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 syndrome...

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Published in:	Human mutation Vol. 34; no. 5; pp. 714 - 724
Main Authors:	Schmidts, Miriam, Frank, Valeska, Eisenberger, Tobias, al Turki, Saeed, Bizet, Albane A., Antony, Dinu, Rix, Suzanne, Decker, Christian, Bachmann, Nadine, Bald, Martin, Vinke, Tobias, Toenshoff, Burkhard, Di Donato, Natalia, Neuhann, Theresa, Hartley, Jane L., Maher, Eamonn R., Bogdanović, Radovan, Peco-Antić, Amira, Mache, Christoph, Hurles, Matthew E., Joksić, Ivana, Guć-Šćekić, Marija, Dobricic, Jelena, Brankovic-Magic, Mirjana, Bolz, Hanno J., Pazour, Gregory J., Beales, Philip L., Scambler, Peter J., Saunier, Sophie, Mitchison, Hannah M., Bergmann, Carsten
Format:	Journal Article
Language:	English
Published:	United States Blackwell Publishing Ltd 01-05-2013 Hindawi Limited
Subjects:	Animals Biological Transport - genetics Cerebellar Ataxia - genetics Child cilia Cilia - metabolism Cohort Studies Disease Progression Exome Genes Humans IFT140 Jeune asphyxiating thoracic dystrophy Kidney diseases Kidney Diseases - genetics Kidney Diseases - pathology Mainzer-Saldino syndrome Male Mice Mutation NGS Retinitis Pigmentosa - genetics
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Summary:	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. Jeune Asphyxiating Thoracic Dysplasia (JATD) is a rare recessive ciliary chondrodysplasia associated with death in infancy due to respiratory failure, and extraskeletal symptoms also occur in some patients. This large next generation sequencing study in 66 JATD and Mainzer‐Saldino syndrome (MSS) families reveals that mutations in the intraflagellar transport protein IFT140 cause MSS and are a frequent cause of JATD with retinal and kidney symptoms but mild thorax phenotype, providing for the first time a clinically significant genotype‐phenotype association in JATD.
Bibliography:	Action Medical Research UK and Henry Smith Charity SP4534, and Newlife Foundation for Disabled Children UK 10-11/15 (HMM) Wellcome Trust Senior Research Fellow (PLB) Wellcome Trust (WT091310) (UK10K) National Institutes of Health (GM060992) (GJP) Deutsche Forschungsgemeinschaft (DFG BE 3910/4-1, DFG ZE 205/14-1, and SFB/TRR57) and Deutsche Nierenstiftung and PKD Foundation (CB) ArticleID:HUMU22294 ark:/67375/WNG-31G9NLZ6-8 Action Medical Research UK Clinical Training Fellowship RTF-1411 (MS) Wellcome Trust and British Heart Foundation (PJS) Agence Nationale de la Recherchet (R09087KS and RPV11012KK) (SS) istex:43163C0E2649EBD4E1C95C381D943285403F854A 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). Additional Supporting Information may be found in the online version of this article. Communicated by Arnold Munnich ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1059-7794 1098-1004
DOI:	10.1002/humu.22294