What is the role of genetics in the pathogenesis of hemolytic disease of the newborn (HDN)?

Updated: Dec 28, 2017
  • Author: Sameer Wagle, MBBS, MD; Chief Editor: Muhammad Aslam, MD  more...
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Although the Rh antibody was and still is the most common cause of severe hemolytic disease of the newborn (HDN), other alloimmune antibodies belonging to Kell (K and k), Duffy (Fya), Kidd (Jka and Jkb), and MNSs (M, N, S, and s) systems do cause severe HDN. [4] The Rh blood group system uses Fisher-Race nomenclature, and the Rh gene complex consists of 3 genetic loci each with 2 major alleles. They code for 5 major antigens denoted by letters, C, c, E, e, and D. Rh blood group antigens are inherited as determined by at least 2 homologous but distinct membrane-associated proteins. Two separate genes (RhCE and RhD), located on the short arm of chromosome 1, encode Rh proteins. Each gene is 10 exons in length, and a 96% homology between these genes is observed.

Production of 2 distinct proteins from the RHCE gene is due to alternative splicing of messenger RNA. Rh gene complex is described by 3 loci, and, therefore, 8 gene complexes are possible. These complexes are as follows (listed in decreasing order of frequency among whites): CDe, cde, CDE, cDe, Cde, cdE, CDE, and CdE. Expression is limited to red blood cells (RBCs), with an increasing density during their maturation, unlike the ABH system, which exists in a wide variety of tissues. Rh antigen is not expressed on RBC progenitors.

Of individuals who are Rh positive, 45% are homozygous (CDe/CDe), and 55% are heterozygous (CDe/cde) for the RhD gene. The Rh-negative phenotype represents absence of D protein on RBCs and most commonly results from deletion of the RHD gene on both chromosomes. However, the RHD gene has significant heterogeneity, and several inherited mutations and rearrangements in its structure can result in a lack of expressions of the RhD phenotype as well.

Important examples of such mutations include the RHD pseudogene and RHD-CE-D hybrid gene. The former leads to a stop codon in RHD gene and results in a lack of transcription product despite all intact exons. It is found in 70% of South African blacks and in 25% of African Americans. The RHD-CE-D (Ccde) gene is also found in 22% of D-negative African Americans. It also results in an Rh positive genotype but a negative phenotype. Most Caucasians who are RhD negative have a complete deletion of RHD gene whereas only 18% of African blacks and 54% of African Americans who are RhD negative have complete deletion of the gene; the rest have above nonfunctional variants of the RHD gene. [5]

Beyond the 5 major antigens, more than 100 antigenic variants of Rh group system have been identified. Individuals with these weak-D phenotypes comprise of 2 populations: first group (90%) that expresses normal but reduced quantities of D antigen on the RBC surface, and most cannot be sensitized to produce anti-D. However, the second group (remaining 10%) known as partial-D (eg, Cw, Du) that express partial D epitopes on RBC surface and can make anti-D and rarely experience fatal HDN. The partial D phenotype results from amino acid sunstitution in the active RhD epitope. [6] Most women with partial-D phenotype are classified as Rh negative on routine testing and are candidates for Rh immune globulin (RhIG). Currently, testing of all Rh-negative women for weak expression of D is not recommended. However, Rh-negative infants born to Rh-negative women should undergo testing to detect the partial-D phenotype so that RhIG can be administeredin theevent ofweak expression.

Frequency of Rh negativity is higher in whites (15%) than in blacks (5%) and Hispanics (8%) and is rare in Eskimos, Native Americans, Japanese, and Asians, especially in Chinese individuals. The paternal heterozygosity determines the likelihood of an Rh-positive child being born to an Rh-negative mother. [3]

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