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

TitleStructural variation and missense mutation in SBDS associated with Shwachman-Diamond syndrome.
Publication TypeJournal Article
Year of Publication2014
AuthorsCarvalho, CMB, Zuccherato, LW, Williams, CL, Neill, NJ, Murdock, DR, Bainbridge, M, Jhangiani, SN, Muzny, DM, Gibbs, RA, Ip, W, Guillerman, RPaul, Lupski, JR, Bertuch, AA
JournalBMC Med Genet
Date Published2014 Jun 04
KeywordsAbdomen, Alleles, Bone Marrow Diseases, Cell Line, Transformed, Child, Preschool, Comparative Genomic Hybridization, DNA Mutational Analysis, Exocrine Pancreatic Insufficiency, Female, Gene Order, Humans, Lipomatosis, Mutagenesis, Insertional, Mutation, Mutation, Missense, Pedigree, Proteins, Radiography, Abdominal, Ultrasonography

BACKGROUND: 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.

CONCLUSION: 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.

Alternate JournalBMC Med. Genet.
PubMed ID24898207
PubMed Central IDPMC4057820
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
T32 GM008307 / GM / NIGMS NIH HHS / United States