PAH may be caused by a gene variant or mutation, which is a permanent change in the DNA sequence of a gene.

Gene variants can be:

• Benign/likely benign: neutral, not harmful.
• Pathogenic/likely pathogenic: disease-causing.
• Of uncertain significance: there is not enough information to predict whether they are harmful or not.

What is a gene?

Genes are units of genetic information that are passed from parents to children. Each gene contains the directions to make one or more proteins that the body needs. Genes control everything about us, including the way that our body grows and functions. All of us receive a full set of about 30,000 genes from each of our parents. Therefore, we have a pair of genes, one from each parent, to make each protein.

How genes can influence PAH

Pulmonary arterial hypertension (PAH) can sometimes be inherited. But having a gene linked to PAH doesn’t always mean you’ll develop the disease.

Heritable PAH often happens when someone inherits one faulty gene from a parent. This is called autosomal dominant inheritance. One copy is enough to raise risk.

Not everyone with the gene gets PAH

Even if a gene is known to cause PAH, not everyone who carries it will get sick. Scientists call this incomplete penetrance. Think of it like carrying a key that could unlock a door, but sometimes the door never opens. Incomplete penetrance happens with most genes linked to PAH. But the exact odds vary by gene, and researchers are still uncovering them. Other factors, either genetic or environmental, are also needed to produce disease

What makes disease more likely?

Some rare childhood forms of PAH occur when a child inherits two faulty gene copies (one from each parent). This is called autosomal recessive inheritance. In these cases, disease is very likely—like having two matching keys that always open the lock. Similarly, when PAH is caused by a brand-new (de novo) variant, the risk is also very high.

Familial PAH and the BMPR2 gene

In familial or heritable PAH, researchers identified mutations in the gene responsible for making a protein called the bone morphogenetic protein type 2 receptor, or BMPR2 for short. This gene makes a protein that helps control how cells grow and repair themselves.

• At least 70 percent of families with PAH have these mutations.
• Because of incomplete penetrance, a family member may have the disease gene without actually developing PAH. Yet their children or grandchildren could develop PAH.
• Men and women face different odds. Only about 10–20% of men who carry the variant develop PAH, compared to about 40% of women.

Genetic testing for PAH

Your doctor may recommend genetic testing if you are diagnosed with suspected genetic forms of PAH and have symptomatic and asymptomatic family members at increased risk for developing PAH. Genetic testing involves a DNA based test that helps to:

• Identify a causal DNA variant for individuals diagnosed with PAH.
• Help understand why a person may have developed PAH.
• Guide clinical management.
• Understand if additional family members may also be at risk for PAH.

A blood draw, saliva, cheek swab or biopsy material can be used for the laboratory test.

What genetic tests may reveal

The BMPR2 gene is the most common genetic cause of familial PAH (when two or more family members are diagnosed).

But BMPR2 isn’t the only one:

• 14 other genes are also known to play a role in different types of PAH, including:
  • Idiopathic PAH (no known cause)
  • Heritable PAH not linked to BMPR2
  • Some cases tied to congenital heart disease
  • A syndrome called TBX4, which involves PAH along with bone and lung development problems

Scientists are also studying at least 8 more genes that may be linked to PAH, but more research is needed.

In children, PAH is often caused by rare, spontaneous gene changes (called de novo variants). These aren’t inherited from parents, and each specific gene usually explains only a small number of cases.

Who should consider genetic testing

• Adults with familial or idiopathic PAH.
• Those with PAH related to congenital heart disease.
• If you have drug-induced PAH.
• Individuals with pulmonary venoocclusive disease (PVOD)/pulmonary capillary hemangiomatosis (PCH).
• If you have children with PAH and PH due to interstitial lung disease or developmental lung disease.

Understanding Hereditary PAH and Genetic Testing

Wendy Chung, MD discusses the basics of genetics, hereditary pulmonary arterial hypertension (HPAH) and the genetic causes of pulmonary arterial hypertension (PAH).

Genetic testing guidelines

In the U.S., genetic testing is regulated by federal laws and guidelines laid out in the Clinical Laboratory Improvement Amendments (CLIA) of 1988.

CLIA ensures that applicable laboratories meet standards to conduct accurate, reliable, and timely testing. Clinical genetic testing can be accessed through PAH clinical specialists or geneticists, who can request testing by CLIA-approved laboratories on behalf of their patients. Research genetic testing can be accessed by contacting the study coordinator for an existing research study; return of research results to families typically requires confirmation by a CLIA-certified laboratory.