A new Fanconi anemia-like disorder, aldehyde degradation deficiency syndrome: two defense mechanisms working together for the genome and hematopoiesis

Abstract

Fanconi anemia (FA), a hereditary bone marrow failure syndrome, has been suggested to be caused by a defect in DNA repair that removes endogenous DNA damage due to aldehydes. In seven Japanese children with aplastic anemia who clinically resembled FA, we identified biallelic variants of the ADH5 gene, encoding formaldehyde degrading enzyme, and a heterozygous ALDH2 variant (rs671). We conclude that the combined defects in ADH5/ALDH2 caused a new disorder now termed Aldehyde Degradation Deficiency Syndrome (ADDS). We suggest that this disease is caused by defective removal of formaldehyde produced by histone demethylation during hematopoietic cell differentiation. Therapeutic targeting of formaldehyde may reduce the hematopoietic deficits of FA as well as ADDS.