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Whole‐exome sequencing of sickle cell disease patients with hyperhemolysis syndrome suggests a role for rare variation in disease predisposition
Author(s) -
Mwesigwa Savannah,
Moulds Joann M.,
Chen Alice,
Flanagan Jonathan,
Sheehan Vivien A.,
George Alex,
Hanchard Neil A.
Publication year - 2018
Publication title -
transfusion
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.045
H-Index - 132
eISSN - 1537-2995
pISSN - 0041-1132
DOI - 10.1111/trf.14431
Subject(s) - exome sequencing , disease , exome , medicine , allele , nonsense , cohort , nonsense mutation , pathogenesis , genetics , mutation , bioinformatics , gene , biology , immunology , missense mutation
BACKGROUND Hyperhemolysis 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 METHODS DNA 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. RESULTS A 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. CONCLUSION Our 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.