Phenotypic and genotypic evaluation of a large Manitoban kindred with hereditary xerocytosis
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Date
2012-03-12
Authors
Houston, Brett
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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.
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medicine