Large Genomic Deletions in Shwachman-Diamond Syndrome

Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome (IBMFS) with gastrointestinal manifestations (pancreatic insufficiency) and cytopenias, primarily neutropenia. Skeletal dysplasias and short stature are frequent. Patients with SDS are at significantly increased risk of myelodysplastic syndrome and acute myeloid leukemia. More than 90% of patients have autosomal recessive inheritance of germline pathogenic variants in SBDS, a ribosome biogenesis gene. The most common variants are c.258+2T>C (disrupts the donor splice site of intron 2, leading to an 8bp deletion and a premature protein truncation due to a frameshift); and c.183_184TA>CT (introduces an in-frame stop codon). To date, the vast majority of pathogenic alleles reported have been single nucleotide variants (SNVs) or small insertions/deletions. Rare cases have been reported with SBDS exon 3 deletions.The National Cancer Institute's IBMFS study is a longitudinal cohort study with 521 families enrolled, including 54 SDS or SDS-like families. Through clinical testing or whole exome sequencing all but nine families have had their disease-causing alleles identified. Three of the nine families had a known single pathogenic variant in SBDS. Array comparative genomic hybridization (aCGH) was uninformative in all but one.We initially focused on the family with a known SBDS c.258+2T>C and potential deletion on aCGH. The 27 year-old (yo) male proband was diagnosed with SDS at 5yo due to a hist...
Source: Blood - Category: Hematology Authors: Tags: 508. Bone Marrow Failure: Poster II Source Type: research