IDENTIFICATION OF MICRODELETIONS SPANNING THE DIAMOND-BLACKFAN ANEMIALOCUS ON 19Q13 AND EVIDENCE FOR GENETIC-HETEROGENEITY

Diamond-Blackfan anemia (DBA) is a rare pure red-cell hypoplasia of un known etiology and pathogenesis. A major DBA locus has previously been localized to chromosome 19q13.2. Samples from additional families hav e been collected to identify key recombinations, microdeletions, and t he possibility of heterogeneity for the disorder. In total, 29 multipl ex DBA families and 50 families that comprise sporadic DBA cases have been analyzed with polymorphic 19q13 markers, including a newly identi fied short-tandem repeat in the critical gene region. The results from DNA analysis of 23 multiplex families revealed that 26 of these were consistent with a DBA gene on 19q localized to within a 4.1-cM interva l restricted by loci D19S200 and D19S178; however, in three multiplex families, the DBA candidate region on 19q13 was excluded from the segr egation of marker alleles. Our results suggest genetic heterogeneity f or DBA, and we show that a gene region on chromosome 19q segregates wi th the disease in the majority of familial cases. Among the 50 familie s comprising sporadic DBA cases, we identified two novel and overlappi ng microdeletions on chromosome 19q13. In combination, the three known , microdeletions associated with. DBA restrict the critical gene regio n to similar to 1 Mb. The results indicate that a proportion of sporad ic DBA cases are caused by deletions in the 19q13 region.