Genetic Disorders and Genetic Testing
You may be visiting this page because your health care provider suspects that you or your child has a genetic disorder. This can be a frightening prospect. Arming yourself with knowledge about the new terminology you’re encountering can be helpful. The goal of the educational pages on this website is to provide you with a foundation of basic genetic terminology and concepts. If you have questions, contact your genetics health care provider for a more in-depth conversation.
One of the first things to know is that there is no single hard and fast rule that defines all genetic disorders except that they are caused by changes in a person’s DNA. Here are some things to know about genetic disorders:
- There is no common age at which genetic disorders develop.
Some genetic disorders develop during adulthood. One example is Huntington disease. However, many disorders that are genetic develop early in life. In fact, disorders that develop in childhood are often genetic in basis. One example of this is sickle cell anemia.
- Inheritance is key feature of a genetic disorder.
Usually, a genetic disorder is inherited from a parent. For example, Phenylketonuria, or PKU, is often inherited from carrier parents. There are genetic disorders, such as Trisomy 13, that are not inherited.
- Usually in a genetic disorder, more than one organ system is affected.
Even this is not a hard and fast rule. For example, Marfan syndrome, can affect many organs, including the heart, the eyes, and the skeletal system. In contrast, retinoblastoma usually only affects the eyes.
Many people new to the world of genetic disorders want to know how genetic disorders happen. Genetic disorders are caused by changes in a person’s DNA. DNA is the set of molecules in every cell that encode the instructions for how cells create proteins and other molecules that are the basis for life. DNA is passed from parent to child and is responsible for traits that are inherited. Genetics can therefore be considered the study of heredity, and the traits and properties that are encoded by an individual’s DNA.
There are many types of changes in DNA that cause genetic disorders- from as small as a single change in a gene, to as large as a missing or extra chromosome. All humans have variations in their DNA that cause one person to be different from another person; even identical twins have some differences in their DNA. But some variants are mutations, meaning that researchers have determined that the variation isn’t considered to be “within normal limits.”
Genetic testing helps to identify a mutation that causes the disorder and so allows the health care provider, the patient, and the family learn more about the condition and what to expect. The health care team and the family can work together to discuss next steps such as treatment options, or to discuss which other specialists need to be seen. Also, the patient’s family members can be counseled about their risk of inheriting the disease and they may choose to have genetic testing performed to determine whether they carry the same genetic change. Furthermore, this knowledge of the genetic disease helps families and patients to find other people who are managing the same disease or researchers who are studying it.
Claritas Genomics tests samples from patients who are suspected by their health care provider to have a genetic disorder. The health care provider orders a specific test, obtains the sample from the patient, and sends the sample to Claritas. At Claritas, we perform the testing that has been requested and return the results to the provider. It is our goal to support the health care provider from the beginning of the ordering process in which we help determine what test would be most appropriate to order, to the delivery of results and beyond. We aim to support health care providers and patients so that they may better navigate the complex world of genetic testing.
From gene to genome
A genetic disorder is an illness that is caused by variation in the DNA sequence of one or more genes. A patient with a genetic disorder often has signs and symptoms from birth, or develops them at an early age. Families bring their child to see a genetic specialist when the pediatrician recognizes that the symptoms are not due to a virus or a bacteria or other common childhood disease.
A gene is a single unit within a DNA sequence that instructs cells to make a protein. Much like a long length of yarn is rolled up on itself into a ball, genes are packaged into structures called chromosomes, which reside within the nucleus of nearly every cell in the body. Humans have a total of 46 chromosomes: 1 pair of sex chromosomes (Chromosomes X or Y) and 22 pairs of autosomes (non-sex chromosomes). Both males and females inherit one set of autosomes (Chromosomes 1-22) from their mother and one set from their father. This means that every person carries two copies of each autosomal gene, one from each parent. The 23rd pair of chromosomes are the sex chromosomes. With few exceptions, females inherit an X chromosome from each parent, while males inherit an X chromosome from their mother and a Y chromosome from their father.
The entirety of the genetic material contained within all 23 pairs of chromosomes is called the genome. The genome consists of over 3 billion DNA base pairs. Base pairs are the building blocks of the DNA code, Adenine (A), Guanine (G), Cytosine (C) and Thiamine (T). Of the 3 billion base pairs that make up the human genome, only a small portion (about 1-2%) actually encodes the proteins that perform the body’s functions. This small portion of the genome is referred to as the exome; the exome represents only the coding regions – known as exons – of the approximately 21,000 genes in the human genome. Genetic testing usually targets either the exome (using a process called whole exome sequencing) or individual genes within the exome.
Some genetic disorders are “monogenic”, meaning that only one gene is involved. One such monogenic disease is cystic fibrosis, a condition caused by mutations in the cystic fibrosis transmembrane conductance regulatory (called CFTR). Other genetic diseases are multigenic or polygenic, in which more than just one gene is involved. Examples of multigenic or polygenic diseases are cleft palate and heart disease.
Claritas Genomics offers a variety of genetic tests performed on different technology platforms, including next generation sequencing-based tests, deletion/ duplication assays, and microarray. To learn more about next generation sequencing (NGS) and the tests that utilize NGS technologies, click here.
While most patients inherit a disease-causing mutation from one or both parents, sometimes a mutation can be de novo, meaning that it arises for the first time in a particular individual. Testing family members can determine whether a mutation is inherited or de novo, and identify other members of the family who are at risk for a disorder.
Inherited genetic disorders are transmitted from a parent to a child at the time of conception. Identifying the inheritance pattern that a genetic disorder follows is helpful in determining the chance that the disorder will occur again in a family or whether others are at risk of having the disorder. The easiest way to determine the inheritance pattern of a disorder within a particular family is to draw a pedigree, or a family tree depiction that shows the inheritance pattern of a family trait or disorder.
Some of the basic inheritance patterns include:
- Autosomal dominant: ‘Autosomal’ refers to the mutation residing in a gene on one of the non-sex chromosomes, and ‘dominant’ means that a mutation on only one copy of the gene is sufficient to cause the disease. Autosomal dominant disorders are passed directly from parent to child, and a pedigree will often show multiple affected generations; for example, grandparents, parents, and children may be affected. In this pattern of inheritance, equal numbers of males and females would be affected; we don’t expect to see only males or only females affected. Also in this model, 50% (one-half) of an affected person’s children would inherit the mutation.
- Autosomal recessive: In order to cause an autosomal recessive disorder, both copies of an autosomal gene must have a mutation. A patient with an autosomal recessive disorder generally has inherited one disease-causing mutation from each parent. A person with one mutation is called a disease “carrier”. They typically do not show any signs of the disorder. In a disorder that has an autosomal recessive inheritance pattern, not every generation will be affected in the family tree, but there may be multiple affected people within one generation, such as siblings and cousins. Similarly to autosomal dominant disorders as described above, males and females are affected in equal numbers. Children of two carrier parents have a 25% (or a ‘one out of four’) chance of inheriting both disease-causing variants and thus showing signs of the disorder.
- X-linked dominant: ‘X-linked’ refers to a disease-causing mutation residing on the X chromosome, which is one of the chromosomes that determines the sex of an individual. In the X-linked dominant inheritance pattern, a single mutation in an X-chromosome gene is sufficient to cause the disorder. A father with an X-linked dominant disorder will transmit the affected X chromosome to all (100%) of his daughters, but because he passes only his Y chromosome to his sons, none of his sons will be affected. A mother with an X-linked dominant disorder will have a 50% chance of transmitting the affected X-chromosome, so about half of her children, whether male or female, will be affected.
- X-linked recessive: A mutation on all available copies of an X-chromosome gene is necessary to cause X-linked recessive disease. Since males only have one X chromosome, one mutation is sufficient for a male to be affected. Females, on the other hand, would require a mutation on both copies of an X-linked gene in order to be affected. Females that carry only one copy of a mutation associated with X-linked recessive disease are said to be carriers, and generally do not exhibit any symptoms. A female carrier will transmit the mutation – and the disorder – to all of her male children, while on average, 50% (or half) of her female children will be carriers and the other 50% (the other half) will not inherit the mutation.
- Y-linked: “Y-linked” refers to a genetic disorder that is caused by a mutation on the Y chromosome. Disorders that are Y-linked appear in males because males have a Y chromosome while females do not. A male with a mutation on the Y chromosome will pass the mutation to all (100%) of his male children and none (0%) of his female children.
- Mitochondrial: Mitochondria are organelles within our cells that produce the energy that cells need to function. Mitochondria are only inherited from a person’s mother, so mitochondrial inheritance is also sometimes called maternal inheritance. Male children and female children both inherit mitochondrial DNA from their mother, but only females pass mitochondrial DNA to their children.
Sometimes, a pedigree will not exhibit a classic inheritance pattern, even if a mutation is known to occur within the family. Some genetic disorders can have different degrees of penetrance, meaning that not everyone who has a mutation associated with the disorder will actually exhibit signs of that disorder. Genetic disorders can also have variable expressivity, meaning that individuals with the same mutation may express different combinations of symptoms, or first show signs of the disorder at varying ages. Finally, it is possible that a mutation appears in some, but not all, cells of a person’s body. This genetic mosaicism can alter expression of the disorder as well as inheritance, and may make it more difficult for a mutation to be detected by genetic testing. Also, it’s important to note that some genetic disorders involve more than one gene (“multigenic” or “polygenic”), or may be influenced by lifestyle or environmental factors (“multi-factorial”). These conditions, such as coronary artery disease and high blood pressure, are unlikely to follow one of the inheritance patterns listed above.
Click the links for more information about DNA sequencing and about interpreting genetic test results. If you have more questions, contact your health care provider or find a genetic counselor at www.NSGC.org.