Chromosomal Abnormalities

People usually have 23 pairs of chromosomes. But, sometimes a person is born with a different number. Having an extra chromosome is called trisomy. Missing a chromosome is called monosomy.

People with Down syndrome have an extra copy of chromosome 21. This extra copy changes the body’s and brain’s normal development and causes intellectual and physical problems for the person. Some disorders are caused by having a different number of sex chromosomes. People with Turner syndrome usually have only one sex chromosome, an X. Women with Turner syndrome can have problems with growth and heart defects.

Sometimes chromosomes are incomplete or shaped differently than usual. Missing a small part of a chromosome is called a deletion. A translocation is when part of one chromosome has moved to another chromosome. An inversion is when part of a chromosome has been flipped over.

People with Williams syndrome are missing a small part of chromosome 7. This deletion can result in intellectual disability and a distinctive facial appearance and personality.

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).

Other types of chromosomal abnormalities include Cri du chat syndrome, triple x syndrome, trisomy 21, trisomy 18, trisomy 13,  Wolf-Hirschorn syndrome, Klinefelter syndrome,  DiGeorge syndrome, Smith-Magenis syndrome, Rett syndrome and microdeletion syndrome.

Chromosomal abnormalities are another cause of genetic disorders. People usually have 23 pairs of chromosomes. But, sometimes a person is born with a different number. Having an extra chromosome is called trisomy. Missing a chromosome is called monosomy.

People with Down syndrome have an extra copy of chromosome 21. This extra copy changes the body’s and brain’s normal development and causes intellectual and physical problems for the person. Some disorders are caused by having a different number of sex chromosomes. People with Turner syndrome usually have only one sex chromosome, an X. Women with Turner syndrome can have problems with growth and heart defects.

Sometimes chromosomes are incomplete or shaped differently than usual. Missing a small part of a chromosome is called a deletion. A translocation is when part of one chromosome has moved to another chromosome. An inversion is when part of a chromosome has been flipped over. People with Williams syndrome are missing a small part of chromosome 7. This deletion can result in intellectual disability and a distinctive facial appearance and personality.

A complex disease is caused by both genetic changes and environmental factors. Complex diseases also are called multifactorial. Most chronic diseases,  some cases of cancer are associated with inherited genetic changes—such as Lynch syndrome and hereditary breast and ovarian cancer, the majority most likely are caused by changes in several genes acting together with environmental exposures.

Chromosome abnormalities usually occur when there is an error in cell division. There are two kinds of cell division, mitosis and meiosis.

• Mitosis results in two cells that are duplicates of the original cell. One cell with 46 chromosomes divides and becomes two cells with 46 chromosomes each. This kind of cell division occurs throughout the body, except in the reproductive organs. This is the way most of the cells that make up our body are made and replaced.
• Meiosis results in cells with half the number of chromosomes, 23, instead of the normal 46. This is the type of cell division that occurs in the reproductive organs, resulting in the eggs and sperm.

In both processes, the correct number of chromosomes is supposed to end up in the resulting cells. However, errors in cell division can result in cells with too few or too many copies of a chromosome. Errors can also occur when the chromosomes are being duplicated.

Other factors that can increase the risk of chromosome abnormalities are:

• Maternal Age: Women are born with all the eggs they will ever have. Some researchers believe that errors can crop up in the eggs' genetic material as they age. Older women are at higher risk of giving birth to babies with chromosome abnormalities than younger women. Because men produce new sperm throughout their lives, paternal age does not increase risk of chromosome abnormalities.
• Environment: Although there is no conclusive evidence that specific environmental factors cause chromosome abnormalities, it is still possible that the environment may play a role in the occurrence of genetic errors.

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.

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.

• 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).

• 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.

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.