title: Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy.
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.
authors.affiliation: Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea.
authors.forename: Hee Gyung
authors.initials: HG
authors.lastname: Kang
authors.affiliation: Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea.
authors.forename: Hyun Kyung
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea.
authors.forename: Yo Han
authors.initials: YH
authors.lastname: Ahn
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: Je-Gun
authors.initials: JG
authors.lastname: Joung
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: Jaeyong
authors.initials: J
authors.lastname: Nam
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: Nayoung K D
authors.initials: NK
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Ko
authors.affiliation: Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Republic of Korea.
authors.forename: Min Hyun
authors.initials: MH
authors.lastname: Cho
authors.affiliation: Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jae Il
authors.initials: JI
authors.lastname: Shin
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Joon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors.forename: Hye Won
authors.initials: HW
authors.lastname: Park
authors.affiliation: Department of Pediatrics, Asian Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Young Seo
authors.initials: YS
authors.lastname: Park
authors.affiliation: Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea.
authors.forename: Il-Soo
authors.initials: IS
authors.lastname: Ha
authors.affiliation: Department of Pediatrics, College of Medicine, Inje University, Busan Paik Hospital, Busan, Republic of Korea.
authors.forename: Woo Yeong
authors.initials: WY
authors.lastname: Chung
authors.affiliation: Department of Pediatrics, College of Medicine, Chonbuk National University, Jeonju, Republic of Korea.
authors.forename: Dae-Yeol
authors.initials: DY
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Pusan National University Children's Hospital, Pusan, Republic of Korea.
authors.forename: Su Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea.|Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea.
authors.forename: Woong Yang
authors.initials: WY
authors.lastname: Park
authors.affiliation: Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea.
authors.forename: Hae Il
authors.initials: HI
authors.lastname: Cheong
mesh_terms: D000293:Adolescent; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D000072661:Ciliopathies / Q000175:diagnosis / Q000235:genetics*; D059472:Exome; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D007223:Infant; D052177:Kidney Diseases, Cystic / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D009154:Mutation; D017422:Sequence Analysis, DNA / Q000379:methods