MAL Gene Deletions Confirmed as Cause of Inherited AnWj-Negative Phenotype in Five Individuals

NHS Blood and Transplant researchers used whole-exome sequencing to scan protein-coding regions across the five rare inherited cases. They found consistent biallelic deletions in MAL, then verified that only the full-length MAL transcript produced surface Mal protein reactive with AnWj antibodies in transfected cell lines. Functional rescue experiments showed the altered alleles could not restore antigenicity, meeting ISBT criteria for a new system (ISBT 047).

This work closes a 52-year gap between the 1972 serological observation and molecular assignment. Unlike the far more common acquired AnWj loss linked to hematologic malignancy or transient suppression, the inherited form is permanent and demands antigen-negative units. The study also explains why routine ABO/Rh matching fails in these patients and why anti-AnWj can cause hemolytic transfusion reactions.

Prior coverage understated the diagnostic pipeline now possible: reference labs can add MAL exon-level copy-number analysis to existing genotyping panels within 18 months. This will allow preemptive identification of at-risk patients before they form alloantibodies, a direct clinical translation rarely achieved for newly defined blood-group systems.

The principal limitation remains sample size; only five inherited cases were available worldwide. Larger international registries and prospective sequencing of transfusion-refractory cohorts will be required to refine allele frequencies and confirm reaction-risk estimates.