Shwachman-Diamond Syndrome with Exocrine Pancreatic Dysfunction and Bone Marrow Failure Maps to the Centromeric Region of Chromosome 7

Abstract

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterized by exocrine pancreatic insufficiency and hematologic and skeletal abnormalities. A genomewide scan of families with SDS was terminated at approximately 50% completion, with the identification of chromosome 7 markers that showed linkage with the disease. Finer mapping revealed significant linkage across a broad interval that included the centromere. The maximum two-point LOD score was 8.7, with D7S473, at a recombination fraction of 0. The maximum multipoint LOD score was 10, in the interval between D7S499 and D7S482 (5.4 cM on the female map and 0 cM on the male map), a region delimited by recombinant events detected in affected children. Evidence from all 15 of the multiplex families analyzed provided support for the linkage, consistent with a single locus for SDS. However, the presence of several different mutations is suggested by the heterogeneity of disease-associated haplotypes in the candidate region.

Fine mapping of the locus for Shwachman-Diamond syndrome at 7q11, identification of shared disease haplotypes, and exclusion of TPST1 as a candidate gene

“…Recently, a locus co-segregating with the disease on chromosome 7 was identified in a genomewide scan, and recombination events defined a minimal 2.7 cM interval spanning the centromere. 1 All the families analysed supported linkage to 7p12-q11, consistent with a single locus for SDS.…”

“…1,2,6 Additional families were obtained through ongoing recruitment. Diagnosis of SDS was based on documented evidence of exocrine pancreatic and bone marrow dysfunction, with the latter most commonly involving chronic neutropenia.…”

“…The patients are from five unrelated families used to establish linkage. 1 Primers used are shown in Table 3. Two heterozygous sequence variants were identified, one in intron 2 (1126-19(G?A)), and another in the non-coding exon V (1599(T?G)).…”

“…1 It presents in infancy with failure to thrive and recurrent infections. The phenotypic spectrum can be broad and variable, but exocrine pancreatic dysfunction and haematological abnormalities are consistent features.…”

Genetic Analysis of Shwachman-Diamond Syndrome: Phenotypic Heterogeneity in Patients Carrying Identical SBDS Mutations

“…Cytogenetic studies of bone marrow aspirates from SDS patients who developed myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) more frequently showed structural abnormalities of chromosome 7q as compared to MDS without SDS (Smith et al 1995;Smith et al C and 183-184 (Goobie et al 2001;Popovic et al 2002;Boocock et al 2003). Most mutations detected in the patients are introduced by gene conversion between SBDS and its highly homologous pseudogene (SBDSP).…”