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Increased frequency of double and triple heterozygous gene variants in children with intrahepatic cholestasis.
Goldschmidt, Monique L; Mourya, Reena; Connor, Jessica; Dexheimer, Phillip; Karns, Rebekah; Miethke, Alexander; Sheridan, Rachel; Zhang, Kejian; Bezerra, Jorge A.
Afiliación
  • Goldschmidt ML; Divisions of Pediatric Gastroenterology, Hepatology and Nutrition, Pediatric Liver Care Center of Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
  • Mourya R; Pediatric Liver Care Center of Cincinnati Children's Hospital Medical Center, Department of Pediatrics of the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
  • Connor J; Divisions of Pediatric Gastroenterology, Hepatology and Nutrition, Pediatric Liver Care Center of Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
  • Dexheimer P; Pediatric Liver Care Center of Cincinnati Children's Hospital Medical Center, Department of Pediatrics of the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
  • Karns R; Human Genetics, Pediatric Liver Care Center of Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
  • Miethke A; Pediatric Liver Care Center of Cincinnati Children's Hospital Medical Center, Department of Pediatrics of the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
  • Sheridan R; Bioinformatics, Pediatric Liver Care Center of Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
  • Zhang K; Pediatric Liver Care Center of Cincinnati Children's Hospital Medical Center, Department of Pediatrics of the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
  • Bezerra JA; Bioinformatics, Pediatric Liver Care Center of Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Hepatol Res ; 46(4): 306-11, 2016 Apr.
Article en En | MEDLINE | ID: mdl-26126923
AIM: Single gene mutations cause syndromes of intrahepatic cholestasis, but previous multi-gene mutation screening in children with idiopathic cholestasis failed to fulfill diagnostic criteria in approximately two-thirds of children. In adults with fibrosing cholestatic disease, heterozygous ABCB4 mutations were present in 34% of patients. Here, we hypothesized that children with idiopathic cholestasis have a higher frequency of heterozygous non-synonymous gene sequence variants. METHODS: We analyzed the frequency and types of variants in 717 children in whom high-throughput sequencing of the genes SERPINA1, JAG1, ATP8B1, ABCB11 and ABCB4 was performed as part of an evaluation for idiopathic intrahepatic cholestasis cholestasis. The frequency of non-synonymous variants (NSV) was compared with those of 1092 control subjects enrolled in the 1000 Genome Project. RESULTS: The frequency of NSV in single genes was similar between disease (25%) and controls (26%, P = 0.518). In contrast, double or triple NSV in two or more genes were more frequent in disease (n = 7%) than controls (n = 4.7%, P = 0.028). Detailed review of clinical and laboratory information in a subgroup of double or triple heterozygous patients revealed variable γ-glutamyltransferase levels and severity of pruritus, with liver biopsies showing stage 2-3 fibrosis. CONCLUSION: Children with idiopathic intrahepatic cholestasis have a higher frequency of double or triple NSV in SERPINA1, JAG1, ATPB1, ABCB11 or ABCB4. These findings raise the potential role for gene-gene relationships in determining the phenotype of cholestatic liver disease in children.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Hepatol Res Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Hepatol Res Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Países Bajos