Phenotypic and genotypic evaluation of a large Manitoban kindred with hereditary xerocytosis

Abstract

The hereditary stomatocytoses are a group of heterogeneous conditions associated with chronic red cell haemolysis for which the causative genetic mutations are not known. We investigated 137 members of a large Manitoban kindred with phenotypic findings consistent with hereditary xerocytosis. The objectives of this study were to systematically characterize the disease phenotype and to define the chromosomal region carrying the disease locus. The mode of inheritance was autosomal dominant. Affected family members were found to have wellcompensated haemolysis, associated with an elevated MCHC, decreased osmotic fragility, decreased haptoglobin, and increased indirect hyperbilirubinemia. Cholelithiasis and progressive iron loading were common, despite normal haemoglobin levels. Quantitative erythrocyte morphologic evaluation revealed increased schistocytes, target cells, reticulocytes, and eccentrocytes in affected individuals; stomatocytes were however not increased. Using DNA linkage analysis, we confirmed the localization of the disease phenotype to chromosome 16q, and we refined the candidate region to 16q24.2 – 16qter, a 2.4 million base pair interval containing 51 known or predicted genes. Exome sequencing, and subsequent bioinformatic analysis identified a single gene mutation within a red cell membrane mechanosensitve ion channel that was present in all affected family members, but in no unaffected individual. Functional studies are necessary to clarify the influence of the identified mutation with regard to erythrocyte structure and function.