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DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot?
Journal article   Open access   Peer reviewed

DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot?

Kevin T Booth, Hela Azaiez and Richard J. H Smith
International journal of molecular sciences, Vol.21(11), p.3951
06/01/2020
DOI: 10.3390/ijms21113951
PMCID: PMC7312536
PMID: 32486382
url
https://doi.org/10.3390/ijms21113951View
Published (Version of record) Open Access

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.
 Biochemistry & Molecular Biology Chemistry Chemistry, Multidisciplinary Life Sciences & Biomedicine Physical Sciences Science & Technology

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