Genetic Disorders

Overview

Genetic disorders are health problems that happen because of some type of abnormality in a person's genetic material. There are several types of genetic disorders. In some cases, a genetic change in a single gene can cause someone to have a disease or condition. In other cases, the gene does not have a genetic change, but a person has more or fewer copies of the gene than most people, and this causes a disease or condition. Some diseases or conditions occur when a person does not have the same number of chromosomes as most people or has part of a chromosome that is missing, extra, or not in the right place.

Most genetic disorders happen due to the combination of many genetic changes acting together with a person's behaviors and environment. These are sometimes called complex conditions.

A detailed description of the basic concepts of genetics can be found here.

Single gene disorders

DNA contains the instructions for making your body work. DNA is made up of two strands that wind around each other. Each DNA strand includes chemicals called nitrogen bases—T (thymine), A (adenine), C (cytosine), and G (guanine)—that make up the DNA code. Genes are specific sections of DNA that have instructions for making proteins. Proteins make up most of the parts of your body and make your body work the right way.

Some diseases and conditions happen when a person has a genetic change (sometimes called a mutation) in one of their genes. These types of diseases are called single gene disorders. Sometimes, what happens is that one of the DNA bases is changed. For example, part of a gene that usually has the sequence TAC is changed to the sequence TTC. This can change the way the gene works, for example, by changing the protein that is made. In other cases, one or more of the bases in the DNA sequence are missing altogether, or there are extra bases.

Genetic changes can be passed down to a child from their parents. When this happens, the disease or condition is called hereditary or inherited. Or the changes can happen for the first time in the process of making the sperm or egg or early in development, so the child will have the genetic change but the parents will not.

Single gene disorders that affect a gene on one of the 22 autosomal chromosome pairs are called autosomal disorders. Disorders that affect the sex chromosome are called X-linked disorders. Disorders are further described according to whether the affected genetic change is dominant or recessive.

For some diseases and conditions, everyone who inherits the genetic change will have the disease or condition, but how serious it is can vary from person to person. In other cases, people who have the genetic change will be more likely to develop the disease or condition, but some of them will never develop it.

Autosomal dominant

With autosomal dominant diseases or conditions, a person only needs a genetic change in one copy of the gene to have the disease. If one parent has an autosomal dominant disease or condition, each child has a 50% (1 in 2) chance of inheriting the genetic change that causes the condition.

Examples of autosomal dominant conditions include hereditary breast and ovarian cancer caused by genetic changes (mutations) to the BRCA1 and BRCA2 genes; Lynch syndrome; and familial hypercholesterolemia.

Autosomal recessive

With autosomal recessive diseases or conditions, a person needs a genetic change in both copies of the gene to have the disease or condition. While a person with a genetic change in only one copy of the gene will not have the disease or condition, they can still pass the genetic change down to their children. These parents are sometimes called "carriers" of the disease because they "carry" the genetic change that causes the disease or condition but do not have the disease themselves.

A parent who is a carrier of a disease has a 50% (1 in 2) chance of passing the gene with the genetic change on to each of their children. If both parents are carriers of the disease, each child has a 25% (1 in 4) chance of inheriting two genes with the genetic change and thus of having the disease. Carrier screening looks for autosomal recessive genetic changes in parents to see if they could have a child with the disease or condition.

Examples of autosomal recessive disorders are sickle cell disease and cystic fibrosis.

X-linked

Females have two X chromosomes, and males have one X chromosome and one Y chromosome. Each daughter gets an X from her mother and an X from her father. Each son gets an X from his mother and a Y from his father.

Some diseases or conditions happen when a gene on the X chromosome has a genetic change. Because males only have one copy of all the genes on the X chromosome, they are much more likely to be affected by X-linked genetic disorders than females. A female with a genetic change on only one of her two X chromosomes may not have the disease or condition at all. However, in some cases, females with the genetic change on one of their X chromosomes can have the disease or condition, but it is often a milder form of the disease than usually occurs in males.

Because males inherit an X chromosome from their mother, a female with a genetic change on one copy of the gene has a 50% (1 in 2) chance of passing the genetic change on to each of her sons. Her sons could have the disease or condition even though she does not.

Examples of X-linked conditions include fragile X syndrome, Duchenne muscular dystrophy, and hereditary hemophilia.

Chromosomal abnormalities

Different number of chromosomes

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.

For example, 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. For example, people with Turner syndrome usually have only one sex chromosome, an X. Women with Turner syndrome can have problems with growth and heart defects.

Changes in chromosomes

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.

For example, 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.

Complex conditions

Complex disorders are caused by genetic changes in many different genes working together with environmental factors. Environmental factors include exposures and behaviors such as air pollution, smoking, alcohol use, the amount of exercise a person gets, or the foods they eat. Having a family health history of a complex condition can make you more likely to have that condition yourself. However, genetic testing would not be recommended because there is not a single genetic change causing the condition that could be found by genetic testing.

Most chronic diseases, such as most cases of heart disease, cancer, diabetes, osteoporosis, and asthma, are complex disorders. So are most cases of developmental disabilities, such as autism spectrum disorder and attention deficit / hyperactivity disorder (ADHD), and mental health conditions, such as depression and schizophrenia.

The vast amount of genetic information available has allowed researchers to develop methods to study which types of genetic changes are found more often in people with a given disease or condition. This allows researchers to estimate a person's risk for a particular disorder based on which genetic changes they have. This estimate is known as the polygenic risk score.

Some important issues need to be considered before polygenic risk scores can be routinely used in health care and public health. Studies are looking at how useful polygenic risk scores are in real-life clinical practice. Information on how each gene change affects disease risk comes from population-level genetic studies. Addressing diversity in development of polygenic risk scores is important, because polygenic risk scores developed from studies in one population (for example, people of Northern European ancestry) might not work as well for other populations (for example, people of West African ancestry). Also, how each gene change affects the polygenic risk score varies from study to study.

Once polygenic risk scores are ready to be used routinely in clinical practice, public health efforts will be needed to address issues such as access, insurance coverage, and sharing of results across health systems.