ORPHA: 90635; DO: 0110575;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7p15.3 | Deafness, autosomal dominant 5 | 600994 | Autosomal dominant | 3 | GSDME | 608798 |
A number sign (#) is used with this entry because autosomal dominant deafness-5 (DFNA5) is caused by heterozygous mutation in the DFNA5 gene (GSDME; 608798) on chromosome 7p15.
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).
In the extended Dutch kindred with autosomal dominant progressive hearing loss starting in the high frequencies originally described by Huizing et al. (1966, 1966), Van Camp et al. (1995) used linkage analysis to localize the causative mutation to a 15-cM interval between markers D7S493 and D7S632. These markers had previously been mapped to 7p15 by in situ hybridization (Green et al., 1994).
Van Laer et al. (1997) refined the DFNA5 candidate region to less than 2 cM and cloned the region in a YAC contig. The refinement of the candidate region of DFNA5 excluded the HOXA1 gene (142955) as a candidate for mutation in this disorder.
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 DFNA5 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. The authors stated that linkage to a locus on chromosome 4 was subsequently found (unpublished results). 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.
Using 2 next-generation sequencing platforms, Booth et al. (2018) identified 5 families with autosomal dominant postlingual progressive nonsyndromic hearing loss with 3 novel and 2 recurrent mutations in the DFNA5 gene. The 3 novel mutations were missense mutations within exon 8 that were predicted to reduce the efficiency of, or abolish, splicing (see, e.g., Q368E, 608798.0005). Functional impact of these 3 mutations was confirmed in vitro using minigenes. The authors noted that previously overlooked silent mutations within exon 8 could alter splicing, and they suggested that families with high frequency progressive hearing loss linked to the DFNA5 gene should be evaluated for variants in the flanking introns and in the exon itself.
Dolowitz and Stephens (1961) described high tone neural deafness present at all ages but more severe in older members of 4 generations of a Mormon kindred. Slow progression of the hearing loss over several decades was well demonstrated.
Paparella et al. (1969) described the anatomic findings in 2 cases of dominant progressive sensorineural deafness. Nance and McConnell (1973) observed a 4-generation kindred.
Higashi (1988) suggested that high-frequency sensorineural hearing loss with autosomal dominant inheritance can be divided into 4 types on the basis of the slope of audiograms. The first type has the steepest audiogram and the fourth has an audiogram close to horizontal; the other 2 types are intermediate.
Bischoff, A. M. L. C., Luijendijk, M. W. J., Huygen, P. L. M., van Duijnhoven, G., De Leenheer, E. M. R., Oudesluijs, G. G., Van Laer, L., Cremers, F. P. M., Cremers, C. W. R. J., Kremer, H. A novel mutation identified in the DFNA5 gene in a Dutch family: a clinical and genetic evaluation. Audiol. Neurootol. 9: 34-46, 2004. [PubMed: 14676472] [Full Text: https://doi.org/10.1159/000074185]
Booth, K. T., Azaiez, H., Kahrizi, K., Wang, D., Zhang, Y., Frees, K., Nishimura, C., Najmabadi, H., Smith, R. J. Exonic mutations and exon skipping: lessons learned from DFNA5. Hum. Mutat. 39: 433-440, 2018. [PubMed: 29266521] [Full Text: https://doi.org/10.1002/humu.23384]
Cheng, J., Han, D. Y., Dai, P., Sun, H. J., Tao, R., Sun, Q., Yan, D., Qin, W., Wang, H. Y., Ouyang, X. M., Yang, S. Z., Cao, J. Y., Feng, G. Y., Du, L. L., Zhang, Y. Z., Zhai, S. Q., Yang, W. Y., Liu, X. Z., He, L., Yuan, H. J. A novel DFNA5 mutation, IVS8+4A-G, in the splice donor site of intron 8 causes late-onset non-syndromic hearing loss in a Chinese family. Clin. Genet. 72: 471-477, 2007. [PubMed: 17868390] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00889.x]
Dolowitz, D. A., Stephens, F. E. Hereditary nerve deafness. Trans. Am. Otol. Soc. 49: 290-300, 1961. [PubMed: 13887072]
Green, E. D., Idol, J. R., Mohr-Tidwell, R. M., Braden, V. V., Peluso, D. C., Fulton, R. S., Massa, H. F., Magness, C. L., Wilson, A. M., Kimura, J., Weissenbach, J., Trask, B. J. Integration of physical, genetic and cytogenetic maps of human chromosome 7: isolation and analysis of yeast artificial chromosome clones for 117 mapped genetic markers. Hum. Molec. Genet. 3: 489-501, 1994. [PubMed: 8012362] [Full Text: https://doi.org/10.1093/hmg/3.3.489]
Higashi, K. Heterogeneity of dominant high-frequency sensorineural deafness. Clin. Genet. 33: 424-428, 1988. [PubMed: 3168315] [Full Text: https://doi.org/10.1111/j.1399-0004.1988.tb03475.x]
Huizing, E. H., Van Bolhuis, A. H., Odenthal, D. W. Studies on progressive hereditary perceptive deafness in a family of 335 members. I. Genetical and general audiological results. Acta Otolaryng. 61: 35-41, 1966. [PubMed: 5919636] [Full Text: https://doi.org/10.3109/00016486609127040]
Huizing, E. H., Van Bolhuis, A. H., Odenthal, D. W. Studies on progressive hereditary perceptive deafness in a family of 335 members. II. Characteristic patterns of hearing deterioration. Acta Otolaryng. 61: 161-167, 1966. [PubMed: 5919633] [Full Text: https://doi.org/10.3109/00016486609127053]
Huizing, E. H., van den Wijngaart, W. S. I. M., Verschuure, J. A follow-up study in a family with dominant progressive inner ear deafness. Acta Otolaryng. 95: 620-626, 1983. [PubMed: 6880675] [Full Text: https://doi.org/10.3109/00016488309139453]
Nance, W. E., McConnell, F. E. Status and progress of research in hereditary deafness. Adv. Hum. Genet. 4: 173-250, 1973. [PubMed: 4205901] [Full Text: https://doi.org/10.1007/978-1-4615-8261-8_3]
Paparella, M. M., Sugiura, S., Hoshino, T. Familial progressive sensorineural deafness. Arch. Otolaryng. 90: 44-51, 1969. [PubMed: 5785987] [Full Text: https://doi.org/10.1001/archotol.1969.00770030046010]
Van Camp, G., Coucke, P., Balemans, W., Van Velzen, D., Van de Bilt, C., Van Laer, L., Smith, R. J. H., Fukushima, K., Padberg, G. W., Frants, R. R., Van de Heyning, P., Smith, S. D., Huizing, E. H., Willems, P. J. Localization of a gene for non-syndromic hearing loss (DFNA5) to chromosome 7p15. Hum. Molec. Genet. 4: 2159-2163, 1995. [PubMed: 8589696] [Full Text: https://doi.org/10.1093/hmg/4.11.2159]
van den Wijngaart, W. S. I. M., Huizing, E. H., Niermeijer, M. F., Verschuure, J., Brocaar, M. P., Blom, W. Follow-up study in a family with dominant progressive hereditary sensorineural hearing impairment. II. Clinical aspects. Audiology 24: 336-342, 1985. [PubMed: 4051882] [Full Text: https://doi.org/10.3109/00206098509078352]
van den Wijngaart, W. S. I. M., Verschuure, J., Brocaar, M. P., Huizing, E. H. Follow-up study in a family with dominant progressive hereditary sensorineural hearing impairment. I. Analysis of hearing deterioration. Audiology 24: 233-240, 1985. [PubMed: 4051873] [Full Text: https://doi.org/10.3109/00206098509070107]
Van Laer, L., Huizing, E. H., Verstreken, M., van Zuijlen, D., Wauters, J. G., Bossuyt, P. J., Van de Heyning, P., McGuirt, W. T., Smith, R. J. H., Willems, P. J., Legan, P. K., Richardson, G. P., Van Camp, G. Nonsyndromic hearing impairment is associated with a mutation in DFNA5. Nature Genet. 20: 194-197, 1998. [PubMed: 9771715] [Full Text: https://doi.org/10.1038/2503]
Van Laer, L., Meyer, N. C., Malekpour, M., Riazalhosseini, Y., Moghannibashi, M., Kahrizi, K., Vandevelde, A., Alasti, F., Najmabadi, H., Van Camp, G., Smith, R. J. H. A novel DFNA5 mutation does not cause hearing loss in an Iranian family. J. Hum. Genet. 52: 549-552, 2007. [PubMed: 17427029] [Full Text: https://doi.org/10.1007/s10038-007-0137-2]
Van Laer, L., Van Camp, G., van Zuijlen, D., Green, E. D., Verstreken, M., Schatteman, I., Van de Heyning, P., Balemans, W., Coucke, P., Greinwald, J. H., Smith, R. J. H., Huizing, E., Willems, P. Refined mapping of a gene for autosomal dominant progressive sensorineural hearing loss (DFNA5) to a 2-cM region, and exclusion of a candidate gene that is expressed in the cochlea. Europ. J. Hum. Genet. 5: 397-405, 1997. [PubMed: 9450185]
Yu, C., Meng, X., Zhang, S., Zhao, G., Hu, L., Kong, X. A 3-nucleotide deletion in the polypyrimidine tract of the intron 7 of the DFNA5 gene causes nonsyndromic hearing impairment in a Chinese family. Genomics 82: 575-579, 2003. [PubMed: 14559215] [Full Text: https://doi.org/10.1016/s0888-7543(03)00175-7]