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Combined NGS Approaches Identify Mutations in the Intraflagellar Transport Gene IFT140 in Skeletal Ciliopathies with Early Progressive Kidney Disease
Author(s) -
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,
PecoAntić Amira,
Mache Christoph,
Hurles Matthew E.,
Joksić Ivana,
GućŠćekić Marija,
Dobricic Jelena,
BrankovicMagic Mirjana,
Bolz Hanno J.,
Pazour Gregory J.,
Beales Philip L.,
Scambler Peter J.,
Saunier Sophie,
Mitchison Hannah M.,
Bergmann Carsten
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22294
Subject(s) - ciliopathy , ciliopathies , intraflagellar transport , cilium , biology , nephronophthisis , polydactyly , joubert syndrome , genetics , bardet–biedl syndrome , penetrance , ciliogenesis , pathology , bioinformatics , phenotype , gene , medicine , mutant
Ciliopathies are genetically heterogeneous disorders characterized by variable expressivity and overlaps between different disease entities. This is exemplified by the short rib‐polydactyly syndromes, J eune, S ensenbrenner, and M ainzer‐ S aldino 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 M ainzer‐ S aldino 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.