single gene disorders

A single gene disorder is caused by variations (or mutations) in the DNA sequence of a specific gene. The DNA changes affect the product that the gene codes for—usually a protein—causing it to be altered or missing. The features of each disorder are related to the specific gene that is affected and the job that the protein has in the body.

Some genetic disorders are so serious that children who have them are extremely sick or cannot survive after birth. Others are relatively easy to manage, and with proper care, people who have them have very fulfilling lives. The chances of a good outcome are much higher if the condition is identified soon after birth, or even before.

Single gene disorders can be inherited from parents

Because they are caused by specific gene variations, many single-gene disorders run in families. When one or both parents are carriers of a genetic disorder, they have a chance of passing it to their children—even if they themselves are healthy.

The chance of a person passing a genetic disorder to their children depends on the characteristics of the disease, including the inheritance pattern.

If someone knows that a genetic disorder runs in their family, they can have a genetic test to find out if they have disease-causing gene variations. Some people choose to be tested before having children. However, people are not always aware when their families have been affected by a genetic disorder. They may not connect it to a pregnancy loss or a baby being sick, especially if it happened a long time ago.

In some cases, single gene disorders are caused by new (also called de novo) mutations. These mutations happen during egg or sperm formation in the parents, or soon after egg and sperm come together to form an embryo. In these cases, the parents do not carry the genetic variation in their other cells, and there is little chance that they would have a second child with the same disorder. Still, the child with the disorder can pass the affected gene, and the disorder, to their children. Tracking down the genetic basis in these cases can be challenging, often requiring extensive testing.

Testing for Single Gene Disorders

For many single-gene disorders, the genetic basis is well understood, and the disease-causing gene variants can be identified with genetic testing. People are tested for two main reasons: to find out if they have a particular genetic disorder, or to find out if they are a carrier.

Making a diagnosis
A doctor may order testing for a specific disorder or set of disorders based on a person's symptoms or characteristics. If symptoms tend to appear later in life, a person may wish to be tested when they are younger, especially if they know the disorder runs in their family, and if there is something they can do to prevent or delay resulting medical problems.

Many genetic disorders are identified in newborn babies through newborn genetic screening, even before symptoms appear. Many of the newborn screening tests look at chemicals in the blood that are signs of a disorder. A positive screening result is usually followed by genetic testing on a DNA sample.

Identifying carrier status
Genetic testing can also reveal whether a person is a carrier of a genetic disorder. A carrier does not have the disorder themselves, but they have an increased risk of having a child with the disorder.

Increasingly commonly, even people with no known family history of a genetic disorder learn of their carrier status through genetic testing before they try to have children. Some doctors and genetic counselors recommend specific genetic tests based on their patients' ethnic backgrounds. However, for many reasons, they are becoming more likely to recommend expanded carrier screening—a single test that looks at dozens of genes. And direct-to-consumer genetic testing kits provide some information about carrier status for some of the most common causes of genetic disorders.

Carriers of a genetic disorder who wish to have a child can use preimplantation genetic testing to greatly increase their chances of having a healthy baby.

Inheritance Patterns for Single Gene Disorders

A mode of inheritance, or inheritance pattern, describes how a disorder passes from parents to children. Single gene disorders have different modes of inheritance. A genetic disorder’s inheritance pattern is influenced by three things:

The type of chromosome the disease-causing gene is located on;
he job of the gene product; and
the how the changes to the gene affect the gene product.

A mode of inheritance, or inheritance pattern, describes how a disorder passes from parents to children.

1. Type of Chromosome

Disorders caused by genes on the autosomes follow an autosomal inheritance pattern. Disorders caused by genes on the sex chromosomes follow a sex-linked inheritance pattern. Most sex-linked genetic disorders are caused by genes on the X chromosome; they are also called X-linked.

Genes on the autosomes come in pairs. One copy comes from each parent, and protein product is made from both. For people with two X chromosomes (generally female), genes on the sex chromosomes also come in pairs. But for people with one X chromosome and one Y chromosome (generally male), there is just one copy of each gene on the sex chromosomes. This difference between XX and XY individuals influences the inheritance pattern of genes on the sex chromosomes.

2. Job of the protein product

Each gene codes for a protein that has a different job in the body. Protein A and protein B have different jobs. So a change to protein A will have a different effect than a change to protein B, and it may also affect the inheritance pattern.

Changes (or variations) in the gene can change the protein that the gene codes for. For example, the protein may have a different shape, there may be more (or less) protein made, or there may be no protein made at all. Each of these changes can not only have a different effect, but they can also cause a different inheritance pattern for the disorder.

Autosomal dominant inheritance
Genetic disorders that follow this inheritance pattern are caused by genes on the autosomes, which are the non-sex chromosomes. People inherit two copies of each autosome: one from each parent. There are 22 autosomes in all, so they account for most of our genes.

Dominant means that a person will have the genetic disorder if they have just one disease-causing copy of a gene. "Dominance" has nothing to do with how a gene is inherited, but with the function of the specific product it codes for.

With a dominant inheritance pattern, genetic disorders pass from an affected parent to an affected child. With some genetic disorders, including Huntington Disease, symptoms appear later in life, often after a person has already had children.

Families affected by these disorders tend to be well aware of them. Some seek out genetic testing for themselves before they have children.

Autosomal recessive inheritance
Genetic disorders that follow this inheritance pattern are caused by genes on the autosomes.

Recessive means that the disorder is caused by having two disease-causing copies of a gene. One copy must be inherited from each parent. A person with just one disease-causing allele does not have the disorder, but they are a "carrier." A carrier has an increased risk of having a child with the disorder. For a child to have the disorder, both parents must be either carriers or affected.

Most disorders that follow a recessive inheritance pattern are caused by having non-working copies of a gene. That is, no protein product is made from the gene, or the protein product is made but it is altered so that it cannot do its job. Often a person who has one working copy can still make enough of the protein product so that they have no effects. But having no functional copies of the gene causes the effects of the disorder.

Many of the people who are carriers do not know that a genetic disorder is even an issue in their family. Few seek out genetic testing for themselves before they have children. And those who learn that they are carriers have the tricky task of deciding what to do with that information. Should they tell other family members, who may also be carriers? How should they tell them?

Semi-dominant inheritance
A disorder with a semi-dominance inheritance pattern is somewhere between dominant and recessive. Having two non-functional copies of the gene causes the full-blown disorder. But having one non-functional copy causes a less severe form.

Sometimes one genetic disorder can have more than one inheritance pattern. This is because the gene that causes it may be affected in different ways. The type of inheritance pattern depends on the specific changes to the gene and the gene product.

X-linked inheritance
X-linked genetic disorders are caused by genes on the X chromosome. X and Y are the sex chromosomes, and they specify whether a person is female (usually XX) or male (usually XY). Genetic disorders with an X-linked inheritance pattern affect males and females differently.

Like autosomal disorders, X-linked genetic disorders can follow dominant or recessive inheritance patterns. Most X-linked genetic disorders are recessive. Dominant ones are rare: one of the parents would also have the disorder, and people with these disorders rarely have children.

For X-linked recessive disorders, males are affected much more often than females. To have the disorder, males need just one copy of the gene variation—which they inherit from their mothers. The mothers are unaffected carriers. This pattern comes about because males have a single X chromosome, which comes from their mother (their Y chromosome comes from their father). Since females inherit two X chromosomes, one from each parent, they usually have one functional copy of the gene.

Though it happens rarely, a girl can end up with a disorder if she inherits two non-functioning copies of a gene—one from a carrier mother and one from an affected father.

There are two rare exceptions to this pattern. Girls with Turner syndrome, who have just one X chromosome, are more susceptible to X-linked disorders. And XXY boys, who have two X chromosomes, are less susceptible.

Most families affected by these disorders are well aware of them. Some seek out genetic testing for themselves before they have children.

What is Alzheimer's disease?

Alzheimer's is a disease that causes dementia, or loss of brain function. It affects the parts of the brain that are important for memory, thought, and language.

The brain of a person with Alzheimer's contains abnormal clumps of cellular debris and protein (plaques) and collapsed microtubules (support structures inside the cell). Microtubule collapse is caused by a malfunctioning protein called tau, which normally stabalizes the microtubules. In Alzheimer's patients, tau proteins instead cluster together to form disabling plaques and tangles. These plaques and tangles damage the healthy cells around them, leading to cell death. The brain also produces smaller amounts of neurotransmitters (acetylcholine, serotonin, and norepinephrine), chemicals that allow nerve cells to talk to one another.

The most common form of the disease, which strikes after age 65, Scientists don't know how apoE4 increases the risk of developing Alzheimer's. They do know that everyone has apoE, which comes in three forms.

One of the forms (apoE4) increases a person's risk of developing Alzheimer's. The other two forms seem to protect against the disease. While people who inherit the apoE4 form of the gene are at increased risk for the disease, they will not necessarily develop it.

Mutations in genes found on chromosomes 1, 14, and 21 are linked to rarer forms of the disease, which strike earlier in life.

How do people get Alzheimer's disease?

Scientists don't know exactly how people develop Alzheimer's, but they believe it is caused by a combination of genes and environmental factors. In other words, it is a multifactorial disorder.

The early-onset forms of Alzheimer's are inherited in an autosomal dominant pattern, which means that only one parent has to pass down a defective copy of the gene for their child to develop the disorder.

What are the symptoms of Alzheimer's disease?

Because Alzheimer's destroys brain cells, people who have the disorder slowly lose their ability to think clearly. At first, they may forget words or names, or have trouble finding things. As the disorder worsens, they may forget how to do simple tasks, such as walking to a friend's house or brushing their hair. Some people with Alzheimer's also feel nervous or sad.

How do doctors diagnose Alzheimer's disease?

There is no single test for Alzheimer's. Doctors use several different tests to check a patient's memory, language skills, and problem solving abilities. These tests don't diagnose Alzheimer's, but they can rule out other disorders that have similar symptoms.

How is Alzheimer's disease treated?

There is no cure for Alzheimer's, but a few medicines can slow its symptoms. A drug called Aricept increases the amount of the neurotransmitter acetylcholine in the brain. Another medicine, Namenda, protects brain cells from a chemical called glutamate, which can damage nerve cells. Doctors may also give their Alzheimer's patients antidepressants or anti-anxiety medicines to ease some of their symptoms.

People with Alzheimer's often need a care giver someone to help them do the things they were once able to do themselves.

Interesting facts about Alzheimer's disease

Alzheimer's was named after the German doctor, Alois Alzheimer, who first named the disorder in 1906.

The older a person gets, the higher his or her risk of getting Alzheimer's. Only about 1 or 2 people out of 100 have Alzheimer's at age 65; whereas, one out of every five people has the disorder by age 80.

As many as 4 million Americans have Alzheimer's disease.

What is breast cancer and ovarian cancer?

Cells normally grow and divide just enough to grow or to replace damaged tissue. But sometimes the mechanisms that regulate cell growth stop working and cells divide out of control. This out-of-control growth is called cancer. Cancer that develops in breast or ovarian tissue is called breast or ovarian cancer, respectively.

Most people who develop breast or ovarian cancer have no history of the disease in their family. In fact, only 5 to 10 percent of all breast and ovarian cancers are caused by inherited genetic factors. These rare cases typically result from inherited mutations in either the BRCA1 or BRCA2 gene.

BRCA1 and BRCA2 are called tumor suppressor genes, because they control cell growth. BRCA1 is located on chromosome 17, and BRCA2 on chromosome 13. Scientists believe BRCA1 and BRCA2 work by fixing damaged or broken DNA. Women who inherit a mutated copy of the BRCA1 or BRCA2 gene accumulate broken and deformed chromosomes, and therefore have a greater chance of accumulating mutations that will lead to uncontrolled cell growth and cancer. Men who inherit the defective genes are also more likely to develop breast and/or prostrate cancer. (Yes, men can get breast cancer.)

How do people get breast or ovarian cancer?

High-risk families include those whose members carry a mutation in either the BRCA1 or BRCA2 gene. The mutated BRCA1 and BRCA2 genes are inherited in an autosomal dominant pattern. A child needs to inherit just one copy of the mutated gene to have an increased cancer risk. Children who have a parent with a BRCA1 or BRCA2 mutation have a 1 in 2 chance of inheriting the mutation.

Just because a person inherits the defective gene does not mean he or she will develop cancer, but inheritance greatly increases the risk. Out of every 100 women who inherit a mutated BRCA1 or BRCA2 gene, as many as 60 will develop breast cancer by age 50; by age 70, approximately 80 will develop breast cancer.

How do doctors test for BRCA1 and BRCA2 mutations?

A person with a strong family history of breast or ovarian cancer is a candidate for genetic screening. By analyzing a sample of the patient's blood, doctors can identify whether the person has inherited a BRCA1 or BRCA2 mutation. The test cannot tell if or when the person will develop breast or ovarian cancer; it can only tell if he or she is at risk because of the faulty gene.

What can a woman do if she inherits these mutations?

Some women who discover that they've inherited a mutated BRCA1 or BRCA2 gene undergo special treatments to protect themselves from breast and ovarian cancer. They can start having mammograms at a younger age to screen for abnormal cell growth in the breasts (most women start having mammograms at age 40).

They may choose to have their breasts and/or ovaries removed, even before cancer begins. And they may take the medicine tamoxifen, which is believed to protect against breast cancer.

Interesting facts about breast and ovarian cancer

The progression from a benign to a malignant cancer typically requires multiple mutations that allow cells to acquire new and abnormal characteristics, such as an increased growth rate, inability to adhere or stick to neighboring cells, propensity to migrate to other places in the body, etc. Genes involved in the repair of DNA damage (such as BRCA1 and BRCA2) are often associated with cancer. This is because they allow mutations to accumulate at a much faster rate.

Usually, people inherit one of several hundred different mutations of the BRCA1 and BRCA2 genes. But for some reason, Eastern European (Ashkenazi) Jews seem to inherit only three of these different mutations. Ashkenazi Jews are also 10 times more likely to have mutations in the BRCA1 and BRCA2 genes than any other ethnic group.

What is colon cancer?

Cells normally grow and divide just enough to grow or to replace damaged tissue. But sometimes, the mechanisms that regulate cell growth stop working and cells divide out of control. This out-of-control growth is called cancer. Cancer that develops in the cells lining the colon (the first part of the large intestine), is called colon cancer.

People who have a history of colon cancer in their family are at greater risk of getting the disease themselves. The risk increases when a relative has had the disease before age 50. People in these families are considered high-risk, because they may have inherited one of two rare genetic conditions: FAP (familial adenomatous polyposis) or HNPCC (hereditary non-polyposis colon cancer).

FAP is caused by mutations of the APC (adenomatous polyposis coli) gene on chromosome 5. APC is a tumor suppressor gene, which means that it controls cell growth. People who inherit a mutated form of this gene develop growths called polyps in their colon. By age 15, they may have hundreds of these polyps. Polyps are not cancerous at first, but if they aren't treated, they will develop into colon cancer.

HNPCC (also called Lynch syndrome) is caused by mutations in one of several genes that fix damaged DNA. People who inherit one of these mutations have a much greater risk of accumulating mutations that will lead to uncontrolled cell growth and cancer.

How do people get colon cancer?

FAP and HNPCC are both inherited in an autosomal dominant pattern. If a parent has FAP or HNPCC, his or her children have a 1 in 2 chance of inheriting the mutated gene. A person who inherits a defective gene will not necessarily develop a malignant cancer. However, the APC gene strikingly predisposes one to colon cancer. People who inherit one bad copy of the APC gene are practically guaranteed to develop colon cancer by age 40. Similarly, people who inherit one bad copy of a gene associated with HNPCC have an 80 percent chance of getting colon cancer. HNPCC also increases a person's risk of developing other cancers, including ovarian, stomach, brain, and liver.

What are the symptoms of colon cancer?

Colon cancer affects the stomach and bowels. Common symptoms include diarrhea or constipation, blood in the stool, vomiting, bloating, cramps, and unexplained weight loss.

How do doctors diagnose colon cancer?

Even before a patient shows symptoms of colon cancer, his or her doctor can screen for the disease using one of several tests:

Fecal Occult Blood Test (FOBT) - Colon cancer can sometimes cause tiny dots of blood, too small for the eye to see, in the feces. The FOBT test uses a chemical to check the patient's stool sample for these traces of blood.
Flexible-Sigmoidoscopy - Using a thin flexible tube called a simoidoscope, the doctor looks inside the patient's colon for growths called polyps.
Double Contrast Barium Enema (DCBA) - A silvery-white metallic substance called barium is inserted into the patient's colon through the rectum. The barium outlines the patient's colon on an x-ray screen.
Colonoscopy - Using a thin instrument called a colonoscope, the doctor looks inside the patient's colon. During the procedure, the doctor removes pieces of tissue (called a biopsy) to test them for cancer. If the doctor finds any polyps, he or she can also remove them. A newer method, called virtual colonoscopy, looks at the colon without going into the body, with an MRI or CT scan.
DNA-Based stool test - This test examines DNA taken from a patient's stool sample to look for genetic defects associated with colon cancer.

How is colon cancer treated?

Colon cancer is very treatable. In fact, about 90 percent of patients survive the disease after treatment. First, doctors stage the disease to see how far it has progressed. If the cancer has not spread to other tissues of the body, it can be treated with chemicals (chemotherapy) or radiation (powerful x-rays) to kill all rapidly dividing cells in the body, including cancer cells or surgery to remove the polyps and/or cancerous part of the colon

Interesting facts about colon cancer

People who have FAP can develop hundreds and even thousands of polyps, whereas people with HNPCC develop relatively few.

The progression from a benign to a malignant cancer typically requires multiple mutations that allow cells to acquire new and abnormal characteristics, such as an increased growth rate, inability to adhere or stick to neighboring cells, and propensity to migrate to other places in the body. At least seven mutations are required to produce a malignant colon tumor.

Inherited cancers often provide clues about the genes mutated in non-inherited (sporadic) cancers. For example, mutations in the APC gene are found not only in FAP tumors but in 85% of all sporadic colon tumors as well.

What is hypothyroidism?

The thyroid is the largest endocrine gland in the body. It sits just below the larynx (voice box) and wraps around the trachea (windpipe). The thyroid gland produces thyroid hormone, which helps the body grow and develop. It also plays an important role in the body's metabolism (the processes in the body that use energy, such as eating, breathing, and regulating heat).

Hypothyroidism (or underactive thyroid) is a common condition in which the thyroid gland makes too little thyroid hormone. About 1 in 5,000 babies is born with congenital hypothyroidism, in which the thyroid fails to grow normally and cannot produce enough hormone. There is no known cause for most cases of congenital hypothyroidism. But about 10 to 20 percent of the time, the condition is caused by an inherited defect that alters the production of thyroid hormone.

The most common inherited form of hypothyroidism is a defect of the TPO (thyroid peroxidase) gene on chromosome 2. This gene plays an important role in thyroid hormone production.

How do people get hypothyroidism?

Hypothyroidism may be caused by (1) an autoimmune disease that attacks the thyroid gland, (2) surgery or radiation to treat thyroid cancer and other conditions, or (3) rare and random genetic events in which a mutation is acquired during early embryonic development.

What are the symptoms of hypothyroidism?

In babies with the inherited form of hypothyroidism, the condition affects growth and cognitive development. It may cause intellectual disability, delayed puberty, stunted growth, and ataxia (uncoordinated muscle movements).

In adults, hypothyroidism slows the body's metabolism, making the patient feel mentally and physically sluggish. Symptoms may include weakness, fatigue, muscle aches, mood swings, hair loss, memory loss, or slow speech. A person's symptoms will depend upon how little thyroid hormone they make, and for how long they have had the disorder.

When the body has too little thyroid hormone, the pituitary gland works overtime, making extra thyroid-stimulating hormone (TSH). Having too much TSH may enlarge the thyroid, forming a goiter.

How do doctors diagnose hypothyroidism?

Babies are normally screened for hypothyroidism 24 hours after birth. A tiny sample of blood taken from the baby's heel is tested for low thyroid hormone levels or high thyroid-stimulating hormone (TSH) levels.

How is hypothyroidism treated?

Hypothyroidism is treated with hormone replacement therapy: people with hypothyroidism must take a synthetic form of thyroid hormone every day to reduce their symptoms. When treatment is started right away, babies develop normally.

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