Identification of Microdeletions Spanning the Diamond-Blackfan Anemia Locus on 19q13 and Evidence for Genetic Heterogeneity

Abstract

Diamond-Blackfan anemia (DBA) is a rare pure red-cell hypoplasia of unknown etiology and pathogenesis. A major DBA locus has previously been localized to chromosome 19q13.2. Samples from additional families have been collected to identify key recombinations, microdeletions, and the possibility of heterogeneity for the disorder. In total, 29 multiplex DBA families and 50 families that comprise sporadic DBA cases have been analyzed with polymorphic 19q13 markers, including a newly identified short-tandem repeat in the critical gene region. The results from DNA analysis of 29 multiplex families revealed that 26 of these were consistent with a DBA gene on 19q localized to within a 4.1-cM interval restricted by loci D19S200 and D19S178; however, in three multiplex families, the DBA candidate region on 19q13 was excluded from the segregation of marker alleles. Our results suggest genetic heterogeneity for DBA, and we show that a gene region on chromosome 19q segregates with the disease in the majority of familial cases. Among the 50 families comprising sporadic DBA cases, we identified two novel and overlapping microdeletions on chromosome 19q13. In combination, the three known microdeletions associated with DBA restrict the critical gene region to approximately 1 Mb. The results indicate that a proportion of sporadic DBA cases are caused by deletions in the 19q13 region.

Evidence for linkage of familial Diamond-Blackfan anemia to chromosome 8p23.3-p22 and for non-19q non-8p disease

“…8,9 However, mutations of the RPS19 gene have only been identified in 25% of cases, 8,10 suggesting a greater degree of genetic heterogeneity than expected from the initial linkage studies. 7,11 In this report we provide evidence for the existence of a second DBA gene on chromosome 8p, and also for further genetic heterogeneity.…”

“…1,[4][5][6] Recently, linkage analysis of 29 European families showed that DBA in 26 of both dominant and recessive families mapped to chromosome 19q. 7 Identification of a patient with a translocation led to the cloning of a gene on chromosome 19q13.2 that encodes a ribosomal protein, RPS19. 8,9 However, mutations of the RPS19 gene have only been identified in 25% of cases, 8,10 suggesting a greater degree of genetic heterogeneity than expected from the initial linkage studies.…”

Telomeres: a diagnosis at the end of the chromosomes

“…Microdeletions in 19q13.2 have been associated with mental retardation, skeletal malformations, and DiamondBlackfan anaemia. [128][129][130] This suggests a contiguous gene syndrome which includes the ribosomal protein S19 that is mutated in Diamond-Blackfan anaemia.…”

Gene transfer improves erythroid development in ribosomal protein S19–deficient Diamond-Blackfan anemia

“…3,[15][16][17][18] Recently, a balanced translocation (X;19) was identified in a patient with DBA and the translocation breakpoint was shown to disrupt the ribosomal protein S19 (RPS19) gene. 8,19,20 Subsequent analysis of the RPS19 gene revealed mutations in a subset of patients with DBA. Heterozygous mutations in the RPS19 gene have to date been found in approximately 25% of patients with DBA and families with a history of DBA, including nonsense, frameshift, splice site, and missense mutations.…”

“…5,6 Most of the reported cases of DBA are sporadic but 10% to 25% have a positive family history. 7,8 Seventy percent of patients respond initially to corticosteroid treatment, 2,9 but 40% become transfusion-dependent. 9 Allogeneic bone marrow transplantation has been shown to be an effective cure for the disease, which demonstrates that the cause of the disease is intrinsic to the bone marrow.…”