title: A novel synonymous mutation causing complete skipping of exon 16 in the SLC26A4 gene in a Korean family with hearing loss.
abstract: BACKGROUND
  Mutations in PDS (or SLC26A4) cause both Pendred syndrome (PS) and DFNB4, two autosomal recessive disorders that share hearing loss as a common feature. PS and DFNB4 are genetically homogeneous disorders caused by bi-allelic SLC26A4 mutations. Here, we report a novel synonymous mutation (c.1803G>A, p.Lys601Lys), that caused aberrant splicing in two Korean family members who were clinically considered to have DFNB4, along with congenital hearing loss and dilated vestibular aqueducts (DVA).
  
  
  METHODS
  After extracting DNA from whole blood using standard procedures, the 21 exons and flanking introns of SLC26A4 were amplified with PCR. To evaluate the implication of a novel synonymous mutation (c.1803G>A), we used The Berkeley Drosophila Genome Project (BDGP) (http://www.fruitfly.org/) as a splice site prediction program and performed exon trapping analysis.
  
  
  RESULTS
  In molecular analysis of the 21 exons of SCL26A4, we detected a known splicing mutation (c.919-2A>G, heterozygote) and a novel variant (c.1803G>A, heterozygote) in the patients (II-1 and II-2). According to in silico analysis, the novel variant (c.1803G>A) affects canonical splice donor nucleotide positioning. To define the transcript level effects of this novel 1803G>A variant, we performed exon trapping and confirmed that exon 16 is completely skipped in this variant type.
  
  
  CONCLUSIONS
  We report a novel synonymous mutation (c.1803G>A) causing complete exon 16 skipping in the SLC26A4 gene in two Korean family members with hearing loss. This is the first case of a synonymous SNP (c.1803G>A) affecting vestibulocochlear organs through altering splicing accuracy by causing a complete skipping of exon 16. An important issue raised by this study is that synonymous mutations that have been previously ignored in clinical diagnoses must now be considered as potential pathogenic mutations.
authors.affiliation: Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Yoonjung
authors.initials: Y
authors.lastname: Kim
authors.forename: Hui Ram
authors.initials: HR
authors.lastname: Kim
authors.forename: Juwon
authors.initials: J
authors.lastname: Kim
authors.forename: Joong-Wook
authors.initials: JW
authors.lastname: Shin
authors.forename: Hong-Joon
authors.initials: HJ
authors.lastname: Park
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Choi
authors.forename: Un-Kyung
authors.initials: UK
authors.lastname: Kim
authors.forename: Kyung-A
authors.initials: KA
authors.lastname: Lee
mesh_terms: D044466:Asian People / Q000235:genetics; D002675:Child, Preschool; D005091:Exons / Q000235:genetics*; D005260:Female; D006044:Goiter, Nodular / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D056910:Republic of Korea; D000076988:Sulfate Transporters
chemical_list: D026901:Membrane Transport Proteins; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters