PURPOSE: IFT81, a core component of the IFT-B complex, involved in the 
bidirectional transport of ciliary proteins, has been recently implicated in 
syndromic ciliopathies. However, none of the IFT-B core complex proteins have 
been associated with nonsyndromic retinal dystrophies. Given the importance of 
ciliary transport in photoreceptor function and structural maintenance, we 
sought to investigate the impact of IFT (intraflagellar transport) mutations in 
nonsyndromic retinopathies.
METHODS: Whole exome sequencing was performed on 50 cone-rod dystrophy (CRD) 
patients that were previously screened for mutations in known retinal disease 
genes. The impact of candidate mutation was studied using in vitro cell system 
and in vivo zebrafish assay to determine the pathogenicity of the variant.
RESULTS: Compound heterozygous mutations in IFT81, including one nonsense 
(c.1213C>T, p.R405*) and one missense variant (c.1841T>C, p.L614P), were 
identified in a nonsyndromic CRD proband. Extensive functional analyses of the 
missense variant in cell culture and zebrafish strongly suggests its pathogenic 
nature. Loss of IFT81 impairs ciliogenesis and, interestingly, the missense 
variant displayed significantly reduced rescue of ciliogenesis in the IFT81 
knockdown in vitro system. Consistently, dramatic reduction of rescue efficiency 
of the ift81 mutant zebrafish embryo by mRNA with the missense variant was 
observed, further supporting its pathogenicity.
CONCLUSIONS: Consistent with the function of the IFT-B complex in the 
maintenance of photoreceptor cilium, we report a case of mutations in a core 
IFT-B protein, IFT81. This represents the first report of mutations in IFT81 as 
a candidate gene for nonsyndromic retinal dystrophy, hence expanding the 
phenotype spectrum of IFT-B components.