What It Means to Be a Carrier of the V122I Variant

Learning that you may carry the V122I variant of the transthyretin (TTR) gene can raise many questions.

A genetic test can identify this variant even if a person does not currently have symptoms. Testing positive for the V122I variant does not automatically mean someone already has active amyloidosis.

A genetic result shows that the variant is present but determining whether ATTR amyloidosis is affecting the body requires evaluation by a healthcare provider experienced in amyloidosis.

This evaluation may include reviewing medical history, a physical exam, heart imaging, blood tests, or other specialized testing.

Some people who carry the variant develop disease later in life, while others may remain healthy throughout their lives.

What Does It Mean to Be Positive for V122I?

A positive result means a change has been identified in the TTR gene, which provides instructions for making the transthyretin protein.

Certain variants in this gene can increase the risk of hereditary ATTR amyloidosis, a condition in which misfolded proteins form amyloid deposits that may build up in organs such as the heart or nerves.

However, not everyone who carries the variant develops disease.

Scientists describe this using the term penetrance, which refers to how often a genetic variant leads to disease in people who carry it. In hereditary ATTR amyloidosis, penetrance is incomplete, meaning some carriers develop symptoms while others remain asymptomatic.

Because of this variable penetrance, the condition may affect people differently even within the same family. Some carriers may never develop disease, while others may develop symptoms. Among those who do develop disease, the age of onset (when symptoms first appear) and the severity or type of symptoms can vary between individuals.

Researchers are still working to better understand why the same genetic variant can affect people in different ways.

What Is the Risk to My Children?

Hereditary ATTR amyloidosis follows an autosomal dominant inheritance pattern.

If a parent carries the variant, each child has a 50 percent chance of inheriting it.

Some children may inherit the variant while others may not. It is also important to remember that inheriting the variant does not guarantee that someone will develop disease.

Because genetic results can affect multiple relatives, genetic counseling can help families understand inheritance patterns and testing options.

When Is Genetic Testing Usually Considered?

Genetic testing is often discussed after a diagnosis has been confirmed in a family member. In these situations, testing may help relatives understand whether they carry the same variant.

Testing may also be considered when someone has symptoms or family history that could suggest hereditary amyloidosis.

In many families:

• Adult relatives may choose to be tested once a variant is identified
• Testing of young children is not recommended currently unless there is a medical reason to test earlier

A genetic counselor or experienced healthcare provider can help guide decisions about testing.

Do I Need Treatment Right Away?

Most people who learn they carry a TTR variant do not begin treatment immediately if there are no symptoms or evidence of disease.

Current treatments for ATTR amyloidosis are generally used after there is evidence that the condition is affecting the body.

Instead, physicians may recommend monitoring over time.

Monitoring may include:

• Heart imaging
• Blood tests
• Neurological evaluation
• Regular follow-up visits

This approach helps clinicians recognize early signs of disease if they develop.

When Do Symptoms Usually Appear?

Different forms of hereditary amyloidosis can develop at different stages of life.

For individuals with the V122I variant, which is the variant we focus on at #hATTRNextGen, symptoms are most often recognized in mid to later adulthood.

However, this pattern does not necessarily apply to every individual or family, and even within the same family the age of onset and symptoms can differ.

Because patterns of disease can vary, evaluation by a healthcare provider experienced in diagnosing and managing amyloidosis is important for understanding personal risk and determining appropriate monitoring.

Why Research Is Still Evolving

Although researchers understand much more about hereditary ATTR amyloidosis today than in the past, there is still more to learn.

Scientists continue to study:

• why some carriers develop disease while others do not
• how genetics and other factors influence risk
• the best ways to monitor individuals who carry the gene

As awareness increases and new therapies continue to emerge, understanding of hereditary ATTR amyloidosis continues to improve.