Exclusion of linkage of Shwachman-Diamond syndrome to chromosome regions 6q and 12q implicated by a de novo translocation

Shwachman-Diamond syndrome is a rare genetic disorder of unknown pathogenes is involving exocrine pancreatic insufficiency and hematological and skelet al abnormalities. There is broad clinical variability; the extent of hetero geneity is unknown but comparisons within a large cohort of patients show n o striking differences between patients of families with single or multiple affected offspring. Segregation analysis of a cohort of 69 families has su ggested an autosomal recessive mode of inheritance. A single constitutional de novo chromosome rearrangement was reported in a Japanese patient involv ing a balanced translocation, t(6;12)(q16.2;q21.2), thereby suggesting poss ible loci for a genetic defect. Evenly spaced microsatellite markers spanni ng 26-32 cM intervals from D6S1056 to D6S304 and D12S375 to D12S346 were an alyzed for linkage in members of 13 Shwachman-Diamond syndrome families wit h two or three affected children. Two-point lod scores were calculated for each marker under assumptions of recessive inheritance and complete penetra nce. Negative lod scores indicated exclusion of both chromosome regions, Fu rther, affected sibs were discordant for inheritance of chromosomes in most families based on constructed haplotypes. The cytogenetic abnormality is n ot associated with most cases of Shwachman-Diamond syndrome. Am. J, Med, Ge net, 85:171-174, 1999, (C) 1999 Wiley-Liss, Inc.