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Large genomic deletions in Shwachman-Diamond syndrome

Wednesday, September 12, 2018 — Poster Session I

12:00 p.m. – 1:30 p.m.
FAES Terrace


  • LJ McReynolds
  • K Jones
  • K Teshome
  • A Kennedy
  • A Shimamura
  • N Giri
  • BP Alter
  • SA Savage


Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome (IBMFS) with gastrointestinal manifestations and cytopenias. More than 90% of patients have autosomal recessive inheritance of germline pathogenic variants in SBDS, a ribosome biogenesis gene. The NCI’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 was uninformative in all but one. Using long-range Single Molecule, Real-Time Sequencing (PacBio Systems) the causative deletion was identified in three additional families. Targeted sequencing across the known SDS genes SBDS, EFL1, DNAJC21 and SRP54 was performed. In a proband with classic SDS phenotype, a very large deletion, 19kb, was identified. This patient also had single known SBDS variant and western blotting showed decreased SBDS protein. The second proband studied an 872bp deletion was identified. This patient had another single known SBDS variant and a western consistent with SBDS loss. The third family had two affected siblings with neutropenia, and normal levels of SBDS protein. An autosomal dominant SRP54 deletion was identified in both siblings. No large deletions or insertions were identified in DNAJC21. Analysis of EFL1 is on-going. These cases illustrate the advantages of using long-read sequencing methodologies to identify large deletions which are not readily found using short-read sequencing, and identify large deletions as a novel mechanism of SDS inheritance.

Category: Genetics and Genomics