Abstract
Deafness due to mutations in the DFNA5 gene is caused by the aberrant splicing of exon 8, which results in a constitutively active truncated protein. In a large family of European descent (MORL-ADF1) segregating autosomal dominant nonsyndromic hearing loss, we used the OtoSCOPE platform to identify the genetic cause of deafness. After variant filtering and prioritization, the only remaining variant that segregated with the hearing loss in the family was the previously described c.991-15_991-13delTTC mutation in DFNA5. This 3-base pair deletion in the polypyrimidine of intron 7 is a founder mutation in the East Asian population. Using ethnicity-informative markers and haplotype reconstruction within the DFNA5 gene, we confirmed family MORL-ADF1 is of European ancestry, and that the c.991-15_991-13delTTC mutation arose on a unique haplotype, as compared to that of East Asian families segregating this mutation. In-depth audiometric analysis showed no statistical difference between the audiometric profile of family MORL-ADF1 and the East Asian families. Our data suggest the polypyrimidine tract in intron 7 may be a hotspot for mutations.
Highlights
The dysregulation of RNA-splicing is a common driver of disease
It is well established that mis-splicing of exon 8 of the DFNA5 (GSDME) gene leads to the translation of a mutant protein that causes autosomal dominant (AD) post-lingual progressive nonsyndromic hearing loss (NSHL) [6,7,8,9,10,11,12]
DFNA5 is widely expressed throughout the body, the toxic gain-of-function protein that is produced as a result of skipping exon 8 results only in deafness [6,7,8,9,15,16]
Summary
The dysregulation of RNA-splicing is a common driver of disease. Most commonly, mis-splicing is caused by alterations at the DNA level that impact the binding of one or more of the spliceosome proteins [1]. The resultant mutant mRNA products are targeted for degradation via the nonsense-mediated decay (NMD) pathway, but, in some cases, translation occurs and a mutant protein is produced that drives disease [2,3,4,5] Such is the case of DFNA5-related hearing loss [6,7]. One mutation (c.991-15_991-13delTTC), has been identified in six families of East Asian descent [7,8,9,15,16]. We report the first family of European descent co-segregating post-lingual progressive ADNSHL and the c.991-15_991-13delTTC mutation in DFNA5. Haplotype analysis shows this mutation arose on a. Analysis of these SNPs defined the ancestry of proband III. as a mix of European ethnicities with the highest probability of Toscani, Ashkenazi Jewish, and Hungarian
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