Every day, the DNA in your body replicates (makes copies of) itself more than 2 trillion times. With that many copies, occasional errors are inevitable. Paroxysmal nocturnal hemoglobinuria (PNH) often develops from one such error in a gene known as PIGA, located on the X chromosome.

Understanding the genetic basis of PNH can be confusing, but it’s an important part of knowing what to expect and how to manage the disease. This article will guide you through the basics of PNH genetics, including the role of the PIGA gene, potential additional genetic factors like mutations in other enzymes, and whether genetic testing might benefit you or your family.

What Is Paroxysmal Nocturnal Hemoglobinuria?

Paroxysmal nocturnal hemoglobinuria is a rare but serious disease that affects two important components of the blood — red blood cells (RBCs) and platelets. Red blood cells — also called erythrocytes — deliver oxygen from the lungs to the rest of your body using a protein called hemoglobin. Platelets are the tiny cell fragments in your blood that help stop bleeding by forming clots when you’re injured.

In PNH, some RBCs are abnormal and can break apart easily — a process called hemolysis. This can cause symptoms like fatigue, shortness of breath, and dark urine. PNH also increases the risk of dangerous blood clots, which can lead to serious complications such as strokes or deep vein thrombosis (DVT). White blood cells, including granulocytes, may also be affected in PNH, contributing to complications of the disease.

Unlike many genetic conditions, PNH is not usually inherited. Most people with PNH are the first in their families to have the disease. This means it develops from a genetic mutation (variation) that occurs after birth, rather than being passed down from parents.

Most people with PNH are the first in their families to have the disease.

Understanding Genes and Their Role in Health and Disease

To grasp the genetic basis of PNH, it helps to start with some basics about genes. Genes are tiny segments of DNA — the material inside our cells that hold the instructions for building and maintaining our bodies. Each gene carries a specific set of instructions, usually for making a protein that has a certain job, like fighting infections or helping blood to clot (form clumps to stop bleeding after an injury).

We inherit our genes from our parents. Each person has two alleles (versions) of most genes — one from their mother and one from their father. Sometimes, a gene can have a change or error in its DNA sequence. This is called a mutation. While many mutations have no noticeable effect, some can lead to diseases or increase the risk of developing them.

When a genetic mutation is passed down from your parents, it’s called a germline mutation. In PNH, however, the mutation happens spontaneously during a person’s lifetime and is usually not inherited. This type is referred to as a somatic mutation.

The PIGA Gene: A Critical Player in PNH

PNH is closely linked to a gene mutation in the PIGA gene, which produces an enzyme responsible for anchoring protective proteins to the surface of RBCs. These surface proteins protect RBCs from being attacked by the complement system — the part of the immune system responsible for defending the body from foreign invaders like viruses and bacteria.

The PIGA gene is responsible for making a protein that protects red blood cells from being destroyed by the complement system.

When the PIGA gene is mutated, these protective proteins are lost from the surface of RBCs. Without this protective shield, the immune system mistakenly identifies these cells as threats and destroys them. This is the underlying cause of PNH.

Unlike many genetic disorders, PIGA mutations are typically not inherited from family members. Instead, they occur spontaneously — meaning they happen suddenly and without a clear cause — during a person’s lifetime. In PNH, this mutation arises in a stem cell — responsible for making other blood cells, including white blood cells and granulocytes — in the bone marrow. Over time, the mutant cells can multiply, leading to more faulty RBCs.

Is PIGA the Only Gene Involved?

While PIGA is central to the development of PNH, it’s not the whole story. Researchers are exploring other genetic factors that might contribute to the disease. Some of these factors involve mutations in genes that affect the immune system or the bone marrow, where RBCs are produced.

Additional Genes and Mutations

The PIGT gene is part of the same pathway as PIGA, helping to create the protective anchor proteins found on the cell surface of RBCs. Mutations in PIGT, found in some people with PNH, also lead to the loss of protective proteins on RBCs. They may influence the severity of the disease.

Some people with PNH also have genetic mutations in other genes, including:

• TET2
• SUZ12
• U2AF1
• JAK2

Mutations in these genes may contribute additional risks, including the possibility of developing certain types of blood cancer or aplastic anemia.

Genes That Control Bone Marrow

RBCs are produced in the bone marrow, which can also be affected by genetic changes. Mutations in genes such as SF3B1, which control the bone marrow’s ability to produce healthy RBCs, may contribute to the onset or worsening of PNH.

Read about bone marrow failure and PNH.

Inheritance and Risk: Should You Get Genetic Testing?

A common question for people with PNH, or those who have a relative living with the disease, is whether genetic testing is necessary or helpful. Here’s what you need to know.

Diagnosis of PNH

Genetic testing is not typically used to diagnose PNH. Doctors usually rely on symptoms, blood tests, and a special assay (test) called flow cytometry. This test detects the absence of protective proteins on RBCs. In certain cases, genetic testing for PIGA mutations may be used to confirm the diagnosis if it’s unclear.

Family Members With PNH

If you have a close relative with PNH, you may wonder about your risk. Since PNH is generally not inherited, having a family member with the condition doesn’t mean you’re likely to develop it. Most people with PNH are the first in their families to be affected, so routine genetic testing for family members is usually not necessary.

PNH isn’t passed down in families like genes for eye color, so it’s not usually recommended for relatives to get tested.

Planning a Family

If you or your partner has PNH and you’re considering starting a family, it’s natural to be concerned about passing the disease to your children. However, because the PIGA mutation occurs spontaneously in the bone marrow, the odds of passing PNH to your children are very low. Discussing your specific situation with a genetic counselor or hematology (blood) specialist can provide more personalized information.

Newborns

Since PNH is usually not inherited, genetic testing in newborns is not needed, even if a parent has the disease. The disease is extremely rare in children, and the chance of a newborn developing PNH is very low.

Do Genetics Matter in PNH?

So, do genetics matter in PNH? The answer is yes, but in a specific way. The PIGA mutation is crucial in the development of PNH, but it is not typically inherited in families. Instead, it occurs randomly during a person’s life. While other genetic factors may influence the severity and progression of the disease, the PIGA mutation is the key player.

Talk With Others Who Understand

On myPNHteam, the social network for people with paroxysmal nocturnal hemoglobinuria and their loved ones, members come together to ask questions, give advice, and share their stories with others who understand life with PNH.

Was genetic testing part of your PNH diagnosis? Do you still have questions about PNH and the PIGA gene? Share in the comments below, or start a conversation by posting on your Activities page.