Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21)

Bardet Biedl syndrome (BBS) is a multisystem genetically heterogeneous ciliopathy that most commonly leads to obesity, photoreceptor degeneration, digit anomalies, genito-urinary abnormalities, as well as cognitive impairment with autism, among other features. Sequencing of a DNA sample from a 17 year old female affected with BBS did not identify any mutation in the known BBS genes. Whole genome sequencing identified a novel loss-of-function disease-causing homozygous mutation (K102*) inC8ORF37, a gene coding for a cilia protein. The proband was overweight (BMI 29.1) with a slowly progressive rod-cone dystrophy, a mild learning difficulty, high myopia, 3 limb post-axial polydactyly, horseshoe kidney, abnormally positioned uterus, and elevated liver enzymes. Mutations inC8ORF37were previously associated with severe autosomal recessive retinal dystrophies (retinitis pigmentosa RP64 and cone-rod dystrophy CORD16) but not BBS. To elucidate the functional role ofC8ORF37in a vertebrate system, we performed gene knockdown inDanio rerioand assessed the cardinal features of BBS and visual function. Knockdown ofc8orf37resulted in impaired visual behavior and BBS-related phenotypes, specifically, defects in the formation of Kupffer's vesicle and delays in retrograde transport. Specificity of these phenotypes to BBS knockdown was shown with rescue experiments. Over-expression of human missense mutations in zebrafish also resulted in impaired visual behavior and BBS-related phenotypes. This is the first functional validation and association ofC8ORF37mutations with the BBS phenotype, which identifies BBS21. The zebrafish studies hereby show thatC8ORF37variants underlie clinically diagnosed BBS-related phenotypes as well as isolated retinal degeneration.