The most common forms of diabetes, type 1 and type 2, are polygenic, meaning they are related to a change, or defect, in multiple genes. Environmental factors, such as obesity in the case of type 2 diabetes, also play a part in the development of polygenic forms of diabetes. Polygenic forms of diabetes often run in families. Doctors diagnose polygenic forms of diabetes by testing blood glucose, also known as blood sugar, in individuals with risk factors or symptoms of diabetes.

Genes provide the instructions for making proteins within the cell. If a gene has a change or mutation, the protein may not function properly. Genetic mutations that cause diabetes affect proteins that play a role in the ability of the body to produce insulin or in the ability of insulin to lower blood glucose. People typically have two copies of most genes, with one gene inherited from each parent.

Some rare forms of diabetes result from mutations or changes in a single gene and are called monogenic. In the United States, monogenic forms of diabetes account for about 1 to 4 percent of all cases of diabetes. In most cases of monogenic diabetes, the gene mutation is inherited from one or both parents. Sometimes the gene mutation develops spontaneously, meaning that the mutation is not carried by either of the parents. Most mutations that cause monogenic diabetes reduce the body’s ability to produce insulin, a protein produced in the pancreas that helps the body use glucose for energy.

Neonatal diabetes mellitus (NDM) and maturity-onset diabetes of the young (MODY) are the two main forms of monogenic diabetes. NDM occurs in newborns and young infants. MODY is much more common than NDM and usually first occurs in adolescence or early adulthood.

Most cases of monogenic diabetes are incorrectly diagnosed. For example, when high blood glucose is first detected in adulthood, type 2 diabetes is often diagnosed instead of monogenic diabetes. If your health care provider thinks you might have monogenic diabetes, genetic testing may be needed to diagnose it and to identify which type. Testing of other family members may also be indicated to determine whether they are at risk for or already have a monogenic form of diabetes that is passed down from generation to generation. Some monogenic forms of diabetes can be treated with oral diabetes medicines (pills), while other forms require insulin injections. A correct diagnosis allows for proper treatment and can lead to better glucose control and improved health in the long term.

MODY is a monogenic form of diabetes that usually first occurs during adolescence or early adulthood. MODY accounts for up to 2 percent of all cases of diabetes in the United States in people ages 20 and younger.

A number of different gene mutations have been shown to cause MODY, all of which limit the ability of the pancreas to produce insulin. This leads to high blood glucose levels and, in time, may damage body tissues, particularly the eyes, kidneys, nerves, and blood vessels.

Clinical features of MODY depend on the gene mutations a person has. People with certain types of mutations may have slightly high blood sugar levels that remain stable throughout life, have mild or no symptoms of diabetes, and do not develop any long-term complications. Their high blood glucose levels may only be discovered during routine blood tests. However, other mutations require specific treatment with either insulin or a type of oral diabetes medication called sulfonylureas.

MODY may be confused with type 1 or type 2 diabetes. In the past, people with MODY have generally not been overweight or obese, or have other risk factors for type 2 diabetes, such as high blood pressure or abnormal blood fat levels. However, as more people in the United States become overweight or obese, people with MODY may also be overweight or obese.

Although both type 2 diabetes and MODY can run in families, people with MODY typically have a family history of diabetes in multiple successive generations, meaning MODY is present in a grandparent, a parent, and a child.

NDM is a monogenic form of diabetes that occurs in the first 6 to 12 months of life. NDM is a rare condition accounting for up to 1 in 400,000 infants in the United States. Infants with NDM do not produce enough insulin, leading to an increase in blood glucose. NDM is often mistaken for type 1 diabetes, but type 1 diabetes is very rarely seen before 6 months of age. Diabetes that occurs in the first 6 months of life almost always has a genetic cause. Researchers have identified a number of specific genes and mutations that can cause NDM. In about half of those with NDM, the condition is lifelong and is called permanent neonatal diabetes mellitus (PNDM). In the rest of those with NDM, the condition is transient, or temporary, and disappears during infancy but can reappear later in life. This type of NDM is called transient neonatal diabetes mellitus (TNDM).

Clinical features of NDM depend on the gene mutations a person has. Signs of NDM include frequent urination, rapid breathing, and dehydration. NDM can be diagnosed by finding elevated levels of glucose in blood or urine. The lack of insulin may cause the body to produce chemicals called ketones, resulting in a potentially life-threatening condition called diabetic ketoacidosis. Most fetuses with NDM do not grow well in the womb, and newborns with NDM are much smaller than those of the same gestational age, a condition called intrauterine growth restriction. After birth, some infants fail to gain weight and grow as rapidly as other infants of the same age and sex. Appropriate therapy may improve and normalize growth and development.

Genetic testing can diagnose most forms of monogenic diabetes. A correct diagnosis with proper treatment should lead to better glucose control and improved health in the long term.

Genetic testing is recommended if

• diabetes is diagnosed within the first 6 months of age
• diabetes is diagnosed in children and young adults, particularly those with a strong family history of diabetes, who do not have typical features of type 1 or type 2 diabetes, such as the presence of diabetes-related autoantibodies, obesity, and other metabolic features
• a person has stable, mild fasting hyperglycemia, especially if obesity is not present

Genetic testing for monogenic diabetes involves providing a blood or saliva sample from which DNA is isolated. The DNA is analyzed for changes in the genes that cause monogenic diabetes. Genetic testing is done by specialized labs.

Abnormal results can determine the gene responsible for diabetes in a particular individual or show whether someone is likely to develop a monogenic form of diabetes in the future. Genetic testing can be helpful in selecting the most appropriate treatment for individuals with monogenic diabetes. Testing is also important in planning for pregnancy and to understand the risk of having a child with monogenic diabetes if you, your partner, or your family members have monogenic diabetes.

Most forms of NDM and MODY are caused by autosomal dominant mutations, meaning that the condition can be passed on to children when only one parent carries or has the disease gene. With dominant mutations, a parent who carries the gene has a 50 percent chance of having an affected child with monogenic diabetes.

In contrast, with autosomal recessive disease, a mutation must be inherited from both parents. In this instance, a child has a 25 percent chance of having monogenic diabetes.

For recessive forms of monogenic diabetes, testing can indicate whether parents or siblings without disease are carriers for recessive genetic conditions that could be inherited by their children.

While not as common, it is possible to inherit mutations from the mother only (X-linked mutations). Also not as common are mutations that occur spontaneously.

More information about the genes that cause NDM and MODY, the types of mutations responsible for the disease (autosomal dominant, autosomal recessive, X-linked, etc.), and clinical features is provided in the American Diabetes Association Standards of Medical Care in Diabetes.

If you suspect that you or a member of your family may have a monogenic form of diabetes, you should seek help from health care professionals—physicians and genetic counselors—who have specialized knowledge and experience in this area. They can determine whether genetic testing is appropriate; select the genetic tests that should be performed; and provide information about the basic principles of genetics, genetic testing options, and confidentiality issues. They also can review the test results with the patient or parent after testing, make recommendations about how to proceed, and discuss testing options for other family members.

Treatment varies depending on the specific genetic mutation that has caused a person’s monogenic diabetes. People with certain forms of MODY and NDM can be treated with a sulfonylurea, an oral diabetes medicine that helps the body release more insulin into the blood. Other people may need insulin injections. Some people with MODY may not need medications and are able to manage their diabetes with lifestyle changes alone, which include physical activity and healthy food choices. Your physician and diabetes care team will work with you to develop a plan to treat and manage your diabetes based on the results of genetic testing.