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Immunohematology and Genetic Testing (red cells/leukocytes and platelets) - Immunohematology (includes serology)

(P-IG-18) Discovery of Novel LAN Variant Alleles in Two Patients with Anti-Lan: ABCB6*01(117A, 926insA, 1361C) Encodes for LANnull and ABCB6*01(117A, 985delC) Encodes for a Lan+w/- Phenotype

Sunday, October 26, 2025
12:00 PM - 1:00 PM  PT

    Presenting Author(s)

  • RV

    Randall W. Velliquette

    New York Blood Center Enterprises, Immunohematology and Genomics Laboratory
    New York, New York, United States

Background/Case Studies: The LAN blood group system consists of only 1 high prevalence antigen (Ag), Lan (LAN1) and is encoded by ABCB6. Lan is carried on ABCB6, a multi-pass membrane glycoprotein which belongs to the ATP-binding cassette (ABC) efflux transporter superfamily. To date there are 39 ABCB6 null alleles and 7 alleles encoding Lan weak phenotypes. ABCB6 null persons do not have serologic detectable Lan on their RBCs and are at risk for anti-Lan. The variability in Ag expression of ABCB6*01W variants is thought to be due to quantitative difference in Lan distribution on the RBC membrane. Anti-Lan has variable clinical relevance in transfusion or HDFN. We studied 2 patients with antibody to high prevalence Ag: a Hispanic female (P1) and a Caucasian female (P2).

Study

Design/Methods: Serologic testing was by standard hemagglutination methods. Rare RBCs and antibodies were from frozen in-house collection. A robust 3+ human source anti-Lan was used for adsorption/elution (ads/elu) studies. Genomic DNA was isolated from WBCs and used for amplification and Sanger sequencing of ABCB6 exons 1-19 and flanking intron regions.

Results/Findings: P1 and P2 RBCs were DAT– and typed group O, D+. P1 plasma (P1P) and P2 plasma (P2P) reacted 1+ by IAT with all RBCs tested, including a battery of rare phenotypes except for Lan–; their RBCs subsequently typed Lan–. P1P and P2P were negative by IAT with 4 genotyped Lan– RBC samples: ABCB6*01N.11, ABC6*01N.12 and ABC6*01N.13 (n=2). P1P reacted micro+ (mi) by IAT with 3 Lan+w RBCs with genotype known for 1 (ABC6*01W.01). P2P reacted mi by IAT with Lan+w RBCs (no genotype) but was negative with Lan+w RBCs (1 ABC6*01W.01, 1 ABC6*01W.03). P1 and P2 were mutually compatible. P1 RBCs typed Lan– with 4 human source (HS) anti-Lan and with OSK43 monoclonal anti-Lan. P2 RBCs typed Lan– with 2 HS anti-Lan. Ads/elu studies showed no serologically detectable Lan Ag on P1 RBCs but showed low level Lan on P2; use of known Lan+w were study controls. ABCB6 sequencing detected variants: c.117G >A (p.Leu39=), c.926insA (p.Tyr309Ter), c.1361T >C (p.Val454Ala)in P1 and c.117G >A (p.Leu39=)], c.985delC (p.Leu329Cys*93fs) in P2. The c.926insA and c.985delC are listed on gnomAD v.4.1.0

Conclusions: In 2 patients with anti-Lan we identified 2 novel ABCB6 alleles: ABCB6*01(117A, 926insA, 1361C) in P1 and ABCB6*01(117A, 985delC) in P2. Variants c.926insA in P1 and c.985delC in P2 predict a LANnull (Lan–) phenotype. Extensive serology showed that P1 has a true serologic Lan− phenotype and P2 a Lan+w/- phenotype. Very low level of Lan Ag on P2 as shown by very sensitive ads/elu studies suggests leaky translation of the c.985delC variant, despite encoding a premature stop codon. This case highlights the importance of extensive serologic testing, including adsorption and elution studies with potent anti-Lan, to define true serologic LANnull phenotypes from Lan+w/– or Lan+w in presumed null alleles.