Genomic characterization of the RH locus detects complex and novel structural variation in multi-ethnic cohorts.
Genet Med
; 21(2): 477-486, 2019 02.
Article
em En
| MEDLINE
| ID: mdl-29955105
ABSTRACT
PURPOSE:
Rh antigens can provoke severe alloimmune reactions, particularly in high-risk transfusion contexts, such as sickle cell disease. Rh antigens are encoded by the paralogs, RHD and RHCE, located in one of the most complex genetic loci. Our goal was to characterize RH genetic variation in multi-ethnic cohorts, with the focus on detecting RH structural variation (SV).METHODS:
We customized analytical methods to estimate paralog-specific copy number from next-generation sequencing (NGS) data. We applied these methods to clinically characterized samples, including four World Health Organization (WHO) genotyping references and 1135 Asian and Native American blood donors. Subsequently, we surveyed 1715 African American samples from the Jackson Heart Study.RESULTS:
Most samples in each dataset exhibited SV. SV detection enabled prediction of the immunogenic RhD and RhC antigens in concordance (>99%) with serological phenotyping. RhC antigen expression was associated with exon 2 hybrid alleles (RHCE*CE-D(2)-CE). Clinically relevant exon 4-7 hybrid alleles (RHD*D-CE(4-7)-D) and exon 9 hybrid alleles (RHCE*CE-D(9)-CE) were prevalent in African Americans.CONCLUSION:
This study shows custom NGS methods can accurately detect RH SV, and that SV is important to inform prediction of relevant RH alleles. Additionally, this study provides the first large NGS survey of RH alleles in African Americans.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Sistema do Grupo Sanguíneo Rh-Hr
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Genômica
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Sequenciamento de Nucleotídeos em Larga Escala
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Anemia Falciforme
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article