Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular backgrounds of variants encountered in Afro-Caribbean black individuals and associated with the production of clinically significant antibodies against high-incidence antigens (anti-RH18, anti-RH34) and against Rhe epitopes were determined. We showed that RH:-18 phenotypes are produced by 3 distinct RHCE alleles: ceEK carrying 48G>C (exon 1), 712A>G, 787A>G, 800T>A (exon 5); ceBI carrying 48G>C (exon 1), 712A>G (exon 5), 818C>T (exon 6), 1132C>G (exon 8); and the already known ceAR allele carrying 48G>C (exon 1), 712A>G, 733C>G, 787A>G, 800T>A (exon 5), and 916A>G (exon 6). The RH:-34 phenotype is produced by the (C)ce(s) haplotype described previously and composed of a hybrid D-CE(3-8)-D gene with 4 extra mutations next to a ce(s) allele (733C>G; exon 5) with an extra mutation in exon 7 (1006G>T). Partial Rhe with risk of immunization against lacking epitopes can be produced by the new ce(s) allele carrying an extra mutation in exon 3 (340C>T) and by the ceMO allele described previously. A population of sickle cell disease patients was screened to estimate the incidence of these rare alleles, with the conclusion that a procedure is required to detect the associated phenotypes in black donors to ensure transfusion safety for patients. We also described a new variant [ce(s)(748)] and variants carrying different altered alleles in nonimmunized patients and for whom the risk of immunization is discussed.
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PMID:Rare RHCE phenotypes in black individuals of Afro-Caribbean origin: identification and transfusion safety. 1239 40

The Rh system is one of the most important and complex blood group systems because of the large number of antigens and the serious complications for the fetus of a woman sensitized by transfusion or pregnancy. Major advances in our understanding of the Rh system have occurred with the cloning of the genes and with functional evidence that the Rh blood group proteins belong to an ancient family of membrane proteins involved in ammonia transport. The arrangement and configuration of the genes at the RH locus promotes genetic exchange, generating new antigens. Importantly, RH genetic testing can now be applied to clinical transfusion medicine and prenatal practice. This includes testing for RHD zygosity, confirmation or resolution of D antigen status, and detection of altered RHD and RHCE genes in individuals at risk for producing antibodies to high-incidence Rh antigens, particularly sickle cell disease (SCD) patients. The Rh proteins form a core complex that is critical to the structure of the erythrocyte membrane, and they may play a physiologic role in the sequestration of blood ammonia. The Rh family of proteins now includes non-erythroid homologs present in many other tissues, and comparative genomics reveal Rh homologs in all domains of life.
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PMID:The structure and function of the Rh antigen complex. 1719 46

The last decade has witnessed an abundance of information detailing the genetic diversity of the RH locus which has exceeded all estimates predicted by serology. Well over 120 RHD and over 60 different RHCE alleles have been documented, and new alleles are still being discovered. For clinical transfusion medicine, RH genetic testing can now be used to determine RHD zygosity, resolve D antigen status, and detect altered RHD and RHCE genes in individuals at risk for producing antibodies to high-incidence Rh antigens, particularly patients with sickle cell disease (SCD).
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PMID:Molecular biology of the Rh system: clinical considerations for transfusion in sickle cell disease. 2000 97

The alleles RHCE*ceBI (RHCE*ce 48C, 712G, 818T, 1132G) and RHCE*ceSM (RHCE*ce 48C, 712G, 818T) encode the low-prevalence Rh antigen STEM. These alleles frequently travel in cis with RHD*DOL. To estimate the frequency of these alleles, we tested a total of more than 700 samples in two populations. Blood samples were obtained from patients with sickle cell disease and from blood donors of African descent. DNA extractions and analyses were performed by standard methods. In the United States, none of 70 patient samples had the RHCE*818 nucleotide change. Two of 220 donors (frequency of 0.009) were heterozygous for RHCE*818C/T (RHCE*ceBI). One of these samples had RHD/RHD*DOL and the other had RHD/RHD*DOL-2. In these 290 samples, no other RHD*DOL alleles were found. In Brazil, 1 of 244 patients with sickle cell disease (frequency of 0.004) and 1 of 171 donors (frequency of 0.006) were heterozygous for RHCE*818C/T (RHCE*ceBI). Testing of more than 500 additional samples from people of African descent, selected because they had a diverse range of common and variant RHCE alleles, did not reveal a sample with RHD*DOL or RHD/RHD*DOL-2 in the absence of RHCE*ce(818T). Although the numbers are small, our study shows that in the United States, the frequency of RHCE*818T is 0.007 (2 in 290 samples) and in Brazil it is 0.004 (2 in 515 samples). The four RHCE*818T alleles were RHCE*ceBI.
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PMID:Prevalence of RHD*DOL and RHCE*ce(818T) in two populations. 2235 22

Since the discovery of the ABO blood group in the early 20th century, more than 300 blood group antigens have been categorized among 35 blood group systems. The molecular basis for most blood group antigens has been determined and demonstrates tremendous genetic diversity, particularly in the ABO and Rh systems. Several blood group genotyping assays have been developed, and 1 platform has been approved by the Food and Drug Administration as a "test of record," such that no phenotype confirmation with antisera is required. DNA-based red blood cell (RBC) phenotyping can overcome certain limitations of hemagglutination assays and is beneficial in many transfusion settings. Genotyping can be used to determine RBC antigen phenotypes in patients recently transfused or with interfering allo- or autoantibodies, to resolve discrepant serologic typing, and/or when typing antisera are not readily available. Molecular RBC antigen typing can facilitate complex antibody evaluations and guide RBC selection for patients with sickle cell disease (SCD), thalassemia, and autoimmune hemolytic anemia. High-resolution RH genotyping can identify variant RHD and RHCE in patients with SCD, which have been associated with alloimmunization. In the future, broader access to cost-efficient, high-resolution RBC genotyping technology for both patient and donor populations may be transformative for the field of transfusion medicine.
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PMID:Red Blood Cell Antigen Genotyping for Sickle Cell Disease, Thalassemia, and Other Transfusion Complications. 2734 38

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.
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PMID:Whole-exome sequencing for RH genotyping and alloimmunization risk in children with sickle cell anemia. 2929 82

Rh alloimmunization remains a challenge for patients with sickle cell disease (SCD) despite transfusion of serologic Rh C, E, and K antigen-matched red cells. Inheritance of altered RH alleles contributes to the prevalence of Rh antibodies after blood transfusion in patients with SCD and explains approximately one-third of cases. The remainder seem to be stimulated by altered Rh proteins on African American donor red cells. Matching patients with donors on the basis of RH genotype may mitigate Rh alloimmunization, but the feasibility and resources required are not known. We compared RH allele frequencies between patients with SCD (n = 857) and African American donors (n = 587) and showed that RH allele frequencies are similar. Overall, 29% of RHD and 53% of RHCE alleles are altered in patients and African American donors. We modeled RH genotype matching compared with serologic Rh D, C, and E, along with K antigen matching, and found that approximately twice the number of African American donors would be required for RH genotype vs Rh serologic matching at our institution. We demonstrated that African American donor recruitment is necessary to maintain an adequate supply of C-, E-, and K-negative donor units to avoid depleting the Rh-negative (RhD-) blood supply. Our results suggest that prophylactic RH genetic matching for patients with SCD is feasible with a donor pool comprised primarily of African-Americans and would optimize the use of our existing minority donor inventory. The current cost of RH genotyping all minority donors and management of the data remain limiting factors.
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PMID:RH genotype matching for transfusion support in sickle cell disease. 3021 39

The development of red blood cell (RBC) alloantibodies and autoantibodies complicates transfusion therapy in sickle cell disease (SCD) patients. In an effort to reduce the risk of alloimmunization, some strategies have been used to provide antigen-matched RBC transfusions to patients with SCD in Brazil, including molecular matching in 3 levels: RH and K matching; extended matching (RH, KEL, FY, JK, MNS, DI), and extended matching including RHD and RHCE variant alleles. Molecular matching has shown clinical benefits to the patients with SCD, contributing significantly to reduce the rates of alloimmunization. Improvements in the clinical outcomes of the patients have also been observed as shown by an increase in their hemoglobin levels and reduction in their percentage of hemoglobin S as well as better in vivo RBC survival and diminished frequency of transfusions. However, prevention of RBC alloimmunization still remains a challenge in Brazil due to the difficulty to fulfill all transfusion requests of the patients with antigen-matching units, inaccuracy of RBC phenotyping, RBC transfusions outside the institution where the patient is treated, advanced age of some patients, the RBC antigen discrepancy between donors and recipients, and the presence of RH variants.
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PMID:Optimized Antigen-Matched in Sickle Cell Disease Patients: Chances and Challenges in Molecular Times - the Brazilian Way. 3028 75

This review presents the French strategy for blood group genotyping in high-responder and newly diagnosed sickle cell disease (SCD) patients. In addition to FY, JK, and MNS genotyping, the RH blood group system is now explored in SCD patients in France. Molecular typing has been used for the deduction of partial RH2 (C) antigens since 2010, and the gradual implementation of systematic RHD and RHCE genotyping nationwide was initiated in late 2014. In our laboratory, 962 RH:2 (C-positive) SCD patients have been tested since 2010, and 1,148 SCD patients of all RH phenotypes have been genotyped for clinically relevant alleles of RHD and RHCE since late 2014.
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PMID:Genotyping in Sickle Cell Disease Patients: The French Strategy. 3028 76

RHD and RHCE genes encode Rh blood group antigens and exhibit extensive single-nucleotide polymorphisms and chromosome structural changes in patients with sickle cell disease (SCD). RH variation can drive loss of antigen epitopes or expression of new epitopes, predisposing patients with SCD to Rh alloimmunization. Serologic antigen typing is limited to common Rh antigens, necessitating a genetic approach to detect variant antigen expression. We developed a novel algorithm termed RHtyper for RH genotyping from existing whole-genome sequencing (WGS) data. RHtyper determined RH genotypes in an average of 3.4 and 3.3 minutes per sample for RHD and RHCE, respectively. In a validation cohort consisting of 57 patients with SCD, RHtyper achieved 100% accuracy for RHD and 98.2% accuracy for RHCE, when compared with genotypes obtained by RH BeadChip and targeted molecular assays and after verification by Sanger sequencing and independent next-generation sequencing assays. RHtyper was next applied to WGS data from an additional 827 patients with SCD. In the total cohort of 884 patients, RHtyper identified 38 RHD and 28 RHCE distinct alleles, including a novel RHD DAU allele, RHD* 602G, 733C, 744T 1136T. RHtyper provides comprehensive and high-throughput RH genotyping from WGS data, facilitating deconvolution of the extensive RH genetic variation among patients with SCD. We have implemented RHtyper as a cloud-based public access application in DNAnexus (https://platform.dnanexus.com/app/RHtyper), enabling clinicians and researchers to perform RH genotyping with next-generation sequencing data.
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PMID:A novel algorithm comprehensively characterizes human RH genes using whole-genome sequencing data. 3291 77


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