title: Rare renal ciliopathies in non-consanguineous families that were identified by targeted resequencing.
abstract: BACKGROUND
  Nephronophthisis-related ciliopathies (NPHP-RC) are a frequent cause of renal failure for children and adolescents. Although diagnosing these diseases clinically is difficult, a comprehensive genetic screening approach of targeted resequencing can uncover the genetic background in this complicated family of diseases.
  
  
  METHODS
  We studied three Japanese female patients with renal insufficiency from non-consanguineous parents. A renal biopsy for clinical reasons was not performed. Therefore, we did not know the diagnosis of these patients from a clinical aspect. We performed comprehensive genetic analysis using the TruSight One Sequencing Panel next generation sequencing technique.
  
  
  RESULTS
  We identified three different rare NPHP-RC variants in the following genes: SDCCAG8, MKKS, and WDR35. Patient 1 with SDCCAG8 homozygous deletions showed no ciliopathy-specific extrarenal manifestations, such as retinitis pigmentosa or polydactyly prior to genetic analysis. Patient 2 with a MKKS splice site homozygous mutation and a subsequent 39-amino acid deletion in the substrate-binding apical domain, had clinical symptoms of Bardet-Biedl syndrome. She and her deceased elder brother had severe renal insufficiency soon after birth. Patient 3 with a compound heterozygous WDR35 mutation had ocular coloboma and intellectual disability.
  
  
  CONCLUSIONS
  Our results suggest that a comprehensive genetic screening system using target resequencing is useful and non-invasive for the diagnosis of patients with an unknown cause of pediatric end-stage renal disease.
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Yamamura
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. morisada@med.kobe-u.ac.jp.|Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. morisada@med.kobe-u.ac.jp.
authors.forename: Naoya
authors.identifier: http://orcid.org/0000-0002-9676-865X
authors.initials: N
authors.lastname: Morisada
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Kandai
authors.initials: K
authors.lastname: Nozu
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Minamikawa
authors.affiliation: Department of Pediatrics, Kakogawa West City Hospital, 384-1, Hiratsu, Yoneda-cho, Kakogawa, 675-8611, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Ishimori
authors.affiliation: Department of Child Neurology, Hyogo Prefectural Kobe Children's Hospital, 1-1-1, Takakuradai, Suma-ku, Kobe, 654-0081, Japan.
authors.forename: Daisaku
authors.initials: D
authors.lastname: Toyoshima
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ninchoji
authors.affiliation: Department of Pediatrics, Fukuyama Capital Hospital, 5-23-1, Zao-cho, Fukuyama, 721-0971, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Yasui
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Taniguchi-Ikeda
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Morioka
authors.affiliation: Department of Pediatrics, Wakayama Medical College, 811-1, Kimiidera, Wakayama, 641-8509, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Nakanishi
authors.affiliation: Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Hisahide
authors.initials: H
authors.lastname: Nishio
authors.affiliation: Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors.forename: Kazumoto
authors.initials: K
authors.lastname: Iijima
mesh_terms: D000293:Adolescent; D000328:Adult; D001324:Autoantigens / Q000235:genetics*; D002675:Child, Preschool; D000072661:Ciliopathies / Q000175:diagnosis / Q000235:genetics*; D003241:Consanguinity; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D056385:Group II Chaperonins / Q000235:genetics*; D053823:Hedgehog Proteins; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007674:Kidney Diseases / Q000175:diagnosis / Q000235:genetics*; D007676:Kidney Failure, Chronic / Q000175:diagnosis / Q000235:genetics; D008279:Magnetic Resonance Imaging; D009363:Neoplasm Proteins / Q000235:genetics*; D010641:Phenotype; D011237:Predictive Value of Tests; D011506:Proteins / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D001324:Autoantigens; D003598:Cytoskeletal Proteins; D005819:Genetic Markers; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; C414726:MKKS protein, human; D009363:Neoplasm Proteins; D011506:Proteins; C472380:SDCCAG8 protein, human; C558596:WDR35 protein, human; D056385:Group II Chaperonins
keywords: MKKS; Nephronophthisis-related ciliopathy; Next generation sequencing; SDCCAG8; Targeted resequencing; WDR35