A Novel Familial <i>BBS12</i> Mutation Associated with a Mild Phenotype: Implications for Clinical and Molecular Diagnostic Strategies

Bardet-Biedl syndrome (BBS) is an autosomal recessively inherited ciliopathy mainly characterized by rod-cone dystrophy, postaxial polydactyly, obesity, renal tract anomalies, and hypogonadism. To date, 14 BBS genes, BBS1 to BBS14, have been identified, accounting for over 75% of mutations in BBS families. In this study, we present a consanguineous family from Pakistan with postaxial polydactyly and late-onset retinal dysfunction. Adult affected individuals did not show any renal or genital anomalies, obesity, mental retardation or learning difficulties and did thus not fulfill the proposed clinical diagnostic criteria for BBS. We mapped the disease in this family to the BBS12 locus on chromosome 4q27 and identified the novel homozygous p.S701X nonsense mutation in BBS12 in all three affected individuals of this family. We conclude that BBS12 mutations might cause a very mild phenotype, which is clinically not diagnosed by the current diagnostic criteria for BBS. Consequently, we suggest the use of less strict diagnostic criteria in familial BBS families with mild phenotypic expression.