title: Structural variation and missense mutation in SBDS associated with Shwachman-Diamond syndrome.
abstract: 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Claudia M B
authors.initials: CM
authors.lastname: Carvalho
authors.forename: Luciana W
authors.initials: LW
authors.lastname: Zuccherato
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Williams
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Neill
authors.forename: David R
authors.initials: DR
authors.lastname: Murdock
authors.forename: Matthew
authors.initials: M
authors.lastname: Bainbridge
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: Wan
authors.initials: W
authors.lastname: Ip
authors.forename: Robert Paul
authors.initials: RP
authors.lastname: Guillerman
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. abertuch@bcm.edu.
authors.forename: Alison A
authors.initials: AA
authors.lastname: Bertuch
mesh_terms: D000005:Abdomen / Q000000981:diagnostic imaging; D000483:Alleles; D001855:Bone Marrow Diseases / Q000175:diagnosis / Q000235:genetics*; D002461:Cell Line, Transformed; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D010188:Exocrine Pancreatic Insufficiency / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D023061:Gene Order; D006801:Humans; D008068:Lipomatosis / Q000175:diagnosis / Q000235:genetics*; D016254:Mutagenesis, Insertional; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D011860:Radiography, Abdominal; D000081003:Shwachman-Diamond Syndrome; D014463:Ultrasonography
chemical_list: D011506:Proteins; C470521:SBDS protein, human