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

Hum Genet. 2013 Aug;132(8):865-84. doi: 10.1007/s00439-013-1297-0. Epub 2013 Apr 5.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Caroli Disease / genetics*
  • Caroli Disease / pathology
  • Cilia / genetics*
  • Cilia / pathology*
  • Cohort Studies
  • DNA Mutational Analysis
  • Female
  • Genes, Recessive / genetics*
  • Global Health
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Kidney Diseases, Cystic / genetics*
  • Kidney Diseases, Cystic / pathology
  • Male
  • Membrane Proteins / genetics*
  • Multiplex Polymerase Chain Reaction
  • Mutation / genetics*
  • Pedigree
  • Pilot Projects

Substances

  • Adaptor Proteins, Signal Transducing
  • Membrane Proteins
  • NPHP1 protein, human