DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot?
1
Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa, Iowa City, IA 52242, USA
2
Department of Neurobiology, Harvard Medical School, Boston, MA 02215, USA
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(11), 3951; https://doi.org/10.3390/ijms21113951
Received: 8 May 2020
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Revised: 27 May 2020
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Accepted: 29 May 2020
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Published: 31 May 2020
(This article belongs to the Section Molecular Genetics and Genomics)
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.
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Keywords:
DFNA5; GSDME; founder mutation; mutational hotspot; RNA splicing
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MDPI and ACS Style
Booth, K.T.; Azaiez, H.; Smith, R.J.H. DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot? Int. J. Mol. Sci. 2020, 21, 3951. https://doi.org/10.3390/ijms21113951
AMA Style
Booth KT, Azaiez H, Smith RJH. DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot? International Journal of Molecular Sciences. 2020; 21(11):3951. https://doi.org/10.3390/ijms21113951
Chicago/Turabian StyleBooth, Kevin T., Hela Azaiez, and Richard J.H. Smith. 2020. "DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot?" International Journal of Molecular Sciences 21, no. 11: 3951. https://doi.org/10.3390/ijms21113951
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