#607017
Table of Contents
A number sign (#) is used with this entry because of evidence that autosomal dominant deafness-21 (DFNA21) is caused by heterozygous mutation in the RIPOR2 gene (611410) on chromosome 6p22.
Autosomal dominant deafness-21 (DFNA21) is characterized by nonsyndromic progressive sensorineural hearing loss. The mean age at onset is 30.6 years, with a range from infancy to late adulthood. There is a high prevalence of this genetic form of deafness in the Dutch population (summary by de Bruijn et al., 2021).
Kunst et al. (2000) described a Dutch family (W97-056) with autosomal dominant nonsyndromic, progressive, nonspecific mid-frequency sensorineural hearing loss. Most affected members of the family had a relatively late age of onset (maximum in the range of 25 to 45 years). However, based on the longitudinal analysis of a patient from the age of 4 years onwards, sensorineural hearing loss might be congenital/prelingual in some patients. Oculovestibular function was found to be normal. Bom et al. (1999) graphed audiogram against age for DFNA21 and 8 other forms of autosomal dominant neurosensory deafness.
De Bruijn et al. (2021) reported multiple affected individuals from 12 unrelated Dutch families, including the family reported by Kunst et al. (2000), with DFNA21. Although the mean age at onset was 30.6 years, the onset ranged from birth to 70 years. Affected individuals had progressive sensorineural hearing loss with variable audiometric configurations. There was no definitive evidence for vestibular dysfunction. The authors postulated that additional environmental or genetic modifiers are responsible for the phenotypic variability, even within families.
The transmission pattern of DFNA21 in the families reported by de Bruijn et al. (2021) was consistent with autosomal dominant inheritance and incomplete penetrance. There were also a few phenocopies within families.
Kunst et al. (2000) reported a Dutch family with nonsyndromic hearing impairment (DFNA21) showing linkage to chromosome 6p, telomeric to the DFNA13 (601868) locus at chromosome 6p21.3.
De Brouwer et al. (2005) performed fine mapping analysis of the DFNA21 locus, which was previously reported as telomeric to the DFNA13 locus. One family member in this region did not carry the at-risk haplotype, although he had the same nonspecific mid-frequency hearing impairment as other affected family members. Hence, the authors performed a whole-genome linkage scan excluding other regions of the genome and confirmed the localization of DFNA21 to chromosome 6p24.1-p22.3. The DFNA21 interval was determined to span 12.4 Mb (approximately 22 cM) and to be delimited on the telomeric side by BV097155 and on the centromeric side by D6S1691. A maximum lod score of 3.51 (theta = 0.066) was calculated for marker D6S1721. The DFNA21 region does not overlap the adjacent DFNA31 (608645) and DFNA13 loci and contains 31 known genes. The coding regions and exon-intron boundaries of 4 candidate genes, SOX4 (184430), MYLIP (610082), adenylate cyclase-associated protein-2 (CAP2; 618385), and RPEL1 (PHACTR1; 608723), were sequenced, but no mutations were identified.
In 20 affected members of a large multigenerational Dutch family (W97-056) DFNA21, (Kunst et al., 2000), de Bruijn et al. (2021) identified a heterozygous 12-bp in-frame deletion (c.1696_1707del) in the RIPOR2 gene (611410.0002). The mutation, which was identified by exome sequencing, segregated with the disorder in the family, although there was evidence for incomplete or age-dependent penetrance. Based on these findings, analysis of existing exome datasets from large cohorts of patients with hereditary hearing loss identified 11 additional probands of Dutch origin who carried this heterozygous deletion. It segregated with the disorder in 6 families, with evidence of incomplete penetrance. Haplotype analysis indicated a founder effect. Expression of the orthologous Ripor2 mutation in the cochlear outer hair cells of wildtype mice did not visibly affect the stereocilia structure in the short term, but the mutant protein did not localize normally to the stereocilia base. Expression of the mutation into Ripor2-null mice was unable to rescue morphologic defects of outer hair cells, suggesting that the small deletion disrupts protein function. Since haploinsufficiency is an unlikely mechanism, de Bruijn et al. (2021) postulated a toxic gain-of-function effect. The deletion was present at low frequencies in the gnomAD database (0.0071-0.0077%). In contrast, the heterozygous deletion was found in 0.0392% of individuals (18 of 22,952) from the southeastern Netherlands with unknown hearing abilities. The authors concluded that mutations in RIPOR2 may be a common cause of hereditary hearing loss in certain northern European populations.
De Bruijn et al. (2021) identified a common founder mutation in the RIPOR2 gene (611410.0002) in affected members of 12 families from the Netherlands. The heterozygous mutation was found in 0.0392% of individuals (18 of 22,952) from the southeastern Netherlands with unknown hearing abilities.
Bom, S. J. H., Kunst, H. P. M., Huygen, P. L. M., Cremers, F. P. M., Cremers, C. W. R. J. Non-syndromal autosomal dominant hearing impairment: ongoing phenotypical characterization of genotypes. Brit. J. Audiol. 33: 335-348, 1999. [PubMed: 10890148, related citations] [Full Text]
de Brouwer, A. P., Kunst, H. P., Krebsova, A., van Asseldonk, K., Reis, A., Snoeckx, R. L., Van Camp, G., Cremers, C. W., Cremers, F. P., Kremer, H. Fine mapping of autosomal dominant nonsyndromic hearing impairment DFNA21 to chromosome 6p24.1-22.3. Am. J. Med. Genet. 137A: 41-46, 2005. [PubMed: 16007628, related citations] [Full Text]
de Bruijn, S. E., Smits, J. J., Liu, C., Lanting, C. P., Beynon, A. J., Blankevoort, J., Oostrik, J., Koole, W., de Vrieze, E., Cremers, C. W. R. J., Cremers, F. P. M., Roosing, S., Yntema, H. G., Kunst, H. P. M., Zhao, B., Pennings, R. J. E., Kremer, H., DOOFNL Consortium. A RIPOR2 in-frame deletion is a frequent and highly penetrant cause of adult-onset hearing loss. J. Med. Genet. 58: 96-104, 2021.
Kunst, H., Marres, H., Huygen, P., Van Duijnhoven, G., Krebsova, A., Van Der Velde, S., Reis, A., Cremers, F., Cremers, C. Non-syndromic autosomal dominant progressive non-specific mid-frequency sensorineural hearing impairment with childhood to late adolescence onset (DFNA21). Clin. Otolaryng. 25: 45-54, 2000. [PubMed: 10764236, related citations] [Full Text]
ORPHA: 90635; DO: 0110551;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p22.3 | Deafness, autosomal dominant 21 | 607017 | Autosomal dominant | 3 | RIPOR2 | 611410 |
A number sign (#) is used with this entry because of evidence that autosomal dominant deafness-21 (DFNA21) is caused by heterozygous mutation in the RIPOR2 gene (611410) on chromosome 6p22.
Autosomal dominant deafness-21 (DFNA21) is characterized by nonsyndromic progressive sensorineural hearing loss. The mean age at onset is 30.6 years, with a range from infancy to late adulthood. There is a high prevalence of this genetic form of deafness in the Dutch population (summary by de Bruijn et al., 2021).
Kunst et al. (2000) described a Dutch family (W97-056) with autosomal dominant nonsyndromic, progressive, nonspecific mid-frequency sensorineural hearing loss. Most affected members of the family had a relatively late age of onset (maximum in the range of 25 to 45 years). However, based on the longitudinal analysis of a patient from the age of 4 years onwards, sensorineural hearing loss might be congenital/prelingual in some patients. Oculovestibular function was found to be normal. Bom et al. (1999) graphed audiogram against age for DFNA21 and 8 other forms of autosomal dominant neurosensory deafness.
De Bruijn et al. (2021) reported multiple affected individuals from 12 unrelated Dutch families, including the family reported by Kunst et al. (2000), with DFNA21. Although the mean age at onset was 30.6 years, the onset ranged from birth to 70 years. Affected individuals had progressive sensorineural hearing loss with variable audiometric configurations. There was no definitive evidence for vestibular dysfunction. The authors postulated that additional environmental or genetic modifiers are responsible for the phenotypic variability, even within families.
The transmission pattern of DFNA21 in the families reported by de Bruijn et al. (2021) was consistent with autosomal dominant inheritance and incomplete penetrance. There were also a few phenocopies within families.
Kunst et al. (2000) reported a Dutch family with nonsyndromic hearing impairment (DFNA21) showing linkage to chromosome 6p, telomeric to the DFNA13 (601868) locus at chromosome 6p21.3.
De Brouwer et al. (2005) performed fine mapping analysis of the DFNA21 locus, which was previously reported as telomeric to the DFNA13 locus. One family member in this region did not carry the at-risk haplotype, although he had the same nonspecific mid-frequency hearing impairment as other affected family members. Hence, the authors performed a whole-genome linkage scan excluding other regions of the genome and confirmed the localization of DFNA21 to chromosome 6p24.1-p22.3. The DFNA21 interval was determined to span 12.4 Mb (approximately 22 cM) and to be delimited on the telomeric side by BV097155 and on the centromeric side by D6S1691. A maximum lod score of 3.51 (theta = 0.066) was calculated for marker D6S1721. The DFNA21 region does not overlap the adjacent DFNA31 (608645) and DFNA13 loci and contains 31 known genes. The coding regions and exon-intron boundaries of 4 candidate genes, SOX4 (184430), MYLIP (610082), adenylate cyclase-associated protein-2 (CAP2; 618385), and RPEL1 (PHACTR1; 608723), were sequenced, but no mutations were identified.
In 20 affected members of a large multigenerational Dutch family (W97-056) DFNA21, (Kunst et al., 2000), de Bruijn et al. (2021) identified a heterozygous 12-bp in-frame deletion (c.1696_1707del) in the RIPOR2 gene (611410.0002). The mutation, which was identified by exome sequencing, segregated with the disorder in the family, although there was evidence for incomplete or age-dependent penetrance. Based on these findings, analysis of existing exome datasets from large cohorts of patients with hereditary hearing loss identified 11 additional probands of Dutch origin who carried this heterozygous deletion. It segregated with the disorder in 6 families, with evidence of incomplete penetrance. Haplotype analysis indicated a founder effect. Expression of the orthologous Ripor2 mutation in the cochlear outer hair cells of wildtype mice did not visibly affect the stereocilia structure in the short term, but the mutant protein did not localize normally to the stereocilia base. Expression of the mutation into Ripor2-null mice was unable to rescue morphologic defects of outer hair cells, suggesting that the small deletion disrupts protein function. Since haploinsufficiency is an unlikely mechanism, de Bruijn et al. (2021) postulated a toxic gain-of-function effect. The deletion was present at low frequencies in the gnomAD database (0.0071-0.0077%). In contrast, the heterozygous deletion was found in 0.0392% of individuals (18 of 22,952) from the southeastern Netherlands with unknown hearing abilities. The authors concluded that mutations in RIPOR2 may be a common cause of hereditary hearing loss in certain northern European populations.
De Bruijn et al. (2021) identified a common founder mutation in the RIPOR2 gene (611410.0002) in affected members of 12 families from the Netherlands. The heterozygous mutation was found in 0.0392% of individuals (18 of 22,952) from the southeastern Netherlands with unknown hearing abilities.
Bom, S. J. H., Kunst, H. P. M., Huygen, P. L. M., Cremers, F. P. M., Cremers, C. W. R. J. Non-syndromal autosomal dominant hearing impairment: ongoing phenotypical characterization of genotypes. Brit. J. Audiol. 33: 335-348, 1999. [PubMed: 10890148] [Full Text: https://doi.org/10.3109/03005369909090117]
de Brouwer, A. P., Kunst, H. P., Krebsova, A., van Asseldonk, K., Reis, A., Snoeckx, R. L., Van Camp, G., Cremers, C. W., Cremers, F. P., Kremer, H. Fine mapping of autosomal dominant nonsyndromic hearing impairment DFNA21 to chromosome 6p24.1-22.3. Am. J. Med. Genet. 137A: 41-46, 2005. [PubMed: 16007628] [Full Text: https://doi.org/10.1002/ajmg.a.30844]
de Bruijn, S. E., Smits, J. J., Liu, C., Lanting, C. P., Beynon, A. J., Blankevoort, J., Oostrik, J., Koole, W., de Vrieze, E., Cremers, C. W. R. J., Cremers, F. P. M., Roosing, S., Yntema, H. G., Kunst, H. P. M., Zhao, B., Pennings, R. J. E., Kremer, H., DOOFNL Consortium. A RIPOR2 in-frame deletion is a frequent and highly penetrant cause of adult-onset hearing loss. J. Med. Genet. 58: 96-104, 2021.
Kunst, H., Marres, H., Huygen, P., Van Duijnhoven, G., Krebsova, A., Van Der Velde, S., Reis, A., Cremers, F., Cremers, C. Non-syndromic autosomal dominant progressive non-specific mid-frequency sensorineural hearing impairment with childhood to late adolescence onset (DFNA21). Clin. Otolaryng. 25: 45-54, 2000. [PubMed: 10764236] [Full Text: https://doi.org/10.1046/j.1365-2273.2000.00327.x]
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