Blood, Vol. 95 No. 7 (April 1), 2000:
pp. 2262-2268
Mapping of a syndrome of X-linked thrombocytopenia
with thalassemia to band Xp11-12: further evidence of
genetic heterogeneity of X-linked thrombocytopenia
Wendy H. Raskind,
Kathy K. Niakan,
John Wolff,
Mark Matsushita,
Ty Vaughan,
George Stamatoyannopoulos,
Chiaki Watanabe,
Jacinda Rios, and
Hans D. Ochs
From the Departments of Medicine (General Internal Medicine and
Medical Genetics) and Pediatrics, University of Washington School of
Medicine, Seattle, WA.
X-linked thrombocytopenia with thalassemia (XLTT; Online Mendelian
Inheritance 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 gene 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, was obtained for markers DXS8054
and DXS1003, at a recombination fraction of 0. Recombination events
observed for XLTT and markers DXS8080 and DXS8023 or DXS991
define a critical region that is less than or equal to 7.65 KcM and 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 thrombocytopenia, eczema,
and immunodeficiency. In WAS/XLT the platelets are usually small,
and bleeding is proportional to the degree of thrombocytopenia. In
contrast, in XLTT the platelet morphology is normal, and the bleeding
time is disproportionately prolonged. In this study no alteration in
the WAS gene was detected by Northern blot or Western blot
analysis, flow cytometry, or complimentary DNA dideoxynucleotide fingerprinting or sequencing. As has been reported for WAS and some
cases of XLT, almost total inactivation of the XLTT
gene-bearing X chromosome was observed in granulocytes and
peripheral blood mononuclear cells from 1 asymptomatic obligate
carrier. The XLTT carrier previously found to have an elevated 
:
hemoglobin chain ratio had a skewed, but not clonal,
X-inactivation pattern favoring activity of the abnormal allele.
Clinical differences and results of the mutation analyses make it very
unlikely that XLTT is another allelic variant of WAS/XLT and strongly
suggest that X-linked thrombocytopenia mapping to band Xp11-12 is a
genetically heterogeneous disorder.
