A rare genetic deletion in a blood group gene caused hemolytic disease of the fetus and newborn (HDFN) in twin infants, demonstrating how certain maternal antibodies can destroy fetal red blood cells and create life-threatening complications, according to a case report published recently in Transfusion and Apheresis Science.
The discovery underscores the urgent need for rare donor registries and advanced genetic testing to prevent and manage similar immune reactions during pregnancy.
The mother carried the extremely uncommon S-s-U- blood phenotype, in which the U antigen, which is normally found on red blood cells, is absent due to a deletion in the GYPB gene. This absence triggered her immune system to form anti-U and anti-D antibodies that crossed the placenta, attacking the twins’ red cells and leading to HDFN, a condition marked by fetal and newborn anemia, jaundice, and in severe cases, organ failure or death.
“Rare blood groups such as these are now increasingly being detected by blood banks suggest the need for a National Rare Donor Program in India for timely and improved transfusion management of such patients,” explained this study’s authors.
Read more about HDFN testing and diagnosis
Both twins tested positive on a direct agglutination test, confirming immune-mediated red cell destruction. One baby, who was RhD positive, required an exchange transfusion to replace damaged blood, while the RhD-negative twin received phototherapy to treat milder anemia. Both infants recovered and were discharged.
The mother, a 26-year-old woman in Mumbai, was referred to the Indian Council of Medical Research–National Institute of Immunohaematology for complex serologic testing after panagglutination reactions suggested multiple antibodies. Further analysis at the International Blood Group Reference Laboratory in the United Kingdom confirmed her rare S-s-U- phenotype and the presence of anti-D, anti-U, and anti-HI antibodies.
Molecular testing revealed that her GYPB gene was completely deleted, a finding consistent with the null alleles GYPB05N.01 or GYPB05N.02. This genetic loss explains the absence of the U antigen and the resulting immune incompatibility that caused HDFN.
More than 25 cases of HDFN due to anti-U antibodies have been reported globally, most in families of African ancestry, but this case represents the first genetically confirmed instance in India. Even though the mother’s antibody titers were low (≤32), they still caused severe HDFN in one twin. For patients and clinicians, this report reinforces the need for molecular blood typing and rare donor databases to ensure safer transfusions and pregnancies in individuals with uncommon blood group variants.
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