Cajun community of Louisiana. By contrast, the carrier rate in the general population as well as in Jews of Sephardic origin is about one in 250.

Among Jews of Sephardic origin and in the general, non-Jewish population, the carrier rate is about 1 in 250. There are certain exceptions. French-Canadian and the Cajun community of Louisiana have the same carrier rate as Ashkenazi Jews, one in 27. Also, individuals with ancestry from Ireland are at increased risk for the Tay-Sachs gene. Current research indicates that among Irish Americans, the carrier rate is about one in 50.

Diagnosis/ prognosis:

The diagnosis for Tay- Sachs disease (TSD) can be made via a blood test in which the Hex A enzyme can be measured in either the serum, the white blood cells, or in the skin fibroblast. Over the past 25 years, carrier screening and genetic counselling within high-risk populations have greatly reduced the number of children born with TSD in these groups. Therefore, a great percentage of the babies born with Tay-Sachs Disease today are born to couples who were not previously thought to be at significant risk.

Prenatal tests that can diagnose Tay-Sachs in the fetus before birth are available. These procedures are referred to as Amniocentesis and Chorionic Villus Sampling. Amniocentesis sampling is performed between the 15th and 16th week of pregnancy. The procedure involves inserting a needle into the mother's abdomen and obtaining a sample of the fluid that surrounds the baby. In Chorionic Villus Sampling a sample of cells from the placenta is retrieved by the doctor during the 10th and 12th week of pregnancy, and tested for the presence of Hex A.

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Fragile X syndrome

The Fragile X syndrome is caused by a "fragile" site at the end of the long arm of the X-chromosome. It is a genetic disorder that manifests itself through a complex range of behavioural and cognitive phenotypes. It is the result of genetic mutation which varies considerably in severity among patients. Fragile X syndrome is the most common cause of inherited mental retardation. Although it is a X-linked recessive trait with variable expression and incomplete penetrance, 30% of all carrier women are affected.

Prevalence:

According to the Fragile X association of Southern California, Fragile X syndrome is the single most common inherited cause of mental impairment affecting 1 in 3600 males and 1 in 4000 to 6000 females with full mutation worldwide. Some studies also suggest that fragile X affects 1 in every 2000 males and 1 in every 4000 females of all races and ethnic groups. Studies have also revealed that 1 in 259 women of all races carry fragile X and could pass it to their children. The number of men who are carriers is thought to be 1 in 800 of all races and ethnicity. Carrier females have a 30% to 40>% chance of giving birth to a retarded male child and a 15 to 20% chance of having a retarded female.

Diagnosis/ prognosis:

The diagnosis of Fragile-X syndrome is made through the detection of errors in the FMR1 gene. Over 99% of individuals have a full mutant FMR1 gene. Tests used for diagnosis include chromosome analysis and various protein tests. Diagnosis is usually made when young, and there is no current cure for this illness. Early diagnosis of the syndrome call allow for therapeutic interventions like speech therapy, occupational therapy, psychotherapy and special education, that can considerably improve the quality of the patients' life.

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Huntington's disease

Huntington’s disease is a degenerative brain disorder, in which afflicted individuals lose their ability to walk, talk, think, and reason. They easily become depressed, and lose their short-term memory capacity. They may also experience a lack of concentration and focus. This disease begins between ages 30-45, and every individual with the gene for the disease will eventually develop the disease. Huntington's is an autosomal dominant genetic disorder which means that if one parent carriers the defective Huntington's gene, his/her offspring have a 50/50 chance of inheriting the disease.

Prevalence:

Huntington's disease (HD) affects males and females equally and crosses all ethnic and racial boundaries. It typically begins in mid-life, between the ages of 30 and 45, though onset may occur as early as the age of 2. Children who develop the juvenile form of the disease rarely live to adulthood. There is a 50/50 chance of inheriting the fatal gene from the parents. Everyone who carries the gene will develop the disease. In Western countries, it's estimated that about five to seven people per 100,000 are affected by HD.

Diagnosis/ prognosis:

There is no treatment or cure for Huntington’s Disease, and the patient eventually becomes completely dependent on others for daily functioning. Individuals may also die due to other secondary complications such as choking, infection, or heart failure. Children who are diagnosed with Huntington’s Disease do not usually live to reach adulthood.

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