Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy

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...

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Bibliographic Details
Published in:	Human genetics 2013-08, Vol.132 (8), p.865-884
Main Authors:	Halbritter, Jan, Porath, Jonathan D., Diaz, Katrina A., Braun, Daniela A., Kohl, Stefan, Chaki, Moumita, Allen, Susan J., Soliman, Neveen A., Hildebrandt, Friedhelm, Otto, Edgar A.
Format:	Article
Language:	eng
Subjects:	Adaptor Proteins, Signal Transducing - genetics Bar codes Biomedical and Life Sciences Biomedicine Caroli Disease - genetics Caroli Disease - pathology Cilia - genetics Cilia - pathology Cohort Studies DNA Mutational Analysis Female Gene Function Genes Genes, Recessive - genetics Genetic aspects Global Health High-Throughput Nucleotide Sequencing Human Genetics Humans Kidney diseases Kidney Diseases, Cystic - genetics Kidney Diseases, Cystic - pathology Kinases Male Membrane Proteins - genetics Metabolic Diseases Molecular Medicine Multiplex Polymerase Chain Reaction Mutation Mutation - genetics Original Investigation Pedigree Pilot Projects
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Summary:	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.
ISSN:	0340-6717 1432-1203