Determination of the genetic etiology causing shwachman-diamond syndrome

Shwachman-Diamond syndrome (SDS, OMIM #260400) is an autosomal recessive disorder characterized by exocrine pancreatic dysfunction, skeletal manifestations, bone marrow failure, increased risk for myelodysplastic syndrome and leukemia (especially acute myeloid leukemia). SDS is classified under hereditary bone marrow failure among ribosomopathies. Recently mutations in new genes have been reported for this syndrome and genetic heterogeneity of the disease which is also clinically heterogeneous, has been demonstrated. In this study, phenotypic and genotypic findings of patients who have SDS preliminary diagnosis was examined. Besides it was aimed to find new genes for etiology by performing whole exom sequencing (WES) analysis in 8 individuals who had SDS phenotype but no mutation was detected in known genes. As a result of WES analysis, a variant which was identified as pathogenic in silico in TBXAS1 gene (causes Ghosal hematodiaphyseal syndrome) was detected in one patient. In another patient with almost all findings of SDS phenotype, a strong candidate gene was revealed by WES analysis and homozygote mapping. This gene encodes a protein of the microtubule-associated protein family and is not currently associated with any phenotype in humans. And a rare nonsense change was detected in a gene which associated with exocytosis in the third patient compatible with SDS phenotype and so another possible candidate gene was revealed. In the remaining 5 patients, no candidate gene was identified from the variant tables by homozygote and compound heterozygote filtration. As a result, strong candidate genes were determined by performing WES as the first step to find new genes that are the aim of this study. Functional studies of these genes will contribute to the elucidation of the etiology and also disease pathogenesis.