Shwachman–Diamond syndrome (SDS; OMIM 260400) is an autosomal recessive disorder with clinical features that include pancreatic exocrine insufficiency, hematological dysfunction and skeletal abnormalities1,2,3,4. Here, we report identification of disease-associated mutations in an uncharacterized gene, SBDS, in the interval of 1.9 cM at 7q11 previously shown to be associated with the disease5,6. We report that SBDS has a 1.6-kb transcript and encodes a predicted protein of 250 amino acids. A pseudogene copy (SBDSP) with 97% nucleotide sequence identity resides in a locally duplicated genomic segment of 305 kb. We found recurring mutations resulting from gene conversion in 89% of unrelated individuals with SDS (141 of 158), with 60% (95 of 158) carrying two converted alleles. Converted segments consistently included at least one of two pseudogene-like sequence changes that result in protein truncation. SDBS is a member of a highly conserved protein family of unknown function with putative orthologs in diverse species including archaea and eukaryotes. Archaeal orthologs are located within highly conserved operons that include homologs of RNA-processing genes7, suggesting that SDS may be caused by a deficiency in an aspect of RNA metabolism that is essential for development of the exocrine pancreas, hematopoiesis and chrondrogenesis.
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We thank the individuals with SDS, their families and their physicians for their cooperation; M. Corey, N. Ehtesham, D. Ellenor, H. Ginzberg, S.L. Goobie, K. Hagerman, W. Ip, K. Kwon, A. Owaisi and M. Rozenberg for their contributions; and the Canadian Institutes of Health Research Genome Resource Facility and the Sequencing Facility of The Center for Applied Genomics for technical support. We acknowledge support from Shwachman–Diamond Syndrome Canada, Shwachman–Diamond Support of Great Britain, The Harrison Wright Appeal, Shwachman Syndrome Support of Australia, Shwachman–Diamond Syndrome International, Pediatric Consultants, and the Canadian Institutes of Health Research. J.M.R. is a member of the Centers of Excellence/Canadian Genetic Diseases Network. M.P. and G.R.B.B. received Ontario Graduate Scholarships and joint training awards from the Canadian Genetic Diseases Network and The Hospital for Sick Children. G.R.B.B. is also the recipient of a Canadian Institutes of Health Research doctoral research award.
NOTE: In the Supplementary Information for this paper originally published online, Web Figure A did not include a legend. We have since added the legend.