EIF2AK4-Associated Disorders

Preferred test to confirm diagnosis or assess carrier status for an EIF2AK4-associated disorder, PCH, and PVOD, especially when previous molecular testing for variants in other genes associated with PAH did not identify a cause.

Related Tests

Preferred test to confirm diagnosis of PAH, especially in those with a family history of PAH.

Recommended test if there is a known familial sequence variant previously identified in a family member. A copy of the family member’s test result documenting the known familial variant is required.

Two disorders are currently associated with EIF2AK4 variants: pulmonary capillary hemangiomatosis (PCH) and pulmonary veno-occlusive disease (PVOD). Both disorders result in pulmonary arterial hypertension and are progressive, leading to death. Presentation is variable, depending on the affected lung structures as well as other genetic modifiers and environmental factors. PCH may mimic idiopathic pulmonary arterial hypertension (PAH), PVOD, or pulmonary hemosiderosis.

PCH is a rare disease caused by proliferation of multiple layers of capillaries that infiltrate multiple structures or tissues within the lungs. PVOD is characterized by a buildup of abnormal fibrous tissue in the small veins in the lungs, resulting in occlusion of the pulmonary veins that carry oxygenated blood from the lungs to the heart.

DISEASE OVERVIEW

  PCH PVOD PAH
Age of onset

Variable but often in third to fourth decades

Variable but most often in third to fifth decades

Fourth to fifth decade

Gender difference

None

None

Females>males

Symptoms

PAH, clubbing of digits more common

PAH, clubbing of digits more common

PAH, clubbing of digits uncommon

Progressive dyspnea

Progressive dyspnea

Dyspnea

Syncope

Syncope

Syncope

Hemoptysis – in 40%

Hemoptysis – rare

Hemoptysis – rare

Pericardial effusions – rare

Pericardial effusions – rare

Pericardial effusions

Pleural effusion in 25%

Pleural effusion in 20%

Pleural effusion in 15%

Increased pulmonary artery pressure with normal wedge

Increased pulmonary artery pressure with normal wedge

Increased pulmonary artery pressure with normal wedge

Clinical Course

Shorter time from onset of symptoms to death

Shorter time from onset of symptoms to death

Slower progression from onset of symptoms to death

Table adapted from Chaisson, 2016 

Incidence

Rare

Inheritance

Autosomal recessive

TEST DESCRIPTION

Clinical Sensitivity

  • >90% for autosomal recessive EIF2AK4-related disorders   
  • <10% for PAH

Analytical Sensitivity/Specificity

99%

References

Additional Resources