Waters, Aoife MAsfahani, RowanCarroll, PaulaBicknell, LouiseLescai, FrancescoBright, AlisonChanudet, EstelleBrooks, AnthonyChristou-Savina, SonjaOsman, GuledWalsh, PatrickBacchelli, ChiaraChapgier, ArianeVernay, BertrandBader, David MDeshpande, CharuO’ Sullivan, MaryOcaka, LouiseStanescu, HoriaStewart, Helen SHildebrandt, FriedhelmOtto, EdgarJohnson, Colin ASzymanska, KatarzynaKatsanis, NicholasDavis, EricaKleta, RobertHubank, MikeDoxsey, StephenJackson, AndrewStupka, EliaWiney, MarkBeales, Philip L2015-04-012015Waters, A. M., R. Asfahani, P. Carroll, L. Bicknell, F. Lescai, A. Bright, E. Chanudet, et al. 2015. “The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes.” Journal of Medical Genetics 52 (3): 147-156. doi:10.1136/jmedgenet-2014-102691. http://dx.doi.org/10.1136/jmedgenet-2014-102691.0022-2593http://nrs.harvard.edu/urn-3:HUL.InstRepos:14351314Background: Mutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly. Regulation of centriole length has been shown to underlie the pathogenesis of certain ciliopathy phenotypes. Using a next-generation sequencing approach, we identified mutations in a novel centriolar disease gene in a kindred with an embryonic lethal ciliopathy phenotype and in a patient with primary microcephaly. Methods and results Whole exome sequencing data from a non-consanguineous Caucasian kindred exhibiting mid-gestation lethality and ciliopathic malformations revealed two novel non-synonymous variants in CENPF, a microtubule-regulating gene. All four affected fetuses showed segregation for two mutated alleles [IVS5-2A>C, predicted to abolish the consensus splice-acceptor site from exon 6; c.1744G>T, p.E582X]. In a second unrelated patient exhibiting microcephaly, we identified two CENPF mutations [c.1744G>T, p.E582X; c.8692 C>T, p.R2898X] by whole exome sequencing. We found that CENP-F colocalised with Ninein at the subdistal appendages of the mother centriole in mouse inner medullary collecting duct cells. Intraflagellar transport protein-88 (IFT-88) colocalised with CENP-F along the ciliary axonemes of renal epithelial cells in age-matched control human fetuses but did not in truncated cilia of mutant CENPF kidneys. Pairwise co-immunoprecipitation assays of mitotic and serum-starved HEKT293 cells confirmed that IFT88 precipitates with endogenous CENP-F. Conclusions: Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes. CENP-F has a novel putative function in ciliogenesis and cortical neurogenesis.en-USClinical geneticsMolecular geneticsCENPFCiliopathyMicrocephalyJournal Article2015-04-0110.1136/jmedgenet-2014-102691