Exp Mol Med.
2016 Aug;48(8):e251. 10.1038/emm.2016.63.
Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy
- Affiliations
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- 1Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea. cheonghi@snu.ac.kr
- 2Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea. woongyang@skku.edu
- 3Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
- 4Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea.
- 5Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
- 6Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
- 7Department of Pediatrics, Asian Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
- 8Department of Pediatrics, College of Medicine, Inje University, Busan Paik Hospital, Busan, Republic of Korea.
- 9Department of Pediatrics, College of Medicine, Chonbuk National University, Jeonju, Republic of Korea.
- 10Department of Pediatrics, Pusan National University Children's Hospital, Pusan, Republic of Korea.
- 11Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
- KMID: 2361538
- DOI: http://doi.org/10.1038/emm.2016.63
Abstract
- Nephronophthisis-related ciliopathy (NPHP-RC) is a common genetic cause of end-stage renal failure during childhood and adolescence and exhibits an autosomal recessive pattern of inheritance. Genetic diagnosis is quite limited owing to genetic heterogeneity in NPHP-RC. We designed a novel approach involving the step-wise screening of Sanger sequencing and targeted exome sequencing for the genetic diagnosis of 55 patients with NPHP-RC. First, five NPHP-RC genes were analyzed by Sanger sequencing in phenotypically classified patients. Known pathogenic mutations were identified in 12 patients (21.8%); homozygous deletions of NPHP1 in 4 juvenile nephronophthisis patients, IQCB1/NPHP5 mutations in 3 Senior-Løken syndrome patients, a CEP290/NPHP6 mutation in 1 Joubert syndrome patient, and TMEM67/MKS3 mutations in 4 Joubert syndrome patients with liver involvement. In the remaining undiagnosed patients, we applied targeted exome sequencing of 34 ciliopathy-related genes to detect known pathogenic mutations in 7 (16.3%) of 43 patients. Another 18 likely damaging heterozygous variants were identified in 13 NPHP-RC genes in 18 patients. In this study, we report a variety of pathogenic and candidate mutations identified in 55 patients with NPHP-RC in Korea using a step-wise application of two genetic tests. These results support the clinical utility of targeted exome sequencing to resolve the issue of allelic and genetic heterogeneity in NPHP-RC.
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