Alternative titles; symbols
ORPHA: 52429; DO: 0060232;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q23.1 | Branchiootic syndrome 3 | 608389 | Autosomal dominant | 3 | SIX1 | 601205 |
A number sign (#) is used with this entry because of evidence that branchiootic syndrome-3 (BOS3) is caused by heterozygous mutation in the SIX1 gene (601205) on chromosome 14q23.
For a phenotypic description and a discussion of genetic heterogeneity of branchiootic syndrome, see BOS1 (602588).
Ruf et al. (2003) reported a large Anglo-Saxon Australian pedigree in which over 40 members had branchiootic syndrome and mutation in the SIX1 gene. In contrast to the pedigree with BOS2 (120502) described by Kumar et al. (2000) in which hearing loss was diagnosed in 50% of the affected subjects, deafness seemed to be a major feature in the Australian pedigree. As 25% of the patients showed association with branchial arch defects, a nonsyndromic form of deafness was unlikely. The finding of lacrimal duct stenosis, a common association in both branchiootorenal (BOR; 113650) and branchiootic syndromes, further confirmed the diagnosis of BOS. The hearing loss varied in form, severity, frequency, and age of onset among the different family members and even between the ears of 1 patient, a characteristic feature of BOR and BOS.
Sanggaard et al. (2007) reported 7 members of a large 5-generation Danish family with branchiootic syndrome and mutation in the SIX1 gene. All affected individuals had hearing impairment, and some had branchial and preauricular defects. There were no subjective complaints indicating renal disease, and no renal anomalies were detected in the 3 affected individuals who underwent renal ultrasound.
By a genomewide search in a large Anglo-Saxon Australian pedigree in which over 40 members had BOS, Ruf et al. (2003) mapped a locus for the disorder, which they designated BOS3, to 14q21.3-q24.3. The highest multipoint lod score was 4.81 for marker D14S980. EYA2 (601654) and EYA3 (601655) were excluded as sites of mutations causing BOS3 in this kindred because these 2 genes are located on chromosomes 20 and 1, respectively. Mutations in another member of the EYA gene family, EYA4 (603550), is responsible for late-onset deafness (601316).
The transmission pattern of BOS in the large Anglo-Saxon pedigree reported by Ruf et al. (2003) was consistent with autosomal dominant inheritance.
Ruf et al. (2004) located the SIX1, SIX4 (606342), and SIX6 (606326) genes, which act within a genetic network of EYA and PAX genes to regulate organogenesis, within a 33-Mb critical interval on chromosome 14q23 to which Ruf et al. (2003) had mapped a BOS locus in a large Australian pedigree. By direct sequencing of exons in these genes, they identified 2 different heterozygous mutations in the SIX1 gene in 3 kindreds with branchiootic syndrome-3 (601205.0001-601205.0002).
In 7 affected individuals from a large 5-generation Danish family with branchiootic syndrome, Sanggaard et al. (2007) identified heterozygosity for a missense mutation in the SIX1 gene (601205.0004). The mutation was not found in unaffected family members or in 140 control chromosomes.
Kumar, S., Deffenbacher, K., Marres, H. A. M., Cremers, C. W. R. J., Kimberling, W. J. Genomewide search and genetic localization of a second gene associated with autosomal dominant branchio-oto-renal syndrome: clinical and genetic implications. Am. J. Hum. Genet. 66: 1715-1720, 2000. [PubMed: 10762556] [Full Text: https://doi.org/10.1086/302890]
Ruf, R. G., Berkman, J., Wolf, M. T. F., Nurnberg, P., Gattas, M., Ruf, E.-M., Hyland, V., Kromberg, J., Glass, I., Macmillan, J., Otto, E., Nurnberg, G., Lucke, B., Hennies, H. C., Hildebrandt, F. A gene locus for branchio-otic syndrome maps to chromosome 14q21.3-q24.3. J. Med. Genet. 40: 515-519, 2003. [PubMed: 12843324] [Full Text: https://doi.org/10.1136/jmg.40.7.515]
Ruf, R. G., Xu, P.-X., Silvius, D., Otto, E. A., Beekmann, F., Muerb, U. T., Kumar, S., Neuhaus, T. J., Kemper, M. J., Raymond, R. M., Jr., Brophy, P. D., Berkman, J., and 10 others. SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. Proc. Nat. Acad. Sci. 101: 8090-8095, 2004. [PubMed: 15141091] [Full Text: https://doi.org/10.1073/pnas.0308475101]
Sanggaard, K. M., Rendtorff, N. D., Kjaer, K. W., Eiberg, H., Johnsen, T., Gimsing, S., Dyrmose, J., Nielsen, K. O., Lage, K., Tranebjaerg, L. Branchio-oto-renal syndrome: detection of EYA1 and SIX1 mutations in five out of six Danish families by combining linkage, MLPA and sequencing analyses. Europ. J. Hum. Genet. 15: 1121-1131, 2007. [PubMed: 17637804] [Full Text: https://doi.org/10.1038/sj.ejhg.5201900]