Alternative titles; symbols
ORPHA: 1435;
Cytogenetic location: Xq21 Genomic coordinates (GRCh38): X:76,800,001-99,100,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq21 | Xq21 deletion syndrome | 303110 | X-linked recessive | 4 |
A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome involving chromosome Xq21 and including at least the CHM (300390) and POU3F4 (300039) genes.
Ayazi (1981) described a kindred in which 2 brothers and their maternal uncle had choroideremia (CHM; 303100), congenital deafness, and mental retardation. Female carriers had typical retinal changes indicative of the choroideremia carrier state (Nussbaum et al., 1987). This family (XL-45) was also reported by Cremers et al. (1989), Merry et al. (1989), and Merry et al. (1992).
Nussbaum et al. (1987) reported a second family (XL-62) in which 2 first cousins through their mothers had choroideremia, mental retardation, deafness, and short stature. In a follow-up of this family, Merry et al. (1989) noted that 1 of the patients had stapes fixation and perilymphatic gusher on stapedectomy, consistent with DFN3 (304400). The boys, both mothers, the maternal grandmother, and a sister were all carriers of an Xq21 deletion. One of the mothers had mild high frequency sensorineural hearing loss at age 41.
Song et al. (2010) reported a 3-year-old Korean boy who showed severe bilateral hearing loss at 8 months of age. He also had central hypotonia, developmental delay, mild mental retardation, and vesicoureteral reflux. High-resolution temporal bone CT scan showed a defective cochlear modiolus resulting in a fistulous connection between the basal turn of the cochlea and the internal auditory canal, typical of DFN3. His mother had mild high-tone hearing loss. Molecular analysis identified a 16-Mb deletion of Xq21, including the POU3F4, RSK4 (300303), and CHM (300390) genes. Although he did not have symptoms of choroideremia, Song et al. (2010) noted that choroideremia is a progressive disorder that may become apparent with age. Multiplex ligation-dependent probe analysis (MLPA) showed that the unaffected mother also carried the deletion.
In affected members of a family (XL-62) in which 2 males had choroideremia, mental retardation, and deafness, Nussbaum et al. (1987) identified an interstitial deletion on chromosome Xq21; markers DXYS1 and DXS72 were deleted. Affected individuals in a second family (XL-45) previously reported by Ayazi (1981) had a submicroscopic deletion of the same region.
Schwartz et al. (1988) reported 2 brothers with mental retardation, sensorineural deafness, and choroideremia associated with a small interstitial deletion of Xq21.2-q31.31. The mother was found to be a carrier of choroideremia. Cremers et al. (1989) performed fine mapping of the deleted Xq21 region. Family XL-62 had a deletion between DXS72 and DXS214 and family XL-42 had a smaller deletion between DXS232 and DXS95. Another patient (DM) reported by Schwartz et al. (1988) with choroideremia, mental retardation, and deafness had a deletion between DXS232 and DXYS5.
Merry et al. (1989) reported similar results as Cremers et al. (1989) in deletion studies of families XL-62 and XL-42. The deletions involved not only the choroideremia locus (303100), as proven at a molecular level, but also the DFN3 locus for X-linked deafness and stapes fixation (304400), which codes for X-linked deafness with stapes fixation. In addition, Merry et al. (1989) reported a patient with choroideremia and mental retardation but no deafness who had a partially overlapping deletion between DXS233 and DXS3.
In a study of several overlapping deletions involving different parts of Xq21 with DNA probes, Bach et al. (1992) assigned the DFN3 locus and a locus for nonspecific X-linked mental retardation to an interval that encompasses the marker DXS232 and that is flanked by DXS26 and DXS121.
Poloschek et al. (2008) studied 2 brothers and a 15-year-old unrelated boy with choroideremia, mental retardation, and problems with motor development. The unrelated patient had ataxic gait (see 300489) and showed the beginnings of auditory hair cell damage affecting low frequency hearing. All 3 patients had deletions on chromosome Xq21, ranging in size from approximately 6.3 to 9.7 Mb in the sibs, and from 8.5 to 14.1 Mb in the unrelated patient. Both deletions encompassed the CHM gene (300390).
Ayazi, S. Choroideremia, obesity, and congenital deafness. Am. J. Ophthal. 92: 63-69, 1981. [PubMed: 7258279] [Full Text: https://doi.org/10.1016/s0002-9394(14)75909-4]
Bach, I., Robinson, D., Thomas, N., Ropers, H.-H., Cremers, F. P. M. Physical fine mapping of genes underlying X-linked deafness and non fra(X)-X-linked mental retardation at Xq21. Hum. Genet. 89: 620-624, 1992. [PubMed: 1511979] [Full Text: https://doi.org/10.1007/BF00221950]
Cremers, F. P. M., van de Pol, D. J. R., Diergaarde, P. J., Wieringa, B., Nussbaum, R. L., Schwartz, M., Ropers, H.-H. Physical fine mapping of the choroideremia locus using Xq21 deletions associated with complex syndromes. Genomics 4: 41-46, 1989. [PubMed: 2914708] [Full Text: https://doi.org/10.1016/0888-7543(89)90312-1]
Merry, D. E., Janne, P. A., Landers, J. E., Lewis, R. A., Nussbaum, R. L. Isolation of a candidate gene for choroideremia. Proc. Nat. Acad. Sci. 89: 2135-2139, 1992. [PubMed: 1549574] [Full Text: https://doi.org/10.1073/pnas.89.6.2135]
Merry, D. E., Lesko, J. G., Sosnoski, D. M., Lewis, R. A., Lubinsky, M., Trask, B., van den Engh, G., Collins, F. S., Nussbaum, R. L. Choroideremia and deafness with stapes fixation: a contiguous gene deletion syndrome in Xq21. Am. J. Hum. Genet. 45: 530-540, 1989. [PubMed: 2491012]
Nussbaum, R. L., Lesko, J. G., Lewis, R. A., Ledbetter, S. A., Ledbetter, D. H. Isolation of anonymous DNA sequences from within a submicroscopic X chromosomal deletion in a patient with choroideremia, deafness, and mental retardation. Proc. Nat. Acad. Sci. 84: 6521-6525, 1987. [PubMed: 3476958] [Full Text: https://doi.org/10.1073/pnas.84.18.6521]
Poloschek, C. M., Kloeckener-Gruissem, B., Hansen, L. L., Bach, M., Berger, W. Syndromic choroideremia: sublocalization of phenotypes associated with Martin-Probst deafness mental retardation syndrome. Invest. Vis. Sci. 49: 4096-4104, 2008.
Schwartz, M., Yang, H.-M., Niebuhr, E., Rosenberg, T., Page, D. C. Regional localization of polymorphic DNA loci on the proximal long arm of the X chromosome using deletions associated with choroideremia. Hum. Genet. 78: 156-160, 1988. [PubMed: 3422216] [Full Text: https://doi.org/10.1007/BF00278188]
Song, M. H., Lee, H. K., Choi, J. Y., Kim, S., Bok, J., Kim, U.-K. Clinical evaluation of DFN3 patients with deletions in the POU3F4 locus and detection of carrier female using MLPA. Clin. Genet. 78: 524-532, 2010. [PubMed: 20412083] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01426.x]