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A. B. Daniels, J. Chen, T. L. McGee, C. Wiegel-DiFranco, M. A. Sandberg, J. F. Hejtmancik, E. L. Berson; Genotype-Phenotype Correlations in the Bardet-Biedl Syndrome. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1382.
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The Bardet-Biedl syndrome (BBS) comprises both ocular and non-ocular findings and is caused by mutations in one of at least 12 different genes (BBS1-12). This study was done to determine whether mutations in different genes result in different clinical ocular phenotypes.
37 patients (from 31 families) were enrolled who met the clinical criteria for BBS and for whom a mutation in a known BBS gene had been identified. 17 patients harbored mutations in BBS1, 10 in BBS10, and 10 in either BBS2, 3, 5, 7, or 12. All underwent an ocular examination; computerized full-field cone ERG responses were obtained from 31 patients.
All three categories of patients (those with mutations in BBS1, BBS10 or another BBS gene) each had a mean age between 24-25 years. The prevalences of bone-spicule pigmentation and posterior subcapsular cataract were comparable in the 3 groups. 41% of patients with a mutation in BBS1 presented with a visual acuity of 20/50 or better, compared to 10% of patients with all other mutations, whose acuities were worse (p=0.01, age-adjusted). 30Hz cone amplitudes were significantly higher among BBS1 patients (geometric mean=5.0µV) than among patients with other BBS mutations (geometric mean=0.25µV; p<0.0001; lower norm=50µV). In fact, 54% of BBS1 patients had amplitudes greater than 9.9µV, whereas no patient with a non-BBS1 mutation had an amplitude greater than 0.7µV. Interestingly, all BBS1 patients harbored at least one missense mutation (and thus presumably formed some protein) as compared to 45% of patients with mutations in other BBS genes (p<0.001); The rest harbored only null alleles (frameshift, termination or splice site mutations). Comparisons of BBS1 with BBS10 led to similar conclusions.
Patients with BBS1 mutations manifest a milder phenotype than patients with mutations in other BBS genes. Clinically, this manifests as significantly better acuity and larger 30Hz cone amplitudes. This difference may relate to the fact that the BBS1 mutations tended to be missense mutations, whereas mutations in other BBS genes were mostly null.
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