title: Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney Disease.
abstract: 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.
authors: Molecular Medicine Unit, University College London Institute of Child Health, London, UK.
authors: Miriam
authors: M
authors: Schmidts
authors: Valeska
authors: V
authors: Frank
authors: Tobias
authors: T
authors: Eisenberger
authors: Saeed
authors: S
authors: Al Turki
authors: Albane A
authors: AA
authors: Bizet
authors: Dinu
authors: D
authors: Antony
authors: Suzanne
authors: S
authors: Rix
authors: Christian
authors: C
authors: Decker
authors: Nadine
authors: N
authors: Bachmann
authors: Martin
authors: M
authors: Bald
authors: Tobias
authors: T
authors: Vinke
authors: Burkhard
authors: B
authors: Toenshoff
authors: Natalia
authors: N
authors: Di Donato
authors: Theresa
authors: T
authors: Neuhann
authors: Jane L
authors: JL
authors: Hartley
authors: Eamonn R
authors: ER
authors: Maher
authors: Radovan
authors: R
authors: Bogdanović
authors: Amira
authors: A
authors: Peco-Antić
authors: Christoph
authors: C
authors: Mache
authors: Matthew E
authors: ME
authors: Hurles
authors: Ivana
authors: I
authors: Joksić
authors: Marija
authors: M
authors: Guć-Šćekić
authors: Jelena
authors: J
authors: Dobricic
authors: Mirjana
authors: M
authors: Brankovic-Magic
authors: Hanno J
authors: HJ
authors: Bolz
authors: Gregory J
authors: GJ
authors: Pazour
authors: Philip L
authors: PL
authors: Beales
authors: Peter J
authors: PJ
authors: Scambler
authors: Sophie
authors: S
authors: Saunier
authors: Hannah M
authors: HM
authors: Mitchison
authors: Carsten
authors: C
authors: Bergmann
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000235:genetics*; D002524:Cerebellar Ataxia / Q000235:genetics; D002648:Child; D002923:Cilia / Q000378:metabolism*; D015331:Cohort Studies; D018450:Disease Progression; D059472:Exome; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D009154:Mutation; D012174:Retinitis Pigmentosa / Q000235:genetics