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A combination of mutations in AKR1D1 and SKIV2L in a family with severe infantile liver disease

Neil V Morgan19*, Jane L Hartley12, Kenneth DR Setchell3, Michael A Simpson4, Rachel Brown5, Louise Tee1, Sian Kirkham6, Shanaz Pasha1, Richard C Trembath4, Eamonn R Maher17, Paul Gissen8 and Deirdre A Kelly2

Author Affiliations

1 Department of Medical and Molecular Genetics and Centre for Rare Diseases and Personalised Medicine, University of Birmingham School of Medicine, Birmingham, UK

2 Liver Unit, Birmingham Children’s Hospital, Steelhouse Lane, Birmingham, UK

3 Department of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA

4 Medical and Molecular Genetics, King’s College London, 8th Floor Tower Wing, Guy’s Hospital, Great Maze Pond, London, UK

5 Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham, UK

6 Department of Paediatric Gastroenterology, Queens Medical Centre, Nottingham, UK

7 West Midlands Regional Genetics Service, Birmingham Women’s Hospital, Birmingham, UK

8 UCL Institute of Child Health and Laboratory for Molecular Cell Biology, London, UK

9 Present address: Centre for Cardiovascular Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK

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Orphanet Journal of Rare Diseases 2013, 8:74  doi:10.1186/1750-1172-8-74

Published: 16 May 2013


Infantile cholestatic diseases can be caused by mutations in a number of genes involved in different hepatocyte molecular pathways. Whilst some of the essential pathways have a well understood function, such as bile biosynthesis and transport, the role of the others is not known. Here we report the findings of a clinical, biochemical and molecular study of a family with three patients affected with a severe infantile cholestatic disease. A novel homozygous frameshift germline mutation (c.587delG) in the AKR1D1 gene; which encodes the enzyme Δ 4-3-oxosteroid 5β–reductase that is required for synthesis of primary bile acids and is crucial for establishment of normal bile flow, was found in all 3 patients. Although the initial bile acid analysis was inconclusive, subsequent testing confirmed the diagnosis of a bile acid biogenesis disorder. An additional novel homozygous frameshift mutation (c.3391delC) was detected in SKIV2L in one of the patients. SKIV2L encodes a homologue of a yeast ski2 protein proposed to be involved in RNA processing and mutations in SKIV2L were recently described in patients with Tricohepatoenteric syndrome (THES). A combination of autozygosity mapping and whole-exome-sequencing allowed the identification of causal mutations in this family with a complex liver phenotype. Although the initial 2 affected cousins died in the first year of life, accurate diagnosis and management of the youngest patient led to successful treatment of the liver disease and disease-free survival.

Bile acid metabolism; Diarrhoea; Gene mutation; Whole exome sequencing; Paediatric liver disease