Duffy-null-associated neutropenia-with a twist! K rushford1.

Abstract

Background: People with the Duffy-null blood type often have a lower absolute neutrophil count than the general population. This Duffy-null associated neutrophil count (DANC) is seen primarily in people of African or Middle Eastern ancestry. In these populations it is most commonly associated with homozygosity for the FY*B (FY*02) allele carrying a single nucleotide polymorphism, rs2814778 (c.-67T>C), in the promoter of the ACKR1 (atypical chemokine receptor 1) gene (formerly known as the Duffy-associated receptor for chemokines [DARC] gene) which disrupts a binding site for the GATA1 erythroid transcription factor. It is associated with the red cell phenotype Fy(a-b-) and RBC resistance to Plasmodium vivax invasion. While people with DANC typically experience no increased risk of infections, in haematology/ oncology patients the low neutrophil count can lead to treatment delays and chemotherapy dose modifications. Aim(s): To report a case that demonstrates the value of gene sequencing in the investigation and diagnosis of Duffy-null associated neutrophil count. Method(s): Case Study: An adult male with diffuse large B-cell lymphoma (DLBCL) in remission was investigated for chronic neutropenia (typical neutrophil count 0.7-1.5+/-109/L). Differential diagnosis included neutropenia secondary to recent viral infections, and delayed medicationinduced neutropenia secondary to rituximab and/or epcoritamab. On review it was noted that the patient had also been mildly neutropenic prior to the DLBCL diagnosis and subsequent chemotherapy. Result(s): Given his Egyptian ethnicity and the duration of the neutropenia, Duffy phenotyping was performed. His serologic phenotype was Fy(a-b-). The Immuncor BioArray HEA Precise Beadchip predicted a phenotype of Fy(a-b+) because the c.125G>A which defines the FY*B allele was homozygous but the expected homozygous GATA mutation was not reported. Gene sequencing was performed to investigate the discrepancy between the phenotype and the genotype. The patient was found to be a compound heterozygote for the FY*02N.01 allele (c.-67T>C and c.125G>A) and FY*02N.07 allele (c.124125delinsA). This predicts a RBC Fy(a-b-) phenotype which is consistent with the serological findings. While the Duffy null phenotype may mean that the patient is at risk of producing anti-Fy3, the FY*02N.01 allele with the GATA mutation silences Fyb expression only on RBCs, not on other (e.g. endothelial) cells, meaning that this patient can receive Fy(a-b+) red cells without increased risk of sensitisation. He had received eight units of RBCs transfused prior to this diagnosis [one Fy(a+b+), one Fy(a-b+) six Duffy untyped]. No antibodies have been detected. Summary/Conclusions: In this patient with neutropenia and Fy (a-b-) phenotype, gene sequencing provided valuable information on the underlying molecular mechanism of the discrepancy between the phenotype and genotype to inform future clinical management.