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Most patients with Ellis-van Creveld syndrome (EvC) are identified with pathogenic changes in  EVC  or  EVC2 , however further genetic heterogeneity has been suggested. In this report we describe pathogenic splicing variants in  WDR35 , encoding retrograde intraflagellar transport protein 121 (IFT121), in three families with a clinical diagnosis of EvC but having a distinctive phenotype. To understand why  WDR35  variants result in EvC, we analysed EVC, EVC2 and Smoothened (SMO) in IFT-A deficient cells. We found that the three proteins failed to localize to  Wdr35 −/−   cilia, but not to the cilium of the IFT retrograde motor mutant  Dync2h1 −/−  , indicating that IFT121 is specifically required for their entry into the ciliary compartment. Furthermore expression of  Wdr35  disease cDNAs in  Wdr35 −/−   fibroblasts revealed that the newly identified variants lead to Hedgehog signalling defects resembling those of  Evc −/−   and  Evc2 −/−   mutants. Together our data indicate that splicing variants in  WDR35 , and possibly in other IFT-A components, underlie a number of EvC cases by disrupting targeting of both the EvC complex and SMO to cilia.

human molecular genetics

Specific variants in  WDR35  cause a distinctive form of Ellis-van Creveld syndrome by disrupting the recruitment of the EvC complex and SMO into the cilium