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

Area of Science:

• Genetics
• Molecular Biology
• Human Disease

Background:

• Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive ribosomopathy.
• Mutations in the SBDS gene are the primary cause of SDS.
• Structural variations (SVs) at the SBDS locus are infrequently associated with SDS.

Observation:

• A patient with SDS lacking biallelic SBDS point mutations was investigated.
• Whole exome sequencing, array comparative genomic hybridization, and Southern blotting were employed.
• Locus-specific PCR, RNA expression, and Western blotting analyzed gene and protein expression.

Findings:

• The patient had a single missense mutation (c.98A > C; p.K33T) in SBDS and an SBDS locus SV.
• The missense mutation was inherited from the mother, and the SV from the father.
• The SV and missense allele segregated according to autosomal recessive inheritance patterns for SDS.
• Analysis indicated the SV disrupted SBDS protein expression in the father and patient.

Implications:

• Genomic rearrangements are implicated in the pathogenesis of some SDS cases.
• Patients with SDS lacking biallelic SBDS point mutations should be evaluated for SBDS locus SVs.
• This expands the understanding of genetic mechanisms underlying SDS.