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Author Notes:

Correspondence: Stella T. Chou, The Children’s Hospital of Philadelphia, 3615 Civic Center Blvd, Abramson Research Center, Room 316D, Philadelphia, PA 19104; e-mail: chous@email.chop.edu.

Contribution: S.T.C., J.M.F., R.E.W., and C.M.W. designed the study, analyzed results, and wrote the manuscript; S.V. conducted research and analyzed results; N.L.C.L. was the SWiTCH transfusion consultant; R.C.B. enrolled patients and collected data for the SWiTCH study; and N.L.C.L. and R.C.B. edited the manuscript.

The authors thank the patients and families who enrolled in the studies, members of the Immunohematology and Genomics Laboratory at the New York Blood Center, the Human Genome Sequencing Centre at Baylor College of Medicine for assistance in generating the whole-exome sequencing data, and Perry Evans for statistical support.

The authors declare no competing financial interests.


Research Funding:

This work was supported by the Doris Duke Innovations in Clinical Research Award grants 2013151 (S.T.C., C.M.W., and R.E.W.), 2011097, and 2015133 (S.T.C. and C.M.W.);

National Institutes of Health (NIH) National Human Genome Research Institute award U54-HGOO3273 (R.E.W.);

NIH National Heart, Lung, and Blood Institute award HL-078787 for the SWiTCH study (R.E.W.);

And in part by a donation from the DiGaetano family (S.T.C.).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Hematology
  • Red blood cell
  • Transfusion
  • Disease
  • Management
  • Zygosity
  • Alleles
  • Encodes

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


Journal Title:

Blood Advances


Volume 1, Number 18


, Pages 1414-1422

Type of Work:

Article | Final Publisher PDF


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.

Copyright information:

© 2017 by The American Society of Hematology.

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