Purpose: Bardet Biedl syndrome (BBS) is a heterogeneous ciliopathy with fourteen genes currently identified. BBS7 and BBS8 are believed to account for a small percentage of cases, with mutations reported in 4.2% and 2.8% of BBS families respectively. We sequenced the coding region of BBS7 and BBS8 in 35 BBS families of multiethnic backgrounds. We also evaluated the potential role of 2 putative modifier genes, MGC1203 and NXNL1.
Method: Coding exons and flanking intronic regions of BBS7, BBS8 and NXNL1 were PCR amplified and directly sequenced from genomic DNA. The presumed modifying C430T variation in MGC1203 was tested by amplification refractory mutation system (ARMS) assay. Novel mutations detected were validated using a control panel of 300 chromosomes and bioinformatic to evaluate the potential effect of novel mutations on splicing, protein structure and function.
Result: Four novel pathogenic BBS7 changes identified in 2/35 families (5.5%). No pathogenic sequence changes were identified in BBS8. No sequence change were identified in the NXNL1 and only the "c" variant of MGC1203 (C430T) was seen. Although the sample size is too small to establish a phenotype-genotype correlation, in one BBS7 family with two affected individuals, a more severe phenotype was associated with a third mutation in BBS4.
Conclusion: The study confirms the small role of BBS7 and BBS8 in the overall mutational load. The potential interaction between BBS4 and BBS7 requires further studies.