Defective IFT57 underlies a novel cause of Bardet-Biedl syndrome.

A 29-year-old male presented with rod-cone degeneration leading to legal blindness, post-axial polydactyly, obesity, cognitive impairment, and fatty liver, features suggestive of a clinical diagnosis of Bardet-Biedl Syndrome (BBS). Following negative clinical genetic testing, genome analysis identified biallelic variants in IFT57: p.(Val397Glu) and p.(Lys225Asnfs*17). IFT57 is part of complex B of the intraflagellar transport (IFT) proteins, which is an adaptor to the anterograde transport of proteins, bringing cargo from the base of the primary cilia to the tip. Variants in IFT57 have not yet been associated with BBS or human retinal degeneration, but biallelic splicing variants were associated with a distinct ciliopathy: oral-facial-digital syndrome. Using patient-derived fibroblasts, IFT57-knockouts (KO) of RPE1, and mIMCD3 cells, we showed that p.(Lys225Asnfs*17) is subjected to non-sense mediated decay, and that p.(Val397Glu) is the predominant variant which leads to cilia defects. Exogenous expression of the p.(Val397Glu) variant partially restored structural and functional primary cilia defects, and of the anterograde transport in Ift57-KO mIMCD3 cells but it did not rescue primary cilia in retinal IFT57-KO-RPE1 cells. The cell autonomous effect, likely explains the retinal dystrophy in our proband with BBS.