Paroxysmal Nocturnal Hemoglobinuria (PNH)

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder affecting hematopoietic stem cells that is characterized by complement-mediated intravascular hemolysis, venous thrombosis, and bone marrow failure with subsequent pancytopenia.1

The Role of PIGA Mutations in PNH 

Earlier Studies on the Genetic Pathophysiology of PNH

In the 1990s, a series of research studies conducted by Takeda and colleagues in Japan identified somatic mutations in the PIGA gene located on the X chromosome.2 These somatic mutations lead to a deficiency in the biosynthesis of glycosylphosphatidylinositol (GPI)-anchor proteins that are not present on the surface membranes of hematopoietic stem cells in patients with PNH.2 

Hematopoietic stem cells that lack these GPI-anchor proteins eventually become mature progeny cells, such as erythrocytes, leukocytes, and platelets, which also lack GPI-anchor proteins, especially CD55 and CD59.3 GPI-anchor proteins are necessary to regulate complement-mediated hemolysis of these cells. 

More Recent Studies on the Genetic Pathophysiology of PNH

Researchers published a study in 2020 following next-generation sequencing of the genomes of 85 patients with PNH. They identified 124 PIGA mutational variations in 92% of the patients: 101 were distinct mutations, and the remaining 23 were recurrent mutations. Of these 124 PIGA mutations, 102 were newly identified. Most mutations occurred on exon 2 of the PIGA gene, and the most frequent mutations were truncated mutations.4

Protein-truncated PIGA mutations are highly specific to the development of PNH clones, whereas singular missense PIGA mutations did not appear to be connected to PNH clones and did not necessarily affect GPI-anchor protein biosynthesis.5 

Further Studies Required

While PIGA mutations play a large role in the pathogenesis of PNH, this genetic mutation is unlikely to be the sole cause of PNH given the phenotypic heterogeneity of patients with PNH, especially those presenting with bone marrow failure and thrombosis.3

Read more about PNH etiology

Genetic Similarities Between PNH, Aplastic Anemia, and Myeloid Malignancies

Similar pathogenic mechanisms involved in aplastic anemia seem to contribute to the development of PNH, given the propensity of patients with comorbid PNH and aplastic anemia. Because aplastic anemia is a major risk factor for the development of PNH, any patients with aplastic anemia require careful and regular screening for PNH.3

Read more about PNH risk factors

Commonly mutated genes in patients with myeloid neoplasms and aplastic anemia carry prognostic significance. Patients with aplastic anemia who have PIGA, BCOR, and BCORL1 mutations respond better to immunosuppressive therapies, whereas those with DNMT3A, RUNX1, JAK2, JAK3, and CSMD1 mutations typically carry a worse prognosis.6 

Some cases of PNH may evolve into myeloid malignancies, most commonly as acute myeloid leukemia.7 Although limited, recent research has begun to focus on the relationship between mutations in myeloid cancer-related genes and PNH.6,8 

Read more about PNH prognosis

Studies on Genetic Similarities Between PNH and Aplastic Anemia

In 2021, researchers discovered that 158 of 178 frequently mutated genes causing myeloid neoplasms occurred in their cohort of 41 patients, including 12 patients with PNH and 29 patients with comorbid PNH and aplastic anemia. Mutations were found in all patients, including6:

  • PIGA mutations in 22 patients 
  • MAP3K4 and CSMD1 mutations, each occurring in 5 patients
  • NOTCH1, FANCD2, RUNX1T1, PEG3, DIS3, BCORL1, and SETBP1 mutations, each occurring in 4 patients
  • FANCG, RAD50, FANCA, CDH23, UMODL1, BRAF, and NCOR2 mutations, each occurring in 3 patients
  • 24 other gene mutations occurred in only 2 of the patients
  • 43 other gene mutations were found in 1 patient

Approximately 95% of these 41 patients exhibited multiple mutations. The highest frequency of mutations occurred in the PIGABCORL1RUNXT1MAP3KCSMD1NOTCH1, FANCD2PEG3DIS3, and SETBP1 genes. The mutational frequency of genes predicting worse outcomes in patients with aplastic anemia decreased as PNH clone sizes increased.6

Another study revealed that in addition to the PIGA mutation, patients with PNH demonstrated genetic mutations in TET2, SUZ12, U2AF1, and JAK2, which are known to be involved in the pathogenesis of myeloid neoplasms. Clonal analysis indicated that these additional mutations occurred either before the PIGA mutation or as secondary somatic events/subclones within the PIGA-mutant population. This may support the hypothesis that PIGA mutations and additional somatic events must correlate with each other to maintain growth and clonal expansion in PNH.8 

Multiple genetic mutations may also explain the phenotypic heterogeneity of patients with PNH, especially in relation to thrombosis and bone marrow failure. 

Read more about PNH clinical trials

Rare PIGT Mutation Causing Inflammatory PNH Subtype

Nearly all cases of PNH are due to acquired somatic mutations in the PIGA gene. However, there have been rare patients with PNH who inherit a rare germline mutation of the PIGT gene on chromosome 20 from one parent. When this germline mutation corresponds with a somatic mutation that causes a deletion of the corresponding PIGT allele from the other parent, it leads to the manifestation of an inflammatory subtype of PNH.9,10 

Read more about common PNH complications


  1. Lee SCW, Abdel-Wahab O. The mutational landscape of paroxysmal nocturnal hemoglobinuria revealed: new insights into clonal dominance. J Clin Invest. 2014;124(10):4227-4230. doi:10.1172/JCI77984
  2. Takeda J, Miyata T, Kawagoe K, et al. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell. 1993;73(4):703-711. doi:10.1016/0092-8674(93)90250-T
  3. Risitano AM, Rotoli B. Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents. Biologics. 2008;2(2):205-222. doi:10.2147/btt.s1420
  4. Li J, Lin Y, Chen L, et al. Identification of acquired PIGA mutations and additional variants by next-generation sequencing in paroxysmal nocturnal hemoglobinuria. Int J Lab Hematol. 2020;42(4):473-481. doi:10.1111/ijlh.13228
  5. Hoermann G, Nadarajah N, Baer C, et al. Incidential findings of mutations in the PIGA gene are highly specific for the presence of PNH clones. Blood. 2021;138(Suppl 1):1117. doi:10.1182/blood-2021-153119
  6. Chen F, Hu S, Ruan J, Chen M, Han B. Mutational landscape and its clinical significance in paroxysmal nocturnal hemoglobinuria. Blood Cancer J. 2021;11(3):58. doi:10.1038/s41408-021-00451-1
  7. Awada H, Rahman S, Durrani J, et al. Leukemia evolving from paroxysmal nocturnal hemoglobinuria. Leukemia. 2020;34(1):327-330. doi:10.1038/s41375-019-0555-0
  8. Shen W, Clemente MJ, Hosono N, et al. Deep sequencing reveals stepwise mutation acquisition in paroxysmal nocturnal hemoglobinuria. J Clin Invest. 2014;124(10):4529-4538. doi:10.1172/JCI74747
  9. Krawitz PM, Höchsmann B, Murakami Y, et al. A case of paroxysmal nocturnal hemoglobinuria caused by a germline mutation and a somatic mutation in PIGT. Blood. 2013;122(7):1312-1315. doi:10.1182/blood-2013-01-481499
  10. Paroxysmal nocturnal hemoglobinuria. MedlinePlus. Updated February 24, 2022. Accessed December 1, 2022.

Reviewed by Harshi Dhingra, MD, on 12/1/2022.