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Blood Adv. 2017 Aug 3;1(18):1414-1422. doi: 10.1182/bloodadvances.2017007898. eCollection 2017 Aug 8.

Whole-exome sequencing for RH genotyping and alloimmunization risk in children with sickle cell anemia.

Author information

1
Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA.
2
Division of Hematology, Department of Pediatrics, Baylor College of Medicine, Houston, TX.
3
Laboratory of Immunohematology and Genomics, New York Blood Center, New York, NY.
4
Department of Transfusion Medicine and Department of Pediatrics, Children's National Medical Center, Washington, DC.
5
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA; and.
6
Division of Hematology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

Abstract

RH genes are highly polymorphic and encode the most complex of the 35 human blood group systems. This genetic diversity contributes to Rh alloimmunization in patients with sickle cell anemia (SCA) and is not avoided by serologic Rh-matched red cell transfusions. Standard serologic testing does not distinguish variant Rh antigens. Single nucleotide polymorphism (SNP)-based DNA arrays detect many RHD and RHCE variants, but the number of alleles tested is limited. We explored a next-generation sequencing (NGS) approach using whole-exome sequencing (WES) in 27 Rh alloimmunized and 27 matched non-alloimmunized patients with SCA who received chronic red cell transfusions and were enrolled in a multicenter study. We demonstrate that WES provides a comprehensive RH genotype, identifies SNPs not interrogated by DNA array, and accurately determines RHD zygosity. Among this multicenter cohort, we demonstrate an association between an altered RH genotype and Rh alloimmunization: 52% of Rh immunized vs 19% of non-immunized patients expressed variant Rh without co-expression of the conventional protein. Our findings suggest that RH allele variation in patients with SCA is clinically relevant, and NGS technology can offer a comprehensive alternative to targeted SNP-based testing. This is particularly relevant as NGS data becomes more widely available and could provide the means for reducing Rh alloimmunization in children with SCA.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

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