ORPHA: 90635; DO: 0110558;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p34.2 | Deafness, autosomal dominant 2A | 600101 | Autosomal dominant | 3 | KCNQ4 | 603537 |
A number sign (#) is used with this entry because of evidence that autosomal dominant deafness-2A (DFNA2A) is caused by heterozygous mutation in the KCNQ4 gene (603537) on chromosome 1p34.2
See also DFNA2B (612644), which is caused by heterozygous mutation in the GJB3 gene (603324) on chromosome 1p34.3.
Autosomal dominant deafness-2A (DFNA2A) is a form of postlingual nonsyndromic progressive sensorineural hearing loss that begins with impairment at high frequencies and progresses to include mid to low frequencies (Kamada et al., 2006; Mencia et al., 2008).
Coucke et al. (1994) reported a large Indonesian family with autosomal dominant nonsyndromic progressive sensorineural hearing loss. The hearing loss first affected the high frequencies during the teens or twenties and became profound within 10 years.
Van Camp et al. (1997) reported 3 families with autosomal dominant hearing loss from Belgium and the Netherlands. The families showed a similar progressive sensorineural hearing loss, starting in the high frequencies and also affecting the middle and low frequencies later in life.
Marres et al. (1997) examined 43 presumably affected persons in a 6-generation Dutch family with autosomal dominant hearing loss and linkage to chromosome 1p. Regression analysis showed significant and equal linear progression in the disorder with age (by about 1 decibel per year) at all frequencies. In 25 to 35% of the patients, an increased vestibuloocular reflex as measured by rotatory responses was observed.
Kubisch et al. (1999) reported a French family with autosomal dominant progressive deafness. In the first generation, deafness was detected in early childhood, in the second generation around puberty, and in the third generation in early childhood. The third generation individual complained about tinnitus since the age of 3 years. In all 3 affected individuals, the hearing loss was more severe on high frequencies, with hearing loss between 50 and 90 dB at 500 Hz and between 90 and 120 dB at 2 and 4 kHz. There was no evidence of vestibular involvement.
In a large Indonesian family with autosomal dominant hearing loss, Coucke et al. (1994) demonstrated linkage to markers on chromosome 1p (multipoint lod score of more than 7). Linkage analyses in an American family also showed linkage to 1p (multipoint lod score of more than 5). In the Indonesian and American families, the deafness locus was situated in a 6-cM region delineated by flanking markers D1S255 and D1S211.
Van Camp et al. (1997) added linkage studies on 3 families with autosomal dominant hearing loss from Belgium and the Netherlands. Combining the information from all families linked to 1p, the candidate region was reduced to a 1.25-Mb region between markers D1S432 and MYCL1 (164850), which maps to 1p34.3.
Kubisch et al. (1999) cloned the voltage-gated potassium channel KCNQ4 gene and identified a heterozygous mutation (G285S; 603537.0001) in affected members of a pedigree with DFNA2A.
In affected members of 2 Dutch families, an American family, and a Belgian family with DFNA2A, Coucke et al. (1999) identified 4 different heterozygous mutations in the KCNQ4 gene (603537.0002-603537.0005).
In affected members of a Japanese family with DFNA2A, Kamada et al. (2006) identified a heterozygous 1-bp deletion (603537.0008) in the KCNQ4 gene, resulting in a truncated protein without transmembrane domains. Affected individuals had late-onset (8 to 50 years) pure high frequency hearing loss, which was less severe compared to previously reported patients with missense mutations in the KCNQ4 gene. Kamada et al. (2006) postulated different pathogenic mechanisms to explain the phenotypic differences: haploinsufficiency in deletion mutations and dominant-negative effects in missense mutations.
In affected members of a 4-generation Spanish family with postlingual, bilateral, symmetric, and progressive sensorineural hearing impairment at mid and high frequencies, Mencia et al. (2008) identified a heterozygous mutation in the KCNQ4 gene (G296S; 603537.0009). The earliest clinical evidence of hearing loss in the family was at 5 years of age. Affected individuals did not exhibit tinnitus or clinical features suggestive of vestibular dysfunction.
Balciuniene et al. (1998) did linkage studies in a Swedish family with postlingual progressive nonsyndromic deafness showing an autosomal dominant inheritance pattern. Markers selected for each of 2 loci, DFNA2 on 1p and DFNA12 (601543) on 11q, provided strong indications for linkage, suggesting that both genes contributed to the etiology of hearing impairment in this family. Linkage with DFNA12 yielded a lod score greater than 3; markers at locus DFNA2 yielded a lod score greater than 2. Further scrutiny of the family showed that severely affected members had haplotypes linked to the disease allele on both chromosomes 1 and 11, whereas individuals with milder hearing loss had haplotypes linked to the disease allele on either chromosome 1 or chromosome 11. The observations suggested an additive effect of 2 genes, each gene resulting in a mild and sometimes undiagnosed phenotype, but the 2 together resulting in a more severe phenotype. This is, then, a possible example of digenic inheritance.
On the basis of linkage analysis in families with autosomal dominant nonsyndromic sensorineural deafness mapping to chromosome 1p35-p34, Van Hauwe et al. (1999) suggested there might even be a third gene causing deafness in this region besides KCNQ4 and GJB3. The authors noted that the Indonesian family reported by Coucke et al. (1994) showed linkage to a region outside of the KCNQ4 locus and did not have mutations in the KCNQ4 gene, suggesting further genetic heterogeneity.
Balciuniene, J., Dahl, N., Borg, E., Samuelsson, E., Koisti, M. J., Pettersson, U., Jazin, E. E. Evidence for digenic inheritance of nonsyndromic hereditary hearing loss in a Swedish family. Am. J. Hum. Genet. 63: 786-793, 1998. [PubMed: 9718342] [Full Text: https://doi.org/10.1086/302012]
Coucke, P. J., Van Hauwe, P., Kelley, P. M., Kunst, H., Schatteman, I., Van Velzen, D., Meyers, J., Ensink, R. J., Verstreken, M., Declau, F., Marres, H., Kastury, K., Bhasin, S., McGuirt, W. T., Smith, R. J. H., Cremers, C. W. R. J., Van de Heyning, P., Willems, P. J., Smith, S. D., Van Camp, G. Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. Hum. Molec. Genet. 8: 1321-1328, 1999. [PubMed: 10369879] [Full Text: https://doi.org/10.1093/hmg/8.7.1321]
Coucke, P., Van Camp, G., Djoyodiharjo, B., Smith, S. D., Frants, R. R., Padberg, G. W., Darby, J. K., Huizing, E. H., Cremers, C. W. R. J., Kimberling, W. J., Oostra, B. A., Van de Heyning, P. H., Willems, P. J. Linkage of autosomal dominant hearing loss to the short arm of chromosome 1 in two families. New Eng. J. Med. 331: 425-431, 1994. [PubMed: 8035838] [Full Text: https://doi.org/10.1056/NEJM199408183310702]
Kamada, F., Kure, S., Kudo, T., Suzuki, Y., Oshima, T., Ichinohe, A., Kojima, K., Niihori, T., Kanno, J., Narumi, Y., Narisawa, A., Kato, K., Aoki, Y., Ikeda, K., Kobayashi, T., Matsubara, Y. A novel KCNQ4 one-base deletion in a large pedigree with hearing loss: implication for the genotype-phenotype correlation. J. Hum. Genet. 51: 455-460, 2006. [PubMed: 16596322] [Full Text: https://doi.org/10.1007/s10038-006-0384-7]
Kubisch, C., Schroeder, B. C., Friedrich, T., Lutjohann, B., El-Amraoui, A., Marlin, S., Petit, C., Jentsch, T. J. KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell 96: 437-446, 1999. [PubMed: 10025409] [Full Text: https://doi.org/10.1016/s0092-8674(00)80556-5]
Marres, H., van Ewijk, M., Huygen, P., Kunst, H., van Camp, G., Coucke, P., Willems, P., Cremers, C. Inherited nonsyndromic hearing loss: an audiovestibular study in a large family with autosomal dominant progressive hearing loss related to DFNA2. Arch. Otolaryng. Head Neck Surg. 123: 573-577, 1997. [PubMed: 9193215] [Full Text: https://doi.org/10.1001/archotol.1997.01900060015002]
Mencia, A., Gonzalez-Nieto, D., Modamio-Hoybjor, S., Etxeberria, A., Aranguez, G., Salvador, N., del Castillo, I., Villarroel, A., Moreno, F., Barrio, L., Moreno-Pelayo, M. A. A novel KCNQ4 pore-region mutation (p.G296S) causes deafness by impairing cell-surface channel expression. Hum. Genet. 123: 41-53, 2008. [PubMed: 18030493] [Full Text: https://doi.org/10.1007/s00439-007-0447-7]
Van Camp, G., Coucke, P. J., Kunst, H., Schatteman, I., Van Velzen, D., Marres, H., van Ewijk, M., Declau, F., Van Hauwe, P., Meyers, J., Kenyon, J., Smith, S. D., Smith, R. J. H., Djelantik, B., Cremers, C. W. R. J., Van de Heyning, P. H., Willems, P. J. Linkage analysis of progressive hearing loss in five extended families maps the DFNA2 gene to a 1.25-Mb region on chromosome 1p. Genomics 41: 70-74, 1997. [PubMed: 9126484] [Full Text: https://doi.org/10.1006/geno.1997.4624]
Van Hauwe, P., Coucke, P. J., Declau, F., Kunst, H., Ensink, R. J., Marres, H. A., Cremers, C. W. R. J., Djelantik, B., Smith, S. D., Kelley, P., Van de Heyning, P. H., Van Camp, G. Deafness linked to DFNA2: one locus but how many genes? (Letter) Nature Genet. 21: 263 only, 1999. [PubMed: 10080176] [Full Text: https://doi.org/10.1038/6778]