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J Hepatol. 2014 Nov;61(5):1056-63. doi: 10.1016/j.jhep.2014.06.038. Epub 2014 Jul 10.

Individual exome analysis in diagnosis and management of paediatric liver failure of indeterminate aetiology.

Author information

1
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States; Digestive Diseases Section, Yale University School of Medicine, New Haven, CT, United States; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, United States; Department of Genetics, Yale University School of Medicine, New Haven, CT, United States.
2
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, United States; Department of Genetics, Yale University School of Medicine, New Haven, CT, United States; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
3
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States; Digestive Diseases Section, Yale University School of Medicine, New Haven, CT, United States; Department of Pathology, Yale University School of Medicine, New Haven, CT, United States.
4
Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, United States.
5
Department of Surgery, Section of Transplantation and Immunology, Yale University School of Medicine, New Haven, CT, United States.
6
Department of Pediatrics, Gastroenterology-Hepatology Section, Yale University School of Medicine, New Haven, CT, United States.
7
Department of Genetics, Yale University School of Medicine, New Haven, CT, United States.
8
Department of Genetics, Yale University School of Medicine, New Haven, CT, United States; Yale Center for Mendelian Genomics, Yale University School of Medicine, New Haven, CT, United States.
9
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, United States; Department of Genetics, Yale University School of Medicine, New Haven, CT, United States; Yale Center for Mendelian Genomics, Yale University School of Medicine, New Haven, CT, United States.
10
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States; Digestive Diseases Section, Yale University School of Medicine, New Haven, CT, United States; Department of Pediatrics, Gastroenterology-Hepatology Section, Yale University School of Medicine, New Haven, CT, United States. Electronic address: pramod.mistry@yale.edu.

Abstract

BACKGROUND & AIMS:

In children with liver failure, as many as half remain of indeterminate aetiology. This hinders timely consideration of optimal treatment options. We posit that a significant subset of these children harbour known inherited metabolic liver diseases with atypical presentation or novel inborn errors of metabolism. We investigated the utility of whole-exome sequencing in three children with advanced liver disease of indeterminate aetiology.

METHODS:

Patient 1 was a 10 year-old female diagnosed with Wilson disease but no detectable ATP7B mutations, and decompensated liver cirrhosis who underwent liver transplant and subsequently developed onset of neurodegenerative disease. Patient 2 was a full-term 2 day-old male with fatal acute liver failure of indeterminate aetiology. Patient 3 was an 8 year-old female with progressive syndromic cholestasis of unknown aetiology since age 3 months.

RESULTS:

Unbiased whole-exome sequencing of germline DNA revealed homozygous mutations in MPV17 and SERAC1 as the disease causing genes in patient 1 and 2, respectively. This is the first demonstration of SERAC1 loss-of-function associated fatal acute liver failure. Patient 1 expands the phenotypic spectrum of the MPV17-related hepatocerebral mitochondrial DNA depletion syndrome. Patient 3 was found to have syndromic cholestasis due to bi-allelic NOTCH2 mutations.

CONCLUSIONS:

Our findings validate the application of whole-exome sequencing in the diagnosis and management of children with advanced liver disease of indeterminate aetiology, with the potential to enhance optimal selection of treatment options and adequate counselling of families. Moreover, whole-exome sequencing revealed a hitherto unrecognized phenotypic spectrum of inherited metabolic liver diseases.

KEYWORDS:

Genetic diagnosis; Germline mutations; Inherited metabolic liver diseases; Liver failure of indeterminate aetiology; Whole-exome sequencing

PMID:
25016221
PMCID:
PMC4203706
DOI:
10.1016/j.jhep.2014.06.038
[Indexed for MEDLINE]
Free PMC Article

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