BBS1, BBS10 and BBS2 are major causative genes for Bardet-Biedl syndrome in Italian patients.

BACKGROUND: Bardet-Biedl Syndrome (BBS) is a rare inherited disorder associated with obesity, retinopathy, renal defects, polydactyly, learning disabilities and hypogenitalism. Fourteen genes (BBS1–14) account for about 80% of the known cases of BBS, indicating that additional BBS genes are yet to be identified. BBS prevalence is 1 in 125.000–160.000 in Caucasian people. The wide clinical spectrum observed in BBS correlates to the high genetic heterogeneity. Usually, BBS is transmitted in autosomal recessive manner. However, in some families, a triallelic inheritance involving BBS1, BBS2 and BBS6 genes has been observed. METHODS: To design a sensitive and time-effective procedure for molecular diagnosis of BBS, we analyzed a cohort of 21 Italian patients (BBL1-BBL21). First, we used the APEX genotyping microarray (Genorama) to search for 300 known mutations in 11 BBS (BBS1-BBS10, BBS12), in PHF6, ALMS1, and GNAS1 genes. Then, we analyzed by direct sequencing the whole coding regions of the BBS1, BBS2 and BBS10 genes, in patients who resulted with one and without a mutation after APEX analysis. RESULTS: The genotyping microarray identified both mutated alleles in 5 patients and one mutated allele in 1 patient, for a total of 11 disease-alleles (6 in BBS1, 3 in BBS10 and 2 in BBS2), yielding a detection rate of about 26.2% (11/42). In addition, sequence analysis allowed us to identify 8 new mutations, 3 in BBS10 (1 point insertion, 1 missense and 1 nonsense mutation), 4 in BBS2 (2 missense, 1 point insertion and 1 point deletion) and 1 missense mutation in BBS1. The detection rate of the whole procedure increased to 45,2%. CONCLUSIONS: Our study indicates that sequencing of BBS1, BBS2 and BBS10 should be chosen as first analytic step in the molecular diagnosis of BBS in Italian patients. The subsequent analytical step might be the APEX array. Obviously, in the complex framework of the molecular diagnosis of BBS, next generation sequencing analysis would be strongly recommended.