Herbst, S. M. and Schirmer, S. and Posovszky, C. and Jochum, F. and Roedl, T. and Schroeder, J. A. and Barth, T. F. and Hehr, U. and Melter, M. and Vermehren, J. (2015) Taking the next step forward - Diagnosing inherited infantile cholestatic disorders with next generation sequencing. MOLECULAR AND CELLULAR PROBES, 29 (5). pp. 291-298. ISSN 0890-8508,
Full text not available from this repository. (Request a copy)Abstract
Identifying rare genetic forms of infantile cholestasis is challenging due to their similar clinical presentation and their diverse etiology. After exclusion of common non-genetic causes a huge list of rare differential diagnosis remains to be solved. More than 90 genes are associated with monogenic forms of infantile cholestasis, thus preventing routine genetic workup by Sanger sequencing. Here we demonstrate a next generation sequencing approach to discover the underlying cause in clinically well characterized patients in whom common causes of infantile cholestasis have been excluded. After validation of the analytical sensitivity massive parallel sequencing was performed for 93 genes in six prospectively studied patients. Six novel mutations (PKHD1: p.Thr777Met, p.Tyr2260Cys; ABCB11: p.Val1112Phe, c.611+1G > A, p.Gly628Trpfs*3 and NPC1: p.Glu391Lys) and two known pathogenic mutations were detected proving our multi gene panel for infantile cholestasis to be a sensitive and specific method overcoming the complexity of the phenotype-based, candidate gene approach. Three exemplary clinical cases of infants with cholestasis are presented and discussed in the context of their genetic and histopathological findings (autosomal recessive polycystic kidney disease, atypical PFIC and Niemann Pick syndrome type Cl). These case reports highlight the critical impact of integrating clinical, histopathological and genetic data during the process of multi gene panel testing to ultimately pinpoint rare genetic diagnoses. (C) 2015 Elsevier Ltd. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | KIDNEY-DISEASE ARPKD; FAMILIAL INTRAHEPATIC CHOLESTASIS; PICK-C-DISEASE; LIVER-TRANSPLANTATION; BILIARY DIVERSION; PKHD1 MUTATIONS; GENE-MUTATIONS; NPC1; PATHOPHYSIOLOGY; IDENTIFICATION; Next generation sequencing; Infantile cholestasis; PFIC; Niemann-Pick-syndrome; PKHD1; Hepatic fibrosis; Massive parallel sequencing |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Humangenetik Medicine > Lehrstuhl für Kinder- und Jugendmedizin Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 Jun 2019 07:53 |
| Last Modified: | 06 Jun 2019 07:53 |
| URI: | https://pred.uni-regensburg.de/id/eprint/4663 |
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