Genetic Disorders

Genetic disorders also are grouped by how they run in families. Disorders can be dominant or recessive, depending on how they cause conditions and how they run in families.

Dominant diseases can be caused by only one copy of a gene having a DNA mutation. If one parent has the disease, each child has a 50 percent chance of inheriting the mutated gene.

For recessive diseases, both copies of a gene must have a DNA mutation in order to get one of these diseases. If both parents have one copy of the mutated gene, each child has a 25 percent chance of having the disease, even though neither parent has it. In such cases, each parent is called a carrier of the disease. They can pass the disease on to their children, but do not have the disease themselves.

Some genetic diseases are caused by a DNA mutation in one of a person’s genes. For example, suppose part of a gene usually has the sequence TAC. A mutation can change the sequence to TTC in some people. This change in sequence can change the way that the gene works, such as by changing the protein that is made. Mutations can be passed down to a child from their parents. Or, they can happen for the first time in the sperm or egg, so that the child will have the mutation but the parents will not. Single gene disorders can be autosomal or X-linked.

Sickle cell disease is an autosomal single gene disorder. It is caused by a mutation in a gene found on chromosome 11. Sickle cell disease causes anemia and other complications. Fragile X syndrome, on the other hand, is an X-linked single gene disorder. It is caused by a change in a gene on the X chromosome. It is the most common known cause of intellectual disability and developmental disability that can be inherited (passed from one generation to the next).

While there is no one cause of genetic disorders, many of them are hereditary and passed from one generation to the next. There are certain risk factors that can cause a baby to develop a genetic disorder during gestation: 
 

• A history of miscarriages or stillbirth
• Older maternal age (35 years plus)
• Older paternal age (40 years plus)
• Generational history of genetic disorders
• Siblings with genetic disorders
• At least one parent with a chromosomal abnormality

Genetic testing looks for changes, sometimes called mutations or variants, in your DNA. Genetic testing is useful in many areas of medicine and can change the medical care you or your family member receives. For example, genetic testing can provide a diagnosis for a genetic condition such as fragile X or information about your risk to develop cancer.

There are many different kinds of genetic tests. Genetic tests are done using a blood or spit sample and results are usually ready in a few weeks. Because we share DNA with our family members, if you are found to have a genetic change, your family members may have the same change. Genetic counseling before and after genetic testing can help make sure that you are the right person in your family to get a genetic test, you’re getting the right genetic test, and that you understand your results.

A good way to think about genetic testing is as if you’re asking the DNA a question. Sometimes we don’t find an answer because we weren’t asking the right question or science just didn’t have the answer yet.

• To learn whether you have a genetic condition that runs in your family before you have symptoms
• To learn about the chance a current or future pregnancy will have a genetic condition
• To diagnose a genetic condition if you or your child has symptoms
• To understand and guide your cancer prevention or treatment plan

After learning more about genetic testing, you might decide it’s not right for you. Some reasons might be that it’s not relevant to you or won’t change your medical care, it’s too expensive, and the results may make you worried or anxious.     

There are several types of screening procedures to determine whether you may be at risk of having a baby with genetic disorders. There is no single genetic test that can detect all genetic conditions. The approach to genetic testing is individualized based on your medical and family history and what condition you’re being tested for. Talk with a fertility specialist about your screening and diagnostic test options, which may include one or more of the following:

1. Prenatal genetic screens: Using maternal blood samples in combination with ultrasounds, the risk can be determined for specific genetic disorders like Down syndrome (trisomy 21) and birth defects like spina bifida.
2. Noninvasive prenatal testing (NIPT): Also known as a “cell-free DNA screening,” blood is drawn from the placenta to check the DNA structure. This test is common in high-risk pregnancies, such as those of advanced maternal age. This blood test can show any evidence of chromosomal abnormalities. 
3. Carrier screening: Using a saliva or blood sample, this test can determine any predisposition to chromosomal disorders. Most potential parents prefer to do this screen prior to pregnancy, but it can also be done while a woman is pregnant.     

Certain genetic disorders can be detected via a diagnostic test that is run during pregnancy. These may check for Down syndrome, fibrosis and defects like spina bifida. Amniocentesis (a second-trimester test that samples the amniotic fluid in the womb) and chorionic villus sampling (a first-trimester test wherein a tissue sample is taken from the placenta) tests are routine tests and may carry a small risk of complications that in rare cases lead to risk of pregnancy loss.

Single gene tests look for changes in only one gene. Single gene testing is done when your doctor believes you or your child have symptoms of a specific condition or syndrome. Some examples of this are Duchenne muscular dystrophy or sickle cell disease. Single gene testing is also used when there is a known genetic mutation in a family.

A panel genetic test looks for changes in many genes in one test. Genetic testing panels are usually grouped in categories based on different kinds of medical concerns. Some examples of genetic panel tests are low muscle tone, short stature or epilepsy. Panel genetic tests can also be grouped into genes that are all associated with higher risk of developing certain kinds of cancer, like breast or colorectal (colon) cancer.

Large-scale genetic or genomic testing. There are two different kinds of large-scale genetic tests. 

• Exome sequencing looks at all the genes in the DNA (whole exome) or just the genes that are related to medical conditions (clinical exome).
• Genome sequencing is the largest genetic test and looks at all of a person’s DNA, not just the genes.

Exome and genome sequencing are ordered by doctors for people with complex medical histories. Large-scale genomic testing is also used in research to learn more about the genetic causes of conditions. Large-scale genetic tests can have findings unrelated to why the test was ordered in the first place (secondary findings). Examples of secondary findings are genes associated with a predisposition to cancer or rare heart conditions when you were looking for a genetic diagnosis to explain a child’s developmental disabilities.

• Chromosomes: DNA is packaged into structures called chromosomes. Some tests look for changes in chromosomes rather than gene changes. Examples of these tests are karyotype and chromosomal microarrays.
• Gene expression: Genes are expressed, or turned on, at different levels in different types of cells. Gene expression tests compare these levels between normal cells and diseased cells because knowing about the difference can provide important information for treating the disease. For example, these tests can be used to guide chemotherapy treatment for breast cancer.

• Positive: The test found a genetic change known to cause disease.
• Negative: The test did not find a genetic change known to cause disease. Sometimes a negative result occurs when the wrong test was ordered or there isn’t a genetic cause for that person’s symptoms. A “true negative” is when there is a known genetic change in the family and the person tested did not inherit it. If your test results are negative and there is no known genetic change in your family, a negative test result may not give you a definite answer. This is because you might not have been tested for the genetic change that runs in your family.
• Uncertain: A variant of unknown or uncertain significance means there isn’t enough information about that genetic change to determine whether it is benign (normal) or pathogenic (disease causing).

Family physicians should be able to recognize symptoms with a physical examination and reviewing family history that suggest the presence of a genetic syndrome or disorder that will aid in the diagnosis and treatment of potentially affected patients. Typical conditions physicians look for include dysmorphic features, co-occurring anomalies in one patient, unexplained neurocognitive impairment and a family history of disease.

• Large or small tongue
• White patches of hair
• Unusual shape of eyes
• Facial features unlike those of other family members
• Excessive or brittle/sparse hair
• Different-colored eyes
• Breathing problems
• Cognitive deficiencies
• Developmental delays

For parents undergoing genetic counseling prior to pregnancy, providing an accurate three-generation family history is invaluable when screening for genetic syndromes. Important elements include the age and sex of family members, when family members were affected by disease or when they died, the ethnic background, and if there is any history of blood relationships between parents.

Early detection of genetic risk factors can make it easier to make a decision about the right and most cost-effective diagnostic tests, the appropriate genetic counseling and timely referral to the best subspecialists.

If screening is being conducted during pregnancy, determining approximate weight, height and head circumference of the fetus can help determine abnormalities. The interpupillary distance (the distance between the center of the pupils) and the size of the limbs are also measured to monitor development.

The absence or presence of certain features in family members can be a clue that a feature is either a potential sign of an abnormality or merely a familial or ethnic variant. For example, inner epicanthal folds (small folds of skin over the eyes) can occur in persons with Down syndrome, and are also symptoms of more than 50 other syndromes, including Noonan syndrome, Rubinstein-Taybi syndrome and Smith-Lemli-Opitz syndrome. However, epicanthal folds are also a normal finding in many persons of Asian or Native American descent. Additionally, some conditions are more common in certain ethnicities, such as Tay-Sachs disease in persons of Ashkenazi Jewish descent and sickle cell disease in persons of African descent.

Neurocognitive impairment related to genetic conditions may be symptomatic and diagnosed in childhood, but others, such as Huntington’s disease or some types of Charcot-Marie-Tooth disease, as well as Parkinson’s disease and Alzheimer’s disease, may manifest much later in life.

Diagnosing genetic disease requires a comprehensive clinical examination composed of three major elements:  

1. Physical examination
2. Detailed medical family history
3. Clinical and laboratory testing, if appropriate and available

Although primary care providers may not always be able to make a definitive diagnosis of a genetic disease, their role is critical in collecting a detailed family history, considering the possibility of a genetic disease in the differential diagnosis, ordering testing as indicated and appropriately referring patients to genetic specialists when possible. Referrals to specialists in genetic diseases like medical geneticists and fertility experts.

Genetic counseling gives you information about how genetic conditions might affect you or your family. The genetic counselor or other healthcare professional will collect your personal and family health history. They can use this information to determine how likely it is that you or your family member has a genetic condition. Based on this information, the genetic counselor can help you decide whether a genetic test might be right for you or your relative.

Based on your personal and family health history, your doctor can refer you for genetic counseling. There are different stages in your life when you might be referred for genetic counseling: 

• Planning for pregnancy: Genetic counseling before you become pregnant can address concerns about factors that might affect your baby during infancy or childhood or your ability to become pregnant, including:
  • Genetic conditions that run in your family or your partner’s family
  • History of infertility, multiple miscarriages or stillbirth
  • Previous pregnancy or child affected by a birth defect or genetic condition
  • Assisted reproductive technology (ART) options
• During pregnancy: Genetic counseling while you are pregnant can address certain tests that may be done during your pregnancy, any detected problems, or conditions that might affect your baby during infancy or childhood, including:
  • History of infertility, multiple miscarriages or stillbirth
  • Previous pregnancy or child affected by a birth defect or genetic condition
  • Abnormal test results, such as a blood test, ultrasound, chorionic villus sampling (CVS) or amniocentesis
  • Maternal infections, such as cytomegalovirus (CMV), and other exposures such as medicines, drugs, chemicals and X-rays
  • Genetic screening that is recommended for all pregnant women, which includes cystic fibrosis, sickle cell disease and any conditions that run in your family or your partner’s family
• Caring for children: Genetic counseling can address concerns if your child is showing signs and symptoms of a disorder that might be genetic, including:
  • Abnormal newborn screening results
  • Birth defects
  • Intellectual disability or developmental disabilities
  • Autism spectrum disorders (ASD)
  • Vision or hearing problems
• Managing your health: Genetic counseling for adults includes specialty areas such as cardiovascular, psychiatric and cancer. Genetic counseling can be helpful if you have symptoms of a condition or have a family history of a condition that makes you more likely to be affected with that condition, including:
  • Hereditary breast and ovarian cancer (HBOC) syndrome
  • Lynch syndrome (hereditary colorectal and other cancers)
  • Familial hypercholesterolemia
  • Muscular dystrophy and other muscle diseases
  • Inherited movement disorders such as Huntington’s disease
  • Inherited blood disorders such as sickle cell disease

Following your genetic counseling session, you might decide to have genetic testing. Genetic counseling after testing can help you better understand your test results and treatment options, help you deal with emotional concerns, and refer you to other healthcare providers and advocacy and support groups.

Genetic therapies aim to treat or cure conditions by correcting problems in your DNA. Your DNA, including specific genes, contains instructions for making proteins that are essential for good health. Mutations, or changes in your DNA, can lead to proteins that do not work properly or that are missing altogether. These changes can cause genetic, or inherited, disorders such as cystic fibrosis, thalassemia, hemophilia and sickle cell disease.

Genetic therapies are approaches that treat genetic disorders by providing new DNA to certain cells or correcting the DNA. Gene transfer approaches, also called gene addition, restore the missing function of a faulty or missing gene by adding a new gene to affected cells. The new gene may be a normal version of the faulty gene or a different gene that bypasses the problem and improves the way the cell works.

Genome editing is a newer approach that allows precise correction or other targeted changes to the DNA in cells to restore a cell’s function. Genome editing can: 

• Remove a stretch of DNA that causes a disease
• Turn off a gene to prevent it from making a harmful protein
• Turn on a gene or instruct a cell to make more of a needed protein
• Correct a mutated gene

Gene transfer or genome editing treatments can directly modify the cells in your body, or your cells can be collected and treated outside of your body and then returned to you. For example, a doctor can remove immune system cells, cells that are part of your body’s natural defense system, or bone marrow cells from your body, modify their DNA, and then re-introduce them to your body.

The only genetic therapies that are currently approved by the U.S. Food and Drug Administration (FDA) are for a rare inherited eye condition, as well as certain types of cancer. Genetic therapies that are in development could treat or cure other inherited disorders, treat other cancers or treat infections, including HIV.

Although genetic conditions have the potential to have significant negative consequences for individuals’ lives, having a genetic condition does not necessarily entail poor quality of life, or an individual’s sense of overall well-being encompassing physical, psychological, emotional, social and spiritual dimensions. Evidence demonstrates that factors beyond the physical manifestations of the disease, such as psychological well-being, coping and type of illness and their own perceptions of their diagnosis, influence quality of life.

Depending on the severity of the diagnosis and condition, many problems are incompatible with life and cause miscarriage. Some babies with serious genetic disorders may only live into childhood. Mild cases show individuals may live into adulthood and have a normal lifespan if related health issues are managed.

To further your understanding of your diagnosis and to contribute to cutting-edge research, consider participating in a clinical trial so clinicians and scientists can learn more about causes, symptoms, treatment and prevention. Clinical research uses human volunteers to help researchers learn more about a disorder and perhaps find better ways to safely detect, treat or prevent disease.

All types of volunteers are needed—those who are healthy or may have an illness or disease—of all different ages, sexes, races and ethnicities to ensure that study results apply to as many people as possible, and that treatments will be safe and effective for everyone who will use them.

For information about participating in clinical research, visit NIH Clinical Research Trials and You. Learn about clinical trials currently looking for participants at Clinicaltrials.gov.