Congenital dyserythropoietic anemia type 1: A case with novel compound heterozygous mutations in the <i>C15orf41</i> gene
Authors: Jan Palmblad, Birgitta Sander, Barbara Bain, Monika Klimkowska, Erik Björck
Journal: American Journal of Hematology (2018)

To the Editor: The congenital dyserythropoietic anemias (CDA) are heterogeneous, rare disorders with characteristic morphological abnormalities including a block in erythroid maturation, leading to macrocytic anemia, hemolysis, splenomegaly, and iron overload. Here, we describe novel mutations causing CDA type 1 (CDA1) with a variant phenotype including mild neutropenia. There are four types of CDA with mutations in different genes. Type 1 is the second most common form. Mutations in the CDAN1 gene, encoding codanin-1, cause approximately 90 percent of CDA1 cases, whereas mutations in the C15orf41 gene has been described in a consanguineous pedigree of Middle-Eastern (Kuwaiti) origin and two families of East-Asian (Pakistani) origin.1, 2 These latter C15orf41 mutations have been reported to lead to severe, transfusion-dependent anemia. Common to both gene mutations is that the bone marrow shows megaloblastic erythropoiesis with bi- or multinuclear erythroblasts. Here, we describe a now 43-year-old male with compound heterozygous mutations in the C15orf41 gene, one mutation inherited from the father and the second from his mother, all of Swedish ancestry. He presented in childhood with stable moderate, non-transfusion dependent non-immune hemolytic anemia, believed to be hereditary spherocytosis. This condition persisted unchanged until adulthood when mild neutropenia (but no thrombocytopenia), jaundice, mild splenomegaly, and mild/moderate iron overload as well as gout were noted. Laboratory details are given in Table 1. Since spectrin, ankyrin, glucose-6-phosphate dehydrogenase, and hemoglobin fraction analyses were unremarkable, further investigations were carried out. His bone marrow sample showed typical features of CDA1 (see footnote1), but no mutation was found in the CDAN1 gene (Centogene, Rostock, Germany). Further investigations showed no mutations in genes previously described as causing other CDA types, viz. GATA1, (Centogene) KLF1, and SEC23B (PreventionGenetics, Marshfield, WI). All sequence analyses were performed with Sanger sequencing. Due to the typical bone marrow findings consistent with CDA1, C15orf41 mutations were eventually analyzed in the patient with the finding of c.[59C > G;707A>G] and p.[Pro20Arg;Tyr236Cys]. These mutations have not previously been described nor were they present in 87614 alleles in Exome Aggregation Consortium3 and according to the American College of Medical Genetics and Genomics standards, and they were hence classified as variants of undetermined significance.4 Although the mutations do not strictly fulfill the criteria for pathogenic mutations, we propose that they are causative of the phenotype. Subsequently, his father (now 67 years old, having a hemoglobin concentration of 134 g/L; lower reference values for males is 134 g/L) was shown to harbor the c.59C>G mutation in one allele and his mother (now 65 years old; hemoglobin concentration 132 g/L, lower reference value 117 g/L) the c.707A>G mutation. Neither of the parents showed signs of hemolysis or neutropenia. No other siblings have been tested. The relation between the mutations of our patient and CDA1 was not proven but, realizing that the Middle-East CDA1 cases identified a homozygous T to A transversion (c.533T>A), predicted to lead to a p.Leu178Gln missense substitution in C15orf41, a gene of unknown function, and a homozygous transition (c.281A>G), predicted to lead to a p.Tyr94Cys substitution, in two further pedigrees of East Asian origin, supported the hypothesis that the mutations observed by us are the cause of CDA1 in our patient. It has been suggested that C15orf41 encodes a novel restriction endonuclease that is a member of the Holliday junction resolvase family of proteins.2 However, there were Asian CDA1-like family members who were negative for the previously described C15orf41 mutations, suggesting the existence of additional disease-causing mutations.2 Thus, we report the first case of CDA1 compound heterozygous mutations, since the consanguineous Middle-East family had a homozygous mutation, and the families of East Asian origin had the same homozygous mutations in both families, most likely due to a founder effect. There are similarities in the clinical presentation of our patient compared with the Asian families, and differences. There are no details on neutrophil counts in the Asian families, while our patient had a mild chronic neutropenia without infection propensity. In contrast to the digital malformations and dysmorphic features mentioned in the Asian cases,5 our patient displayed no such malformations. Likewise, the Asian patients were transfusion dependent but our patient, despite anemia, led a normal life and needed no transfusions. There are no animal models or other genetic manipulations reported that link the mutations causally to CDA1. However, the addition of one more case, with a similar (but not identical) C15orf41 mutation to that found in the other C15orf41 cases, adds strength to the suggestion that this gene is of significance for erythroid cell production and maturation (and perhaps also for neutrophil production). Authors thank the patient and his family for providing information and blood and samples. Nothing to report.