Combined NGS Approaches Identify Mutations in the Intraflagellar Transport GeneIFT140in Skeletal Ciliopathies with Early Progressive Kidney Disease

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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 inIFT140,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 rareIFT140alleles in JATD compared with nonciliopathy diseases, implying putative modifier effects for certain alleles.IFT140patients 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 ofIft140conditional knockout mice, and the higher level ofIft140expression in kidney and retina compared with the skeleton at E15.5 in the mouse.IFT140is therefore a major cause of cono-renal syndromes (JATD and MSS). The present study strengthens the rationale forIFT140screening in skeletal ciliopathy spectrum patients that have kidney disease and/or retinal dystrophy.

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