%607841
Table of Contents
Cytogenetic location: 12q13-q14 Genomic coordinates (GRCh38) : 12:46,000,001-67,300,000
D'Adamo et al. (2003) reported a large multigenerational Italian family from Sardinia in which 22 members, aged 8 to 83 years, had nonsyndromic hearing loss. Patients presented with postlingual, slowly progressive, bilateral, and symmetric sensorineural hearing impairment, which appeared to be completely penetrant. The age at onset varied from the first to the third decade. The degree of deafness ranged from moderate to severe.
The transmission pattern of nonsyndromic hearing loss in the Italian family reported by D'Adamo et al. (2003) was consistent with autosomal dominant inheritance.
D'Adamo et al. (2003) mapped a novel locus for autosomal dominant nonsyndromic deafness, which they designated DFNA48, to chromosome 12q13-q14 by linkage study of a large multigenerational Italian family. A maximum lod score of 3.31 was obtained with marker D12S83.
Exclusion Studies
Donaudy et al. (2003) screened the MYO1A (601478) gene, which maps within the DFNA48 locus, for mutations in patients from the large Italian family reported by D'Adamo et al. (2003) and did not identify a mutation in the coding region or exon-intron boundaries of the gene.
Donaudy et al. (2003) also screened the MYO1A gene for mutations in 230 hearing-impaired patients. They reported mutations in the MYO1A gene in 8 unrelated patients from central and southern Italy affected by sensorineural bilateral hearing loss of variable degree, usually ranging from moderate to severe but never profound. However, these variants in the MYO1A gene have been reclassified as variants of unknown significance based on a report by Eisenberger et al. (2014). By targeted next-generation sequencing of 66 deafness genes in 109 patients with autosomal dominant nonsyndromic hearing loss, Eisenberger et al. (2014) identified 2 novel nonsense and 1 known missense variant in the MYO1A gene that challenged the findings of Donaudy et al. (2003). The variants were identified in heterozygous state not only in index patients but also in unaffected relatives. One healthy individual was even found to be homozygous for one of the nonsense mutations. In a search of genomewide databases, Eisenberger et al. (2014) found that most of the 10 reported MYO1A variants in patients with nonsyndromic hearing loss had documented allele frequencies, with 4 above the MAF cutoff of 0.1% in at least 1 database. Eisenberger et al. (2014) also noted that Myo1a knockout mice lack any overt hearing or balance pathology. The authors suggested that MYO1A is not required for proper sound perception.
D'Adamo, P., Pinna, M., Capobianco, S., Cesarini, A., D'Eustacchio, A., Fogu, P., Carella, M., Seri, M., Gasparini, P. A novel autosomal dominant non-syndromic deafness locus (DFNA48) maps to 12q13-q14 in a large Italian family. Hum. Genet. 112: 319-320, 2003. [PubMed: 12596055, related citations] [Full Text]
Donaudy, F., Ferrara, A., Esposito, L., Hertzano, R., Ben-David, O., Bell, R. E., Melchionda, S., Zelante, L., Avraham, K. B., Gasparini, P. Multiple mutations of MYO1A, a cochlear-expressed gene, in sensorineural hearing loss. Am. J. Hum. Genet. 72: 1571-1577, 2003. [PubMed: 12736868, images, related citations] [Full Text]
Eisenberger, T., Di Donato, N., Baig, S. M., Neuhaus, C., Beyer, A., Decker, E., Murbe, D., Decker, C., Bergmann, C., Bolz, H. J. Targeted and genomewide NGS data disqualify mutations in mYO1A, the 'DFNA48 gene,' as a cause of deafness. Hum. Mutat. 35: 565-579, 2014. [PubMed: 24616153, related citations] [Full Text]
ORPHA: 90635; DO: 0110571;
Cytogenetic location: 12q13-q14 Genomic coordinates (GRCh38) : 12:46,000,001-67,300,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13-q14 | Deafness, autosomal dominant 48 | 607841 | Autosomal dominant | 2 |
D'Adamo et al. (2003) reported a large multigenerational Italian family from Sardinia in which 22 members, aged 8 to 83 years, had nonsyndromic hearing loss. Patients presented with postlingual, slowly progressive, bilateral, and symmetric sensorineural hearing impairment, which appeared to be completely penetrant. The age at onset varied from the first to the third decade. The degree of deafness ranged from moderate to severe.
The transmission pattern of nonsyndromic hearing loss in the Italian family reported by D'Adamo et al. (2003) was consistent with autosomal dominant inheritance.
D'Adamo et al. (2003) mapped a novel locus for autosomal dominant nonsyndromic deafness, which they designated DFNA48, to chromosome 12q13-q14 by linkage study of a large multigenerational Italian family. A maximum lod score of 3.31 was obtained with marker D12S83.
Exclusion Studies
Donaudy et al. (2003) screened the MYO1A (601478) gene, which maps within the DFNA48 locus, for mutations in patients from the large Italian family reported by D'Adamo et al. (2003) and did not identify a mutation in the coding region or exon-intron boundaries of the gene.
Donaudy et al. (2003) also screened the MYO1A gene for mutations in 230 hearing-impaired patients. They reported mutations in the MYO1A gene in 8 unrelated patients from central and southern Italy affected by sensorineural bilateral hearing loss of variable degree, usually ranging from moderate to severe but never profound. However, these variants in the MYO1A gene have been reclassified as variants of unknown significance based on a report by Eisenberger et al. (2014). By targeted next-generation sequencing of 66 deafness genes in 109 patients with autosomal dominant nonsyndromic hearing loss, Eisenberger et al. (2014) identified 2 novel nonsense and 1 known missense variant in the MYO1A gene that challenged the findings of Donaudy et al. (2003). The variants were identified in heterozygous state not only in index patients but also in unaffected relatives. One healthy individual was even found to be homozygous for one of the nonsense mutations. In a search of genomewide databases, Eisenberger et al. (2014) found that most of the 10 reported MYO1A variants in patients with nonsyndromic hearing loss had documented allele frequencies, with 4 above the MAF cutoff of 0.1% in at least 1 database. Eisenberger et al. (2014) also noted that Myo1a knockout mice lack any overt hearing or balance pathology. The authors suggested that MYO1A is not required for proper sound perception.
D'Adamo, P., Pinna, M., Capobianco, S., Cesarini, A., D'Eustacchio, A., Fogu, P., Carella, M., Seri, M., Gasparini, P. A novel autosomal dominant non-syndromic deafness locus (DFNA48) maps to 12q13-q14 in a large Italian family. Hum. Genet. 112: 319-320, 2003. [PubMed: 12596055] [Full Text: https://doi.org/10.1007/s00439-002-0880-6]
Donaudy, F., Ferrara, A., Esposito, L., Hertzano, R., Ben-David, O., Bell, R. E., Melchionda, S., Zelante, L., Avraham, K. B., Gasparini, P. Multiple mutations of MYO1A, a cochlear-expressed gene, in sensorineural hearing loss. Am. J. Hum. Genet. 72: 1571-1577, 2003. [PubMed: 12736868] [Full Text: https://doi.org/10.1086/375654]
Eisenberger, T., Di Donato, N., Baig, S. M., Neuhaus, C., Beyer, A., Decker, E., Murbe, D., Decker, C., Bergmann, C., Bolz, H. J. Targeted and genomewide NGS data disqualify mutations in mYO1A, the 'DFNA48 gene,' as a cause of deafness. Hum. Mutat. 35: 565-579, 2014. [PubMed: 24616153] [Full Text: https://doi.org/10.1002/humu.22532]
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