title: Molecular Genetic Dissection and Neonatal/Infantile Intrahepatic Cholestasis Using Targeted Next-Generation Sequencing.
abstract: OBJECTIVE
  To ascertain a molecular genetic diagnosis for subjects with neonatal/infantile intrahepatic cholestasis (NIIC) by the use of next-generation sequencing (NGS) and to perform a genotype-phenotype correlation.
  
  
  METHODS
  We recruited Japanese subjects with NIIC who had no definitive molecular genetic diagnosis. We developed a diagnostic custom panel of 18 genes, and the amplicon library was sequenced via NGS. We then compared clinical data between the molecular genetically confirmed subjects with NIIC.
  
  
  RESULTS
  We analyzed 109 patients with NIIC ("genetic cholestasis," 31 subjects; "unknown with complications" such as prematurity, 46 subjects; "unknown without complications," 32 subjects), and a molecular genetic diagnosis was made for 28 subjects (26%). The rate of positive molecular genetic diagnosis in each category was 22 of 31 (71%) for the "genetic cholestasis" group, 2 of 46 (4.3%) for the "unknown with complications" group, and 4 of 32 (12.5%) for the "unknown without complications" group. The grouping of the molecular diagnoses in the group with genetic cholestasis was as follows: 12 with Alagille syndrome, 5 with neonatal Dubin-Johnson syndrome, 5 with neonatal intrahepatic cholestasis caused by citrin deficiency, and 6 with progressive familial intrahepatic cholestasis or benign recurrent intrahepatic cholestasis with low gamma-glutamyl transpeptidase levels. Several clinical datasets, including age of onset, direct bilirubin, and aminotransferases, were significantly different between the disorders confirmed using molecular genetic diagnosis.
  
  
  CONCLUSIONS
  Targeted NGS can be used for molecular genetic diagnosis in subjects with NIIC. Clinical diagnosis should be accordingly redefined in the view of molecular genetic findings.
authors: Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors: Takao
authors: T
authors: Togawa
authors: Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. Electronic address: tokio@med.nagoya-cu.ac.jp.
authors: Tokio
authors: T
authors: Sugiura
authors: Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors: Koichi
authors: K
authors: Ito
authors: Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors: Takeshi
authors: T
authors: Endo
authors: Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors: Kohei
authors: K
authors: Aoyama
authors: Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors: Kei
authors: K
authors: Ohashi
authors: Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors: Yutaka
authors: Y
authors: Negishi
authors: Department of Hepatology, National Medical Center for Children and Mothers, National Center for Child Health and Development, Tokyo, Japan.
authors: Toyoichiro
authors: T
authors: Kudo
authors: Department of Hepatology, National Medical Center for Children and Mothers, National Center for Child Health and Development, Tokyo, Japan.
authors: Reiko
authors: R
authors: Ito
authors: Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.
authors: Atsuo
authors: A
authors: Kikuchi
authors: Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.
authors: Natsuko
authors: N
authors: Arai-Ichinoi
authors: Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.
authors: Shigeo
authors: S
authors: Kure
authors: Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors: Shinji
authors: S
authors: Saitoh
mesh_terms: D016738:Alagille Syndrome / Q000175:diagnosis / Q000235:genetics; D001663:Bilirubin / Q000097:blood; D002135:Calcium-Binding Proteins / Q000172:deficiency; D002780:Cholestasis, Intrahepatic / Q000175:diagnosis* / Q000235:genetics*; D002869:Chromosome Aberrations; D005091:Exons; D005260:Female; D017353:Gene Deletion; D056726:Genetic Association Studies; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007564:Japan; D007566:Jaundice, Chronic Idiopathic / Q000175:diagnosis / Q000235:genetics; D008297:Male; D008967:Molecular Biology; D027361:Organic Anion Transporters / Q000172:deficiency; D005723:gamma-Glutamyltransferase / Q000235:genetics
chemical_list: D002135:Calcium-Binding Proteins; D027361:Organic Anion Transporters; C008822:citrin; D005723:gamma-Glutamyltransferase; D001663:Bilirubin