Entry - #600316 - DEAFNESS, AUTOSOMAL RECESSIVE 3; DFNB3 - OMIM

 
ICD+
# 600316

DEAFNESS, AUTOSOMAL RECESSIVE 3; DFNB3


Alternative titles; symbols

NEUROSENSORY NONSYNDROMIC RECESSIVE DEAFNESS 3; NSRD3


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key 		Gene/Locus Gene/Locus
MIM number
17p11.2 Deafness, autosomal recessive 3 600316 AR 3 MYO15A 602666
Clinical Synopsis
 
Phenotypic Series
 

Ears
- Profound, congenital, neurosensory, nonsyndromal deafness
Inheritance
- Autosomal recessive (17p12-q12)
▲ Close
Deafness, autosomal recessive - PS220290 - 109 Entries
Location Phenotype Inheritance Phenotype
mapping key 		Phenotype
MIM number 		Gene/Locus Gene/Locus
MIM number
1p36.31-p36.13 Deafness, autosomal recessive 96 AR 2 614414 DFNB96 614414
1p36.31 Deafness, autosomal recessive 36 AR 3 609006 ESPN 606351
1p36.31 Deafness, neurosensory, without vestibular involvement, autosomal dominant AR 3 609006 ESPN 606351
1p34.3 Deafness, digenic, GJB2/GJB3 AR, DD 3 220290 GJB3 603324
1p31.3 ?Deafness, autosomal recessive 108 AR 3 617654 ROR1 602336
1p21.2 Deafness, autosomal recessive 32, with or without immotile sperm AR 3 608653 CDC14A 603504
1q23.2 Enlarged vestibular aqueduct, digenic AR 3 600791 KCNJ10 602208
1q43-q44 Deafness, autosomal recessive 45 AR 2 612433 DFNB45 612433
2p25.1-p24.3 Deafness, neurosensory, autosomal recessive 47 AR 2 609946 DFNB47 609946
2p23.3 Deafness, autosomal recessive 9 AR 3 601071 OTOF 603681
2p23.3 Auditory neuropathy, autosomal recessive, 1 AR 3 601071 OTOF 603681
2p16.1 Deafness, autosomal recessive 70, with or without adult-onset neurodegeneration AR 3 614934 PNPT1 610316
2p11.2 ?Deafness, autosomal recessive 88 AR 3 615429 ELMOD3 615427
2q23-q31 Deafness, autosomal recessive 27 AR 2 605818 DFNB27 605818
2q31.2 Deafness, autosomal recessive 59 AR 3 610220 PJVK 610219
3p25.3 {Deafness, autosomal recessive 12, modifier of} AR 3 601386 ATP2B2 108733
3p21.31 Deafness, autosomal recessive 6 AR 3 600971 TMIE 607237
3q13.33 Deafness, autosomal recessive 121 AR 3 620551 GPR156 610464
3q13.33 Deafness, autosomal recessive 42 AR 3 609646 ILDR1 609739
4p15.32 Deafness, autosomal recessive 117 AR 3 619174 CLRN2 618988
4p13 Deafness, autosomal recessive 25 AR 3 613285 GRXCR1 613283
4q12-q13.2 Deafness, autosomal recessive 55 AR 2 609952 DFNB55 609952
4q31.21 ?Deafness, autosomal recessive 26 AR 3 605428 GAB1 604439
5q13.2 Deafness, autosomal recessive 49 AR 3 610153 MARVELD2 610572
5q13.2 ?Deafness, autosomal recessive 112 AR 3 618257 BDP1 607012
5q21.1 Deafness, autosomal recessive 100 AR 3 618422 PPIP5K2 611648
5q23.3 Deafness, autosomal recessive 120 AR 3 620238 MINAR2 620215
5q32 ?Deafness, autosomal recessive 101 AR 3 615837 GRXCR2 615762
5q35.1 Enlarged vestibular aqueduct AR 3 600791 FOXI1 601093
6p25.2 ?Deafness, autosomal recessive 91 AR 3 613453 SERPINB6 173321
6p22.3 ?Deafness, autosomal recessive 66 AR 3 610212 DCDC2 605755
6p22.3 ?Deafness, autosomal recessive 104 AR 3 616515 RIPOR2 611410
6p21.32 Deafness, autosomal recessive 53 AR 3 609706 COL11A2 120290
6p21.31 Deafness, autosomal recessive 67 AR 3 610265 LHFPL5 609427
6p21.1 ?Deafness, autosomal recessive 103 AR 3 616042 CLIC5 607293
6q14.1 Deafness, autosomal recessive 37 AR 3 607821 MYO6 600970
6q26-q27 Deafness, autosomal recessive 38 AR 2 608219 DFNB38 608219
7p12.3 ?Deafness, autosomal recessive 44 AR 3 610154 ADCY1 103072
7q21.11 Deafness, autosomal recessive 39 AR 3 608265 HGF 142409
7q22.1 ?Deafness, autosomal recessive 61 AR 3 613865 SLC26A5 604943
7q22.3 Deafness, autosomal recessive 4, with enlarged vestibular aqueduct AR 3 600791 SLC26A4 605646
7q31 Deafness, autosomal recessive 14 AR 2 603678 DFNB14 603678
7q31 Deafness, autosomal recessive 17 AR 2 603010 DFNB17 603010
7q31.2 ?Deafness, autosomal recessive 97 AR 3 616705 MET 164860
7q34-q36 Deafness, autosomal recessive 13 AR 2 603098 DFNB13 603098
8p22-p21.3 Deafness, autosomal recessive 71 AR 2 612789 DFNB71 612789
8q22 Deafness, autosomal recessive 118, with cochlear aplasia AR 4 619553 DFNB118 619553
8q22.1 ?Deafness, autosomal recessive 109 AR 3 618013 ESRP1 612959
8q23.1-q23.2 Deafness, autosomal recessive 124 AR 3 620794 PKHD1L1 607843
9p23-p21.2 Deafness, autosomal recessive 83 AR 2 613685 DFNB83 613685
9q21.13 Deafness, autosomal recessive 7 AR 3 600974 TMC1 606706
9q32 Deafness, autosomal recessive 31 AR 3 607084 WHRN 607928
9q34.3 Deafness, autosomal recessive 79 AR 3 613307 TPRN 613354
10p12.1 Deafness, autosomal recessive 30 AR 3 607101 MYO3A 606808
10p11.23-q21.1 Deafness, autosomal recessive 33 AR 2 607239 DFNB33 607239
10q21.1 Deafness, autosomal recessive 23 AR 3 609533 PCDH15 605514
10q22.1 Deafness, autosomal recessive 12 AR 3 601386 CDH23 605516
10q24.31 Deafness, autosomal recessive 57 AR 3 618003 PDZD7 612971
11p15.5 Deafness autosomal recessive 106 AR 3 617637 EPS8L2 614988
11p15.1 Deafness, autosomal recessive 18A AR 3 602092 USH1C 605242
11p15.1 Deafness, autosomal recessive 18B AR 3 614945 OTOG 604487
11p14.3 ?Deafness, autosomal recessive 125 AR 3 620877 GAS2 602835
11p13-p12 Deafness, autosomal recessive 51 AR 2 609941 DFNB51 609941
11q13.2 Deafness, autosomal recessive 93 AR 3 614899 CABP2 607314
11q13.4 Deafness, autosomal recessive 63 AR 3 611451 LRTOMT 612414
11q13.5 Deafness, autosomal recessive 2 AR 3 600060 MYO7A 276903
11q14.1 ?Deafness, autosomal recessive 94 AR 3 618434 NARS2 612803
11q22.3 Deafness, autosomal recessive 24 AR 3 611022 RDX 179410
11q23.3 Deafness, autosomal recessive 111 AR 3 618145 MPZL2 604873
11q23.3 Deafness, autosomal recessive 21 AR 3 603629 TECTA 602574
11q25-qter Deafness, autosomal recessive 20 AR 2 604060 DFNB20 604060
12p13.2-p11.23 Deafness, autosomal recessive 62 AR 2 610143 DFNB62 610143
12p12.3 ?Deafness, autosomal recessive 102 AR 3 615974 EPS8 600206
12q14.3 Deafness, autosomal recessive 74 AR 3 613718 MSRB3 613719
12q21.31 Deafness, autosomal recessive 84B AR 3 614944 OTOGL 614925
12q21.31 Deafness, autosomal recessive 84A AR 3 613391 PTPRQ 603317
13q12.11 Deafness, autosomal recessive 1A AR, DD 3 220290 GJB2 121011
13q12.11 Deafness, digenic GJB2/GJB6 AR, DD 3 220290 GJB6 604418
13q12.11 Deafness, autosomal recessive 1B AR 3 612645 GJB6 604418
13q32.3 ?Deafness, autosomal recessive 122 AR 3 620714 TMTC4 618203
14q12 Deafness, autosomal recessive 5 AR 2 600792 DFNB5 600792
14q12 ?Deafness, autosomal recessive 110 AR 3 618094 COCH 603196
14q24.3 Deafness, autosomal recessive 35 AR 3 608565 ESRRB 602167
15q15.3 Deafness, autosomal recessive 16 AR 3 603720 STRC 606440
15q21.1 Deafness, autosomal recessive 119 AR 3 619615 AFG2B 619578
15q25.1 Deafness, autosomal recessive 48 AR 3 609439 CIB2 605564
16p13.3 Deafness, autosomal recessive 86 AR 3 614617 TBC1D24 613577
16p13.3 Deafness, autosomal recessive 116 AR 3 619093 CLDN9 615799
16p12.2 Deafness, autosomal recessive 22 AR 3 607039 OTOA 607038
16p11.2 ?Deafness, autosomal recessive 123 AR 3 620745 STX4 186591
16q23.1 Deafness, autosomal recessive 89 AR 3 613916 KARS1 601421
17p13.2 ?Deafness, autosomal recessive 115 AR 3 618457 SPNS2 612584
17p12-q11.2 Deafness, autosomal recessive 85 AR 2 613392 DFNB85 613392
17p11.2 Deafness, autosomal recessive 3 AR 3 600316 MYO15A 602666
17p11.2 Deafness, autosomal recessive 114 AR 3 618456 GRAP 604330
17q12 Deafness, autosomal recessive 99 AR 3 618481 TMEM132E 616178
17q25.1 Deafness, autosomal recessive 107 AR 3 617639 WBP2 606962
18p11.32-p11.31 Deafness, autosomal recessive 46 AR 2 609647 DFNB46 609647
18q21.1 Deafness, autosomal recessive 77 AR 3 613079 LOXHD1 613072
19p13.3 Deafness, autosomal recessive 15 AR 3 601869 GIPC3 608792
19p13.2 Deafness, autosomal recessive 68 AR 3 610419 S1PR2 605111
19q13.12 Deafness, autosomal recessive 76 AR 3 615540 SYNE4 615535
19q13.31-q13.32 Deafness, autosomal recessive 113 AR 3 618410 CEACAM16 614591
20q13.2-q13.3 Deafness, autosomal recessive 65 AR 2 610248 DFNB65 610248
21q22.13 Deafness, autosomal recessive 29 AR 3 614035 CLDN14 605608
21q22.3 Deafness, autosomal recessive 8/10 AR 3 601072 TMPRSS3 605511
21q22.3 ?Deafness, autosomal recessive 98 AR 3 614861 TSPEAR 612920
22q11.21-q12.1 Deafness, autosomal recessive 40 AR 2 608264 DFNB40 608264
22q13.1 Deafness, autosomal recessive 28 AR 3 609823 TRIOBP 609761
▲ Close

▼ TEXT

A number sign (#) is used with this entry because of evidence that autosomal recessive deafness-3 (DFNB3) is caused by homozygous or compound heterozygous mutation in the gene encoding unconventional myosin XVA (MYO15A; 602666) on chromosome 17p11.

▼ Description

Autosomal recessive deafness-3 (DFNB3) is a congenital, profound, neurosensory deafness. There are no apparent vestibular abnormalities or dysmorphic features (Friedman et al., 1995).


▼ Clinical Features

Friedman et al. (1995) reported that 2% of the residents of Bengkala, an Indonesian village on the north shore of Bali, have profound, congenital, neurosensory, nonsyndromal deafness due to an autosomal recessive mutation at a locus designated DFNB3 (for the third autosomal recessive, nonsyndromic deafness locus to be mapped). This remote village dates to at least the 13th century as documented by charters inscribed in Sanskrit on metallic plates. Of the 2,185 residents, 47 had profound deafness of the type described. As an adaptation to the high percentage of deaf individuals, the citizens of Bengkala had developed a unique sign language used by most of the hearing persons as well as the deaf villagers. Deaf couples produced all deaf progeny. In 4- and 5-generation Bengkala kindreds, 2 of which were illustrated, there were no consanguineous marriages. The deaf individuals had no apparent vestibular abnormalities or dysmorphic features.


▼ Inheritance

The transmission pattern of DFNB3 in the families reported by Wang et al. (1998) was consistent with autosomal recessive inheritance.


▼ Mapping

Friedman et al. (1995) used a direct genomewide disequilibrium search strategy, allele-frequency-dependent homozygosity mapping (AHM), and analysis of historical recombinants to map DFNB3 and position the locus relative to flanking markers. They found that DFNB3 maps to chromosome 17. In individuals homozygous for DFNB3, historical recombinant phenotypes for the flanking markers D17S122 and D17S783 placed DFNB3 in a 5.3-cM interval of the pericentromeric region of chromosome 17 (17p12-q12).

With new short tandem repeats (STRs) from the DFNB3 region and additional DNA samples from affected individuals from Bengkala, Bali, Liang et al. (1997, 1998) found 2 historical recombinants for marker D17S953 from the telomeric side of 17p11.2 and 5 historical recombinants for marker D17S2201 on the centromeric side of 17p11.2. These recombinants further delimited the DFNB3 critical region to less than 4 cM within the Smith-Magenis syndrome common deletion region (182290), for which there were good physical maps. Liang et al. (1997, 1998) also had evidence that mutations in DFNB3 are responsible for recessive deafness outside of Bali. Nonsyndromic congenital recessive deafness in 2 unrelated consanguineous families in India were also linked to the DFNB3 region. The haplotypes of affected individuals in these 2 Indian families were different from each other and different from the Bengkala haplotype, suggesting that these 3 DFNB3 mutations arose independently.


▼ Population Genetics

Winata et al. (1995) studied further the congenital deafness prevalent in the Bengkala village population. They estimated the frequency of the DFNB3 mutant allele to be 9.4% among hearing people, who have a 17.2% chance of being heterozygotes.


▼ Molecular Genetics

In affected individuals from a kindred in Bengkala, Bali, with autosomal recessive deafness-3, Wang et al. (1998) identified homozygosity for a missense mutation (I892F; 602666.0001) in the MYO15 gene. In 2 unrelated Indian families, Wang et al. (1998) identified a homozygous missense (N890Y; 602666.0002) and nonsense (K1300X; 602666.0003) mutation, respectively.

Intrafamilial Heterogeneity

In a large multigenerational consanguineous Brazilian pedigree with prelingual severe to profound sensorineural deafness, negative for mutations in the deafness-associated GJB2 (121011) and GJB6 (604418) genes and for the A1555G mitochondrial mutation in the MTRNR1 gene (561000.0001), Lezirovitz et al. (2008) identified unexpected genetic heterogeneity: 15 affected individuals from 'branch 2' of the family were homozygous for a 1-bp deletion (10573delA; 602666.0012) in the MYO15A gene, whereas 4 affected sibs from 'branch 1' and 1 individual from 'branch 2' were compound heterozygous for 10573delA and a 4-bp deletion (602666.0013) in MYO15A. In 1 patient, only the 10573delA mutation could be identified. No mutations in MYO15A were identified in 5 patients from 2 additional branches of the family: the 3 mutation-negative patients from 'branch 4' of the family had a distinct clinical presentation, with 2 having mental retardation and 1 a mixed hearing loss, whereas the 2 mutation-negative patients from 'branch 3' had a phenotype similar to that of their mutation-positive relatives.

In a consanguineous Turkish family (family 2450) in which 2 brothers and a sister had bilateral profound prelingual hearing loss and were negative for mutation in GJB2, Ramzan et al. (2024) identified homozygosity for a missense mutation (S1481P) in the MYO15A gene in 2 of the affected sibs (II-1 and II-3). However, the other affected sib (II-2) did not carry the MYO15A variant, but was found to be homozygous for a nonsense mutation in the TOGARAM2 gene (Q515X; 620949); sib II-1 was heterozygous for the Q515X variant, whereas II-3 did not carry the TOGARAM2 variant. Their unaffected parents were first cousins; their father was heterozygous for both mutations, but the mutation status of their mother was not reported. The authors noted that the same MYO15A S1481P mutation previously had been identified in a Turkish family with autosomal recessive nonsyndromic sensorineural deafness by Cengiz et al. (2010). Ramzan et al. (2024) concluded that variants in a single deafness-associated gene may not explain hearing loss in all affected members of a family, and that affected individuals may need to be analyzed separately.


▼ Animal Model

Liang et al. (1998) proposed, on the basis of conserved synteny, that the recessive mouse deafness mutations 'shaker-2' (sh2) and sh2(j) are models of DFNB3. Genetic mapping of sh2 refined the location to a 0.6-cM interval of mouse chromosome 11. Three homologous genes map within the sh2 and DFNB3 intervals, suggesting that sh2 is the homolog of DFNB3.

Probst et al. (1998) demonstrated that deafness in shaker-2 mice was corrected by a bacterial artificial chromosome (BAC) transgene containing the unconventional myosin XVA (MYO15A; 602666). Because of its location in a region of homology of synteny to 17p, shaker-2 was thought to be the homolog of DFNB3. Wang et al. (1998) demonstrated that this was indeed the case by finding mutations of MYO15A in consanguineous Bengkala and Indian families.

Anderson et al. (2000) described the shaker-2(J) lesion, which is a 14.7-kb deletion that removes the last 6 exons from the 3-prime terminus of the Myo15 transcript.


▼ REFERENCES

  1. Anderson, D. W., Probst, F. J., Belyantseva, I. A., Fridell, R. A., Beyer, L., Martin, D. M., Wu, D., Kachar, B., Friedman, T. B., Raphael, Y., Camper, S. A. The motor and tail regions of myosin XV are critical for normal structure and function of auditory and vestibular hair cells. Hum. Molec. Genet. 9: 1729-1738, 2000. [PubMed: 10915760, related citations] [Full Text]

  2. Cengiz, F. B., Duman, D., Sirmaci, A., Tokgoz-Yilmaz, S., Erbek, S., Ozturkmen-Akay, H., Incesulu, A., Edwards, Y. J. K., Ozdag, H., Liu, X. Z., Tekin, M. Recurrent and private MYO15A mutations are associated with deafness in the Turkish population. Genet. Test. Molec. Biomarkers 14: 543-550, 2010. [PubMed: 20642360, related citations] [Full Text]

  3. Friedman, T. B., Liang, Y., Weber, J. L., Hinnant, J. T., Barber, T. D., Winata, S., Arhya, I. N., Asher, J. H., Jr. A gene for congenital, recessive deafness DFNB3 maps to the pericentromeric region of chromosome 17. Nature Genet. 9: 86-91, 1995. [PubMed: 7704031, related citations] [Full Text]

  4. Lezirovitz, K., Pardono, E., de Mello Auricchio, M. T. B., de Carvalho e Silva, F. L., Lopes, J. J., Abreu-Silva, R. S., Romanos, J., Batissoco, A. C., Mingroni-Netto, R. C. Unexpected genetic heterogeneity in a large consanguineous Brazilian pedigree presenting deafness. Europ. J. Hum. Genet. 16: 89-96, 2008. Note: Erratum: Europ. J. Hum. Genet. 16: 660 only, 2008. [PubMed: 17851452, related citations] [Full Text]

  5. Liang, Y., Wang, A., Morell, R., Wilcox, E., Jain, P., Li, X. C., Negrini, C., Deshmukh, D., Lupski, J. R., Chen, K.-S., Hinnant, J. T., Barber, T., Winata, S., Arhya, I. N., Moeljopawiro, S., Friedman, T. B. Nonsyndromic recessive deafness segregating with different haplotypes in families from Bali and India mapped to the 4 cM DFNB3 region of 17p11.2. (Abstract) Am. J. Hum. Genet. 61 (suppl.): A282 only, 1997.

  6. Liang, Y., Wang, A., Probst, F. J., Arhya, I. N., Barber, T. D., Chen, K.-S., Deshmukh, D., Dolan, D. F., Hinnant, J. T., Carter, L. E., Jain, P. K., Lalwani, A. K., and 9 others. Genetic mapping refines DFNB3 to 17p11.2, suggests multiple alleles of DFNB3, and supports homology to the mouse model shaker-2. Am. J. Hum. Genet. 62: 904-915, 1998. [PubMed: 9529344, related citations] [Full Text]

  7. Probst, F. J., Fridell, R. A., Raphael, Y., Saunders, T. L., Wang, A., Liang, Y., Morell, R. J., Touchman, J. W., Lyons, R. H., Noben-Trauth, K., Friedman, T. B., Camper, S. A. Correction of deafness in shaker-2 mice by an unconventional myosin in a BAC transgene. Science 280: 1444-1447, 1998. [PubMed: 9603735, related citations] [Full Text]

  8. Ramzan, M., Zafeer, M. F., Abad, C., Guo, S., Owrang, D., Alper, O., Mutlu, A., Atik, T., Duman, D., Bademci, G., Vona, B., Kalcioglu, M. T., Walz, K., Tekin, M. Genetic heterogeneity in hereditary hearing loss: potential role of kinociliary protein TOGARAM2. Europ. J. Hum. Genet. 32: 639-646, 2024. [PubMed: 38374469, related citations] [Full Text]

  9. Wang, A., Liang, Y., Fridell, R. A., Probst, F. J., Wilcox, E. R., Touchman, J. W., Morton, C. C., Morell, R. J., Noben-Trauth, K., Camper, S. A., Friedman, T. B. Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3. Science 280: 1447-1451, 1998. [PubMed: 9603736, related citations] [Full Text]

  10. Winata, S., Arhya, I. N., Moeljopawiro, S., Hinnant, J. T., Liang, Y., Friedman, T. B., Asher, J. H., Jr. Congenital non-syndromal autosomal recessive deafness in Bengkala, an isolated Balinese village. J. Med. Genet. 32: 336-343, 1995. [PubMed: 7616538, related citations] [Full Text]


Contributors:
Marla J. F. O'Neill - updated : 11/25/2024
Marla J. F. O'Neill - updated : 5/6/2008
George E. Tiller - updated : 9/21/2000
Victor A. McKusick - updated : 5/26/1998
Victor A. McKusick - updated : 5/13/1998
Victor A. McKusick - updated : 11/4/1997
Creation Date:
Victor A. McKusick : 1/20/1995
Edit History:
alopez : 11/25/2024
alopez : 06/20/2024
alopez : 05/01/2024
carol : 07/11/2023
carol : 04/28/2022
carol : 06/21/2016
terry : 8/9/2012
carol : 1/10/2011
alopez : 6/25/2009
terry : 12/12/2008
carol : 5/7/2008
terry : 5/6/2008
carol : 6/14/2001
alopez : 9/21/2000
alopez : 9/21/2000
dkim : 12/10/1998
dkim : 10/12/1998
alopez : 5/28/1998
terry : 5/26/1998
alopez : 5/20/1998
terry : 5/13/1998
terry : 5/13/1998
mark : 11/4/1997
terry : 11/4/1997
terry : 11/4/1997
joanna : 8/14/1997
alopez : 7/30/1997
alopez : 7/8/1997
alopez : 3/19/1997
mimadm : 9/23/1995
mark : 6/21/1995
carol : 1/20/1995

# 600316

DEAFNESS, AUTOSOMAL RECESSIVE 3; DFNB3


Alternative titles; symbols

NEUROSENSORY NONSYNDROMIC RECESSIVE DEAFNESS 3; NSRD3


ORPHA: 90636;   DO: 0110488;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key 		Gene/Locus Gene/Locus
MIM number
17p11.2 Deafness, autosomal recessive 3 600316 Autosomal recessive 3 MYO15A 602666

TEXT

A number sign (#) is used with this entry because of evidence that autosomal recessive deafness-3 (DFNB3) is caused by homozygous or compound heterozygous mutation in the gene encoding unconventional myosin XVA (MYO15A; 602666) on chromosome 17p11.

Description

Autosomal recessive deafness-3 (DFNB3) is a congenital, profound, neurosensory deafness. There are no apparent vestibular abnormalities or dysmorphic features (Friedman et al., 1995).


Clinical Features

Friedman et al. (1995) reported that 2% of the residents of Bengkala, an Indonesian village on the north shore of Bali, have profound, congenital, neurosensory, nonsyndromal deafness due to an autosomal recessive mutation at a locus designated DFNB3 (for the third autosomal recessive, nonsyndromic deafness locus to be mapped). This remote village dates to at least the 13th century as documented by charters inscribed in Sanskrit on metallic plates. Of the 2,185 residents, 47 had profound deafness of the type described. As an adaptation to the high percentage of deaf individuals, the citizens of Bengkala had developed a unique sign language used by most of the hearing persons as well as the deaf villagers. Deaf couples produced all deaf progeny. In 4- and 5-generation Bengkala kindreds, 2 of which were illustrated, there were no consanguineous marriages. The deaf individuals had no apparent vestibular abnormalities or dysmorphic features.


Inheritance

The transmission pattern of DFNB3 in the families reported by Wang et al. (1998) was consistent with autosomal recessive inheritance.


Mapping

Friedman et al. (1995) used a direct genomewide disequilibrium search strategy, allele-frequency-dependent homozygosity mapping (AHM), and analysis of historical recombinants to map DFNB3 and position the locus relative to flanking markers. They found that DFNB3 maps to chromosome 17. In individuals homozygous for DFNB3, historical recombinant phenotypes for the flanking markers D17S122 and D17S783 placed DFNB3 in a 5.3-cM interval of the pericentromeric region of chromosome 17 (17p12-q12).

With new short tandem repeats (STRs) from the DFNB3 region and additional DNA samples from affected individuals from Bengkala, Bali, Liang et al. (1997, 1998) found 2 historical recombinants for marker D17S953 from the telomeric side of 17p11.2 and 5 historical recombinants for marker D17S2201 on the centromeric side of 17p11.2. These recombinants further delimited the DFNB3 critical region to less than 4 cM within the Smith-Magenis syndrome common deletion region (182290), for which there were good physical maps. Liang et al. (1997, 1998) also had evidence that mutations in DFNB3 are responsible for recessive deafness outside of Bali. Nonsyndromic congenital recessive deafness in 2 unrelated consanguineous families in India were also linked to the DFNB3 region. The haplotypes of affected individuals in these 2 Indian families were different from each other and different from the Bengkala haplotype, suggesting that these 3 DFNB3 mutations arose independently.


Population Genetics

Winata et al. (1995) studied further the congenital deafness prevalent in the Bengkala village population. They estimated the frequency of the DFNB3 mutant allele to be 9.4% among hearing people, who have a 17.2% chance of being heterozygotes.


Molecular Genetics

In affected individuals from a kindred in Bengkala, Bali, with autosomal recessive deafness-3, Wang et al. (1998) identified homozygosity for a missense mutation (I892F; 602666.0001) in the MYO15 gene. In 2 unrelated Indian families, Wang et al. (1998) identified a homozygous missense (N890Y; 602666.0002) and nonsense (K1300X; 602666.0003) mutation, respectively.

Intrafamilial Heterogeneity

In a large multigenerational consanguineous Brazilian pedigree with prelingual severe to profound sensorineural deafness, negative for mutations in the deafness-associated GJB2 (121011) and GJB6 (604418) genes and for the A1555G mitochondrial mutation in the MTRNR1 gene (561000.0001), Lezirovitz et al. (2008) identified unexpected genetic heterogeneity: 15 affected individuals from 'branch 2' of the family were homozygous for a 1-bp deletion (10573delA; 602666.0012) in the MYO15A gene, whereas 4 affected sibs from 'branch 1' and 1 individual from 'branch 2' were compound heterozygous for 10573delA and a 4-bp deletion (602666.0013) in MYO15A. In 1 patient, only the 10573delA mutation could be identified. No mutations in MYO15A were identified in 5 patients from 2 additional branches of the family: the 3 mutation-negative patients from 'branch 4' of the family had a distinct clinical presentation, with 2 having mental retardation and 1 a mixed hearing loss, whereas the 2 mutation-negative patients from 'branch 3' had a phenotype similar to that of their mutation-positive relatives.

In a consanguineous Turkish family (family 2450) in which 2 brothers and a sister had bilateral profound prelingual hearing loss and were negative for mutation in GJB2, Ramzan et al. (2024) identified homozygosity for a missense mutation (S1481P) in the MYO15A gene in 2 of the affected sibs (II-1 and II-3). However, the other affected sib (II-2) did not carry the MYO15A variant, but was found to be homozygous for a nonsense mutation in the TOGARAM2 gene (Q515X; 620949); sib II-1 was heterozygous for the Q515X variant, whereas II-3 did not carry the TOGARAM2 variant. Their unaffected parents were first cousins; their father was heterozygous for both mutations, but the mutation status of their mother was not reported. The authors noted that the same MYO15A S1481P mutation previously had been identified in a Turkish family with autosomal recessive nonsyndromic sensorineural deafness by Cengiz et al. (2010). Ramzan et al. (2024) concluded that variants in a single deafness-associated gene may not explain hearing loss in all affected members of a family, and that affected individuals may need to be analyzed separately.


Animal Model

Liang et al. (1998) proposed, on the basis of conserved synteny, that the recessive mouse deafness mutations 'shaker-2' (sh2) and sh2(j) are models of DFNB3. Genetic mapping of sh2 refined the location to a 0.6-cM interval of mouse chromosome 11. Three homologous genes map within the sh2 and DFNB3 intervals, suggesting that sh2 is the homolog of DFNB3.

Probst et al. (1998) demonstrated that deafness in shaker-2 mice was corrected by a bacterial artificial chromosome (BAC) transgene containing the unconventional myosin XVA (MYO15A; 602666). Because of its location in a region of homology of synteny to 17p, shaker-2 was thought to be the homolog of DFNB3. Wang et al. (1998) demonstrated that this was indeed the case by finding mutations of MYO15A in consanguineous Bengkala and Indian families.

Anderson et al. (2000) described the shaker-2(J) lesion, which is a 14.7-kb deletion that removes the last 6 exons from the 3-prime terminus of the Myo15 transcript.


REFERENCES

  1. Anderson, D. W., Probst, F. J., Belyantseva, I. A., Fridell, R. A., Beyer, L., Martin, D. M., Wu, D., Kachar, B., Friedman, T. B., Raphael, Y., Camper, S. A. The motor and tail regions of myosin XV are critical for normal structure and function of auditory and vestibular hair cells. Hum. Molec. Genet. 9: 1729-1738, 2000. [PubMed: 10915760] [Full Text: https://doi.org/10.1093/hmg/9.12.1729]

  2. Cengiz, F. B., Duman, D., Sirmaci, A., Tokgoz-Yilmaz, S., Erbek, S., Ozturkmen-Akay, H., Incesulu, A., Edwards, Y. J. K., Ozdag, H., Liu, X. Z., Tekin, M. Recurrent and private MYO15A mutations are associated with deafness in the Turkish population. Genet. Test. Molec. Biomarkers 14: 543-550, 2010. [PubMed: 20642360] [Full Text: https://doi.org/10.1089/gtmb.2010.0039]

  3. Friedman, T. B., Liang, Y., Weber, J. L., Hinnant, J. T., Barber, T. D., Winata, S., Arhya, I. N., Asher, J. H., Jr. A gene for congenital, recessive deafness DFNB3 maps to the pericentromeric region of chromosome 17. Nature Genet. 9: 86-91, 1995. [PubMed: 7704031] [Full Text: https://doi.org/10.1038/ng0195-86]

  4. Lezirovitz, K., Pardono, E., de Mello Auricchio, M. T. B., de Carvalho e Silva, F. L., Lopes, J. J., Abreu-Silva, R. S., Romanos, J., Batissoco, A. C., Mingroni-Netto, R. C. Unexpected genetic heterogeneity in a large consanguineous Brazilian pedigree presenting deafness. Europ. J. Hum. Genet. 16: 89-96, 2008. Note: Erratum: Europ. J. Hum. Genet. 16: 660 only, 2008. [PubMed: 17851452] [Full Text: https://doi.org/10.1038/sj.ejhg.5201917]

  5. Liang, Y., Wang, A., Morell, R., Wilcox, E., Jain, P., Li, X. C., Negrini, C., Deshmukh, D., Lupski, J. R., Chen, K.-S., Hinnant, J. T., Barber, T., Winata, S., Arhya, I. N., Moeljopawiro, S., Friedman, T. B. Nonsyndromic recessive deafness segregating with different haplotypes in families from Bali and India mapped to the 4 cM DFNB3 region of 17p11.2. (Abstract) Am. J. Hum. Genet. 61 (suppl.): A282 only, 1997.

  6. Liang, Y., Wang, A., Probst, F. J., Arhya, I. N., Barber, T. D., Chen, K.-S., Deshmukh, D., Dolan, D. F., Hinnant, J. T., Carter, L. E., Jain, P. K., Lalwani, A. K., and 9 others. Genetic mapping refines DFNB3 to 17p11.2, suggests multiple alleles of DFNB3, and supports homology to the mouse model shaker-2. Am. J. Hum. Genet. 62: 904-915, 1998. [PubMed: 9529344] [Full Text: https://doi.org/10.1086/301786]

  7. Probst, F. J., Fridell, R. A., Raphael, Y., Saunders, T. L., Wang, A., Liang, Y., Morell, R. J., Touchman, J. W., Lyons, R. H., Noben-Trauth, K., Friedman, T. B., Camper, S. A. Correction of deafness in shaker-2 mice by an unconventional myosin in a BAC transgene. Science 280: 1444-1447, 1998. [PubMed: 9603735] [Full Text: https://doi.org/10.1126/science.280.5368.1444]

  8. Ramzan, M., Zafeer, M. F., Abad, C., Guo, S., Owrang, D., Alper, O., Mutlu, A., Atik, T., Duman, D., Bademci, G., Vona, B., Kalcioglu, M. T., Walz, K., Tekin, M. Genetic heterogeneity in hereditary hearing loss: potential role of kinociliary protein TOGARAM2. Europ. J. Hum. Genet. 32: 639-646, 2024. [PubMed: 38374469] [Full Text: https://doi.org/10.1038/s41431-024-01562-6]

  9. Wang, A., Liang, Y., Fridell, R. A., Probst, F. J., Wilcox, E. R., Touchman, J. W., Morton, C. C., Morell, R. J., Noben-Trauth, K., Camper, S. A., Friedman, T. B. Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3. Science 280: 1447-1451, 1998. [PubMed: 9603736] [Full Text: https://doi.org/10.1126/science.280.5368.1447]

  10. Winata, S., Arhya, I. N., Moeljopawiro, S., Hinnant, J. T., Liang, Y., Friedman, T. B., Asher, J. H., Jr. Congenital non-syndromal autosomal recessive deafness in Bengkala, an isolated Balinese village. J. Med. Genet. 32: 336-343, 1995. [PubMed: 7616538] [Full Text: https://doi.org/10.1136/jmg.32.5.336]


Contributors:
Marla J. F. O'Neill - updated : 11/25/2024
Marla J. F. O'Neill - updated : 5/6/2008
George E. Tiller - updated : 9/21/2000
Victor A. McKusick - updated : 5/26/1998
Victor A. McKusick - updated : 5/13/1998
Victor A. McKusick - updated : 11/4/1997

Creation Date:
Victor A. McKusick : 1/20/1995

Edit History:
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NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2025 Johns Hopkins University.
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