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Structural variation and missense mutation in SBDS associated with Shwachman-Diamond syndrome

Claudia M B Carvalho12, Luciana W Zuccherato1, Christopher L Williams4, Nicholas J Neill1, David R Murdock3, Matthew Bainbridge3, Shalini N Jhangiani3, Donna M Muzny3, Richard A Gibbs3, Wan Ip6, Robert Paul Guillerman57, James R Lupski145 and Alison A Bertuch145*

Author Affiliations

1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

2 Centro de Pesquisas René Rachou – FIOCRUZ, Belo Horizonte, MG, Brazil

3 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA

4 Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

5 Texas Children’s Hospital, 1102 Bates, FC 1200, Houston, TX 77030, USA

6 Program in Physiology and Experimental Medicine, The Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada

7 Department of Radiology, Baylor College of Medicine, Houston, TX, USA

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BMC Medical Genetics 2014, 15:64  doi:10.1186/1471-2350-15-64

Published: 4 June 2014



Shwachman–Diamond syndrome (SDS) is an autosomal recessive ribosomopathy caused mainly by compound heterozygous mutations in SBDS. Structural variation (SV) involving the SBDS locus has been rarely reported in association with the disease. We aimed to determine whether an SV contributed to the pathogenesis of a case lacking biallelic SBDS point mutations.

Case presentation

Whole exome sequencing was performed in a patient with SDS lacking biallelic SBDS point mutations. Array comparative genomic hybridization and Southern blotting were used to seek SVs across the SBDS locus. Locus-specific polymerase chain reaction (PCR) encompassing flanking intronic sequence was also performed to investigate mutation within the locus. RNA expression and Western blotting were performed to analyze allele and protein expression. We found the child harbored a single missense mutation in SBDS (c.98A > C; p.K33T), inherited from the mother, and an SV in the SBDS locus, inherited from the father. The missense allele and SV segregated in accordance with Mendelian expectations for autosomal recessive SDS. Complementary DNA and western blotting analysis and locus specific PCR support the contention that the SV perturbed SBDS protein expression in the father and child.


Our findings implicate genomic rearrangements in the pathogenesis of some cases of SDS and support patients lacking biallelic SBDS point mutations be tested for SV within the SBDS locus.

Shwachman-Diamond syndrome; SBDS; Structural variation; Genomic rearrangement; Non-allelic homologous recombination; Low copy repeat; Whole exome sequencing; Copy number variation; Recessive disease