Huizing et al. (1966, 1966) studied 5 generations of an extensive Dutch kindred in which 67 persons had noncongenital progressive perceptive deafness. Onset was in early childhood with impairment of high frequencies. The loss increased rapidly with gradual ... Huizing et al. (1966, 1966) studied 5 generations of an extensive Dutch kindred in which 67 persons had noncongenital progressive perceptive deafness. Onset was in early childhood with impairment of high frequencies. The loss increased rapidly with gradual extension of the impairment to lower frequencies. Huizing et al. (1983) and van den Wijngaart et al. (1985, 1985) provided follow-up on the family reported by Huizing et al. (1966, 1966).
By a positional cloning strategy, Van Laer et al. (1998) isolated a gene from the DFNA5 region that is expressed in the cochlea. In members of the family originally described by Huizing et al. (1966, 1966), they identified ... By a positional cloning strategy, Van Laer et al. (1998) isolated a gene from the DFNA5 region that is expressed in the cochlea. In members of the family originally described by Huizing et al. (1966, 1966), they identified an insertion/deletion mutation in intron 7 of this gene that did not affect intron-exon boundaries, but deleted 5 G-triplets at the 3-prime end of the intron (600994.0001). The mutation cosegregated with deafness in the family and caused skipping of exon 8, resulting in premature termination of the open reading frame. In a Chinese family with autosomal dominant nonsyndromic sensorineural deafness, Yu et al. (2003) identified a 3-bp deletion in the DFNA5 gene (608798.0002) that segregated with the phenotype and was predicted to cause skipping of exon 8, like the DFNA5 mutation previously reported by Van Laer et al. (1998). In a 5-generation Dutch family with autosomal dominant deafness, Bischoff et al. (2004) identified a splice site mutation in the DFNA5 gene (608798.0003) that caused skipping of exon 8. Because of the relatively low amount of short transcript in affected members in this family, the authors suggested that the mutation may have a dominant-negative effect rather than haploinsufficiency. Cheng et al. (2007) identified a heterozygous splice site mutation in the DFNA5 gene (608798.0004) in affected members of a large Chinese family with late-onset sensorineural hearing loss. Onset ranged from 11 to 50 years of age, and hearing loss first affected high frequencies but later involved all frequencies. The authors noted that all of the pathogenic mutations described in the DFNA5 gene result in skipping of exon 8, suggesting a very specific gain-of-function effect. In a 5-generation Iranian family segregating nonsyndromic autosomal dominant sensorineural hearing loss that appeared to map to the DNFA5 locus, Van Laer et al. (2007) identified a heterozygous truncating mutation in exon 5 of the DFNA5 gene. However, further analysis revealed that the mutation did not segregate with hearing loss in this family, and linkage to a locus on chromosome 4 was subsequently found. Van Laer et al. (2007) stated that these findings supported the hypothesis that only a very specific gain-of-function mutation caused by skipping of exon 8 can lead to DFNA5-associated hearing loss.