title: Individual exome analysis in diagnosis and management of paediatric liver failure of indeterminate aetiology.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Vilarinho
authors.affiliation: 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.
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.affiliation: 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.
authors.forename: Dhanpat
authors.initials: D
authors.lastname: Jain
authors.affiliation: Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: Ajay
authors.initials: A
authors.lastname: Malhotra
authors.affiliation: Department of Surgery, Section of Transplantation and Immunology, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kulkarni
authors.affiliation: Department of Pediatrics, Gastroenterology-Hepatology Section, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Pashankar
authors.affiliation: Department of Pediatrics, Gastroenterology-Hepatology Section, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: Uma
authors.initials: U
authors.lastname: Phatak
authors.affiliation: Department of Pediatrics, Gastroenterology-Hepatology Section, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: Mohini
authors.initials: M
authors.lastname: Patel
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: Allen
authors.initials: A
authors.lastname: Bale
authors.affiliation: 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.
authors.forename: Shrikant
authors.initials: S
authors.lastname: Mane
authors.affiliation: 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.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.affiliation: 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.
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Mistry
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002265:Carboxylic Ester Hydrolases / Q000235:genetics; D002648:Child; D002779:Cholestasis / Q000235:genetics; D004252:DNA Mutational Analysis; D058625:End Stage Liver Disease / Q000235:genetics; D059472:Exome; D017809:Fatal Outcome; D005260:Female; D005808:Genes, Recessive; D006527:Hepatolenticular Degeneration / Q000175:diagnosis / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D017093:Liver Failure / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D017114:Liver Failure, Acute / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D010375:Pedigree; D022821:RNA Splice Sites; D051883:Receptor, Notch2 / Q000235:genetics; D017386:Sequence Homology, Amino Acid
chemical_list: C530370:MPV17 protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C497764:NOTCH2 protein, human; D022821:RNA Splice Sites; D051883:Receptor, Notch2; D002265:Carboxylic Ester Hydrolases; C576043:SERAC1 protein, human
keywords: Genetic diagnosis; Germline mutations; Inherited metabolic liver diseases; Liver failure of indeterminate aetiology; Whole-exome sequencing