• Open Access

Combined NGS Approaches Identify Mutations in the Intraflagellar Transport Gene IFT140 in Skeletal Ciliopathies with Early Progressive Kidney Disease


  • Additional Supporting Information may be found in the online version of this article.

  • Communicated by Arnold Munnich

  • Contract grant sponsors: Wellcome Trust (WT091310) (UK10K); National Institutes of Health (GM060992) (GJP); Wellcome Trust Senior Research Fellow (PLB); Wellcome Trust and British Heart Foundation (PJS); Agence Nationale de la Recherchet (R09087KS and RPV11012KK) (SS); Deutsche Forschungsgemeinschaft (DFG BE 3910/4–1, DFG ZE 205/14–1, and SFB/TRR57) and Deutsche Nierenstiftung and PKD Foundation (CB); Action Medical Research UK and Henry Smith Charity SP4534, and Newlife Foundation for Disabled Children UK 10-11/15 (HMM); Action Medical Research UK Clinical Training Fellowship RTF-1411 (MS).

Correspondence to: Hannah M. Mitchison, Molecular Medicine Unit, University College London (UCL) Institute of Child Health, London, UK. E-mail: h.mitchison@ucl.ac.uk


Ciliopathies are genetically heterogeneous disorders characterized by variable expressivity and overlaps between different disease entities. This is exemplified by the short rib-polydactyly syndromes, Jeune, Sensenbrenner, and Mainzer-Saldino chondrodysplasia syndromes. These three syndromes are frequently caused by mutations in intraflagellar transport (IFT) genes affecting the primary cilia, which play a crucial role in skeletal and chondral development. Here, we identified mutations in IFT140, an IFT complex A gene, in five Jeune asphyxiating thoracic dystrophy (JATD) and two Mainzer-Saldino syndrome (MSS) families, by screening a cohort of 66 JATD/MSS patients using whole exome sequencing and targeted resequencing of a customized ciliopathy gene panel. We also found an enrichment of rare IFT140 alleles in JATD compared with nonciliopathy diseases, implying putative modifier effects for certain alleles. IFT140 patients presented with mild chest narrowing, but all had end-stage renal failure under 13 years of age and retinal dystrophy when examined for ocular dysfunction. This is consistent with the severe cystic phenotype of Ift140 conditional knockout mice, and the higher level of Ift140 expression in kidney and retina compared with the skeleton at E15.5 in the mouse. IFT140 is therefore a major cause of cono-renal syndromes (JATD and MSS). The present study strengthens the rationale for IFT140 screening in skeletal ciliopathy spectrum patients that have kidney disease and/or retinal dystrophy.