DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot?
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.
['Booth|Kevin T|KT|0000-0003-3061-3652', 'Azaiez|Hela|H|0000-0002-2863-6970', 'Smith|Richard J H|RJH|0000-0003-1201-6731']
D001299:Audiometry D005091:Exons D005260:Female D018703:Founder Effect D017353:Gene Deletion D006239:Haplotypes D006319:Hearing Loss, Sensorineural D006801:Humans D007438:Introns D008297:Male D009154:Mutation D010375:Pedigree D020641:Polymorphism, Single Nucleotide D011743:Pyrimidines D012326:RNA Splicing D011960:Receptors, Estrogen
DFNA5 GSDME founder mutation mutational hotspot RNA splicing