title: Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy.
abstract: Nephronophthisis-related ciliopathies (NPHP-RC) are autosomal-recessive cystic kidney diseases. More than 13 genes are implicated in its pathogenesis to date, accounting for only 40 % of all cases. High-throughput mutation screenings of large patient cohorts represent a powerful tool for diagnostics and identification of novel NPHP genes. We here performed a new high-throughput mutation analysis method to study 13 established NPHP genes (NPHP1-NPHP13) in a worldwide cohort of 1,056 patients diagnosed with NPHP-RC. We first applied multiplexed PCR-based amplification using Fluidigm Access-Array™ technology followed by barcoding and next-generation resequencing on an Illumina platform. As a result, we established the molecular diagnosis in 127/1,056 independent individuals (12.0 %) and identified a single heterozygous truncating mutation in an additional 31 individuals (2.9 %). Altogether, we detected 159 different mutations in 11 out of 13 different NPHP genes, 99 of which were novel. Phenotypically most remarkable were two patients with truncating mutations in INVS/NPHP2 who did not present as infants and did not exhibit extrarenal manifestations. In addition, we present the first case of Caroli disease due to mutations in WDR19/NPHP13 and the second case ever with a recessive mutation in GLIS2/NPHP7. This study represents the most comprehensive mutation analysis in NPHP-RC patients, identifying the largest number of novel mutations in a single study worldwide.
authors.affiliation: Department of Pediatrics, University of Michigan Health System, 8220A MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5646, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Halbritter
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Porath
authors.forename: Katrina A
authors.initials: KA
authors.lastname: Diaz
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Braun
authors.forename: Stefan
authors.initials: S
authors.lastname: Kohl
authors.forename: Moumita
authors.initials: M
authors.lastname: Chaki
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Allen
authors.forename: Neveen A
authors.initials: NA
authors.lastname: Soliman
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D016767:Caroli Disease / Q000235:genetics* / Q000473:pathology; D002923:Cilia / Q000235:genetics* / Q000473:pathology*; D015331:Cohort Studies; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D014943:Global Health; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010865:Pilot Projects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; C108725:NPHP1 protein, human
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