EIF2AK4-Associated Disorders

EIF2AK4-Associated Disorders (EIF2AK4) Sequencing 2010696
Method: Polymerase Chain Reaction/Sequencing

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
Pulmonary Arterial Hypertension (PAH) Panel, Sequencing and Deletion/Duplication 2009345
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

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

Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

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.


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





PAH, clubbing of digits more common

PAH, clubbing of digits more common

PAH, clubbing of digits uncommon

Progressive dyspnea

Progressive dyspnea





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 




Autosomal recessive


Clinical Sensitivity

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

Analytical Sensitivity/Specificity


  1. Chaisson NF, Dodson MW, Elliott CG. Pulmonary Capillary Hemangiomatosis and Pulmonary Veno-occlusive Disease. Clin Chest Med. 2016; 37(3): 523-34. PubMed
  2. Galiè N, Humbert M, Vachiery J, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Noordegraaf AV, Beghetti M, Ghofrani A, Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M, Aboyans V, Carneiro AV, Achenbach S, Agewall S, Allanore Y, Asteggiano R, Badano LP, Barberà JA, Bouvaist H, Bueno H, Byrne RA, Carerj S, Castro G, Erol C, Falk V, Funck-Brentano C, Gorenflo M, Granton J, Iung B, Kiely DG, Kirchhof P, Kjellstrom B, Landmesser U, Lekakis J, Lionis C, Lip GY, Orfanos SE, Park MH, Piepoli MF, Ponikowski P, Revel M, Rigau D, Rosenkranz S, Völler H, Zamorano JL. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016; 37(1): 67-119. PubMed
  3. Ma L, Bao R. Pulmonary capillary hemangiomatosis: a focus on the EIF2AK4 mutation in onset and pathogenesis. Appl Clin Genet. 2015; 8: 181-8. PubMed
  4. Austin ED, Loyd JE. The genetics of pulmonary arterial hypertension. Circ Res. 2014; 115(1): 189-202. PubMed
  5. Best H, Sumner KL, Smith BP, Damjanovich-Colmenares K, Nakayama I, Brown LM, Ha Y, Paul E, Morris A, Jama MA, Dodson MW, Bayrak-Toydemir P, Elliott G. EIF2AK4 Mutations in Patients Diagnosed With Pulmonary Arterial Hypertension. Chest. 2017; 151(4): 821-828. PubMed
  6. Best H, Sumner KL, Austin ED, Chung WK, Brown LM, Borczuk AC, Rosenzweig EB, Bayrak-Toydemir P, Mao R, Cahill BC, Tazelaar HD, Leslie KO, Hemnes AR, Robbins IM, Elliott G. EIF2AK4 mutations in pulmonary capillary hemangiomatosis. Chest. 2014; 145(2): 231-236. PubMed
  7. Eyries M, Montani D, Girerd B, Perret C, Leroy A, Lonjou C, Chelghoum N, Coulet F, Bonnet D, Dorfmüller P, Fadel E, Sitbon O, Simonneau G, Trégouët D, Humbert M, Soubrier F. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat Genet. 2014; 46(1): 65-9. PubMed

Last Update: June 2019