ORPHA: 65; DO: 0110079;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q31.3 | Leber congenital amaurosis 8 | 613835 | Autosomal recessive | 3 | CRB1 | 604210 |
A number sign (#) is used with this entry because Leber congenital amaurosis-8 (LCA8) is caused by homozygous or compound heterozygous mutation in the CRB1 gene (604210) on chromosome 1q31.
Homozygous or compound heterozygous mutation in CRB1 can also cause retinitis pigmentosa-12 (RP12; 600105).
Leber congenital amaurosis comprises a group of early-onset childhood retinal dystrophies characterized by vision loss, nystagmus, and severe retinal dysfunction. Patients usually present at birth with profound vision loss and pendular nystagmus. Electroretinogram (ERG) responses are usually nonrecordable. Other clinical findings may include high hypermetropia, photodysphoria, oculodigital sign, keratoconus, cataracts, and a variable appearance to the fundus (summary by Chung and Traboulsi, 2009).
For a general description and a discussion of genetic heterogeneity of LCA, see 204000.
Abouzeid et al. (2006) reported 4 members of a Middle Eastern family with Leber congenital amaurosis who had high to extreme hyperopia (average spherical refractive errors ranging from +5.00 to +10.00).
Lotery et al. (2001) screened the candidate gene CRB1 in 190 patients with Leber congenital amaurosis (LCA8; 613835) who were negative for mutation in 6 known LCA genes and 140 controls, and identified 21 patients and 2 controls who harbored amino acid-altering sequence variants (p = 0.03; see, e.g., 604210.0013). The authors noted that the 21 CRB1 mutation-carrying patients represented 9% of their total cohort of 233 LCA patients, making CRB1 the most commonly mutated gene in this group of patients.
Den Hollander et al. (2001) identified mutations in the CRB1 gene in 7 of 52 patients with LCA from the Netherlands, Germany, and the US. In 2 affected brothers, they identified compound heterozygous mutations (604210.0006-604210.0007). Den Hollander et al. (2001) noted that patients with LCA8 carried null alleles more frequently than did patients with RP12.
In all 4 affected members of a Middle Eastern family with LCA8 with high to extreme hyperopia, Abouzeid et al. (2006) found linkage of the disorder to 1q31 and identified homozygosity for a mutation in the CRB1 gene (G1103R; 604210.0011). Abouzeid et al. (2006) showed that hyperopia and LCA were linked to the mutant CRB1 gene itself and were not dependent on unlinked modifiers. Abouzeid et al. (2006) noted that the G1103R mutation had previously been identified in compound heterozygous state in a patient with sporadic LCA by Hanein et al. (2004).
Abouzeid, H., Li, Y., Maumenee, I. H., Dharmaraj, S., Sundlin, O. A G1103R mutation in CRB1 is co-inherited with high hyperopia and Leber congenital amaurosis. Ophthalmic Genet. 27: 15-20, 2006. [PubMed: 16543197] [Full Text: https://doi.org/10.1080/13816810500481840]
Chung, D. C., Traboulsi, E. I. Leber congenital amaurosis: clinical correlations with genotypes, gene therapy trials update, and future directions. J. AAPOS 13: 587-592, 2009. [PubMed: 20006823] [Full Text: https://doi.org/10.1016/j.jaapos.2009.10.004]
den Hollander, A. I., Heckenlively, J. R., van den Born, L. I., de Kok, Y. J. M., van der Velde-Visser, S. D., Kellner, U., Jurklies, B., van Schooneveld, M. J., Blankenagel, A., Rohrschneider, K., Wissinger, B., Cruysberg, J. R. M., Deutman, A. F., Brunner, H. G., Apfelstedt-Sylla, E., Hoyng, C. B., Cremers, F. P. M. Leber congenital amaurosis and retinitis pigmentosa with Coats-like exudative vasculopathy are associated with mutations in the Crumbs homologue 1 (CRB1) gene. Am. J. Hum. Genet. 69: 198-203, 2001. Note: Erratum: Am. J. Hum. Genet. 69: 1160 only, 2001. [PubMed: 11389483] [Full Text: https://doi.org/10.1086/321263]
Hanein, S., Perrault, I., Gerber, S., Tanguy, G., Barbet, F., Ducroq, D., Calvas, P., Dollfus, H., Hamel, C., Lopponen, T., Munier, F., Santos, L., Shalev, S., Zafeiriou, D., Dufier, J.-L., Munnich, A., Rozet, J.-M., Kaplan, J. Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis. Hum. Mutat. 23: 306-317, 2004. [PubMed: 15024725] [Full Text: https://doi.org/10.1002/humu.20010]
Lotery, A. J., Jacobson, S. G., Fishman, G. A., Weleber, R. G., Fulton, A. B., Namperumalsamy, P., Heon, E., Levin, A. V., Grover, S., Rosenow, J. R., Kopp, K. K., Sheffield, V. C., Stone, E. M. Mutations in the CRB1 gene cause Leber congenital amaurosis. Arch. Ophthal. 119: 415-420, 2001. [PubMed: 11231775] [Full Text: https://doi.org/10.1001/archopht.119.3.415]