Cold Agglutinin Disease and Genetics

Cold-agglutinin disease (CAD) is a rare type autoimmune hemolytic anemia. It is characterized by the production of autoantibodies called cold agglutinin that, under cold conditions, mistakenly attack and cause the premature lysis or disintegration of red blood cells. The cold-induced clumping of red blood cells and their subsequent breakdown result in the various symptoms associated with CAD.

Genes associated with CAD

CAD is not a hereditary condition, and no genetic mutations are linked to CAD directly. However, a recent study identified mutations in two different genes in antibody-producing B-cells that were isolated from the bone marrow of 16 primary CAD patients ages 56 to 84.

The mutations were found in the genes KMT2D and CARD11. The KMT2D gene carries the instruction to make an enzyme called lysine-specific methyltransferase 2D, which regulates several other genes, including those involved in the development and workings of immune cells. The CARD11 gene encodes for a protein that is involved in signaling the growth and function of immune cells. It does so via the nuclear factor‐κB, a protein that plays a crucial role in mounting an immune response.

The mutation in KMT2D noted in this study resulted in the production of a non-working enzyme, which can overstimulate the production of autoantibodies from B-cells. The CARD11 mutation resulted in the proliferation of B-cells and triggered autoantibody production.

Additional in-depth studies with more participants are needed to confirm the association of these genes to CAD, and other studies are required to possibly identify other genes.

Other information

Mutations in the KMT2D gene are associated with other disorders, including such types of lymphoma as diffuse large B‐cell lymphoma (DLBCL), follicular lymphoma, and nodal marginal zone lymphoma. They are also associated with Kabuki syndrome, a birth defect marked by developmental disabilities.

The CARD11 mutation has also been linked to DLBCL.


Last updated: August 18, 2019.


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