Journal
TRANSFUSION
Volume 58, Issue 3, Pages 726-735Publisher
WILEY
DOI: 10.1111/trf.14431
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Funding
- National Blood Foundation [1103112502]
- National Human Genome Research Institute [U54 HG003273]
- Doris Duke Charitable Foundation [2013096]
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [U54HG003273] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [K08DK110448] Funding Source: NIH RePORTER
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BACKGROUNDHyperhemolysis syndrome (HHS) is an uncommon, but life-threatening, transfusion-related complication of red blood cell transfusion. HHS has predominantly been described in patients with sickle cell disease (SCD) and is difficult to diagnose and treat. The pathogenesis of HHS, including its occurrence in only a subset of apparently susceptible individuals, is poorly understood. We undertook whole-exome sequencing (WES) of 12 SCD-HHS patients to identify shared genetic variants that might be relevant to the development of HHS. STUDY DESIGN AND METHODSDNA from adults with SCD having at least one previous episode of HHS were subject to WES. High-quality variants were passed through a series of bioinformatics filters to identify variants that were uncommon among African populations represented in public databases. Recurrent, putative loss-of-function variants occurring in biologically plausible genes were prioritized and then genotyped in a larger, ancestry-matched cohort of non-HHS controls. RESULTSA rare, heterozygous stop-gain variant (p.Glu210Ter) in MBL2 was significantly enriched among HHS cases (p = 0.002). This variant is predicted to result in a premature termination codon that escapes nonsense-mediated mRNA decay, potentially leading to a novel phenotype. We also observed a complex insertion-deletion variant in the final exon of KLRC3 that was enriched among cases (p = 0.0019), although neither variant was found among seven pediatric SCD-HHS patients. CONCLUSIONOur results suggest a potential role for rare genetic defects in the development of HHS among adult SCD patients. Such enriched variants may ultimately be useful for identifying high-risk individuals and informing therapeutic approaches in HHS.
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