Mapping of a syndrome of X-linked thrombocytopenia with thalassemia to band Xp11-12: further evidence of genetic heterogeneity of X-linked thrombocytopenia

X-linked thrombocytopenia with thalassemia (XLTT; Online Mendelian Inherita nce in Man [OMIM] accession number 314050) is a rare disorder characterized by thrombocytopenia, platelet dysfunction, splenomegaly, reticulocytosis, and unbalanced hemoglobin chain synthesis. In a 4-generation family, the ge ne responsible for XLTT was mapped to the X chromosome, short arm, bands 11 -12 (band Xp11-12), The maximum lod score possible in this family, 2.39, wa s obtained for markers DXS8054 and DXS1003, at a recombination fraction of 0. Recombination events observed for XLTT and markers DXS8080 and DXS8023 o r DXS991 define a critical region that is less than or equal to 7.65 KcM an d contains the gene responsible for the Wiskott-Aldrich syndrome (WAS; OMIM accession number 301000) and its allelic variant X-linked thrombocytopenia (XLT; OMIM accession number 313900), Manifestations of WAS include thrombo cytopenia, eczema, and immunodeficiency. In WAS/XLT the platelets are usual ly small, and bleeding is proportional to the degree of thrombocytopenia, I n contrast, in XLTT the platelet morphology is normal, and the bleeding tim e is disproportionately prolonged. In this study no alteration in the WAS g ene was detected by Northern blot or Western blot analysis, flow cytometry, or complimentary DNA dideoxynucleotide fingerprinting or sequencing. As ha s been reported for WAS and some cases of XLT, almost total inactivation of the XLTT gene-bearing X chromosome was observed in granulocytes and periph eral blood mononuclear cells from I asymptomatic obligate carrier. The XLTT carrier previously found to have an elevated alpha:beta hemoglobin chain r atio had a skewed, but not clonal, X-inactivation pattern favoring activity of the abnormal allele, Clinical differences and results of the mutation a nalyses make it very unlikely that XLTT is another allelic variant of WAS/X LT and strongly suggest that X-linked thrombocytopenia mapping to band Xp11 -12 is a genetically heterogeneous disorder, (Blood, 2000;95:2262-2268) (C) 2000 by The American Society of Hematology.