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

Abstract

Background & Aims In children with liver failure, as many as half remain of indeterminate etiology. This hinders timely consideration of optimal treatment options. We posit that a significant subset of these children harbor 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 etiology. 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 etiology. Patient 3 was an 8 year-old female with progressive syndromic cholestasis of unknown etiology 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 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 etiology, with the potential to enhance optimal selection of treatment options and adequate counseling of families. Moreover, whole-exome sequencing revealed hitherto unrecognized phenotypic spectrum of inherited metabolic liver diseases.

MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects

“…Infrequent manifestations occurring in less than 10% of affected individuals are dystonia, ataxia, retinopathy, nystagmus, corneal anesthesia and ulcers, renal tubulopathy, nephrocalcinosis, and hypoparathyroidism. In addition, three affected individuals developed hepatocellular carcinoma between ages 7 and 11 years (El‐Hattab et al., ; Karadimas et al., ; Vilarinho et al., ) (Table and and ).…”

“…To date, 75 individuals with MPV17 ‐related mtDNA maintenance defect have been reported with 39 different MPV17 pathogenic variants (Al‐Hussaini et al., ; Al‐Jasmi, Penefsky, & Souid, ; AlSaman, Tomoum, Invernizzi, & Zeviani, et al., ; Bijarnia‐Mahay, Mohan, Goyal, & Verma, ; Bitting & Hanson, ; Blakely et al., ; Choi et al., ; El‐Hattab et al., ; Garone et al., ; Kaji et al., ; Karadimas et al., ; Kim et al., ; McKiernan et al., ; Mendelsohn et al., ; Merkle, Nascene, & McKinney, ; Navarro‐Sastre et al., ; Nogueira et al., ; Piekutowska‐Abramczuk et al., ; Sarkhy, Al‐Sunaid, Abdullah, AlFadhel, & Eiyad, ; Spinazzola et al., , ; Uusimaa et al., ; Vilarinho et al., ; Wong et al., ). In this report, we present additional 25 affected individuals and nine novel MPV17 pathogenic variants.…”

ACOX2 deficiency: A disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment

“…One example of an unmet medical need is idiopathic liver disease, which remains a challenge in both pediatric and adult hepatology. We and others have shown the utility of whole-exome sequencing in the diagnosis of such patients (2)(3)(4)(5)(6). Children with unexplained liver disease who are the offspring of a consanguineous union are excellent candidates for recessive disease-causing mutations.…”

Progressive deafness–dystonia due to SERAC1 mutations: A study of 67 cases

“…Additionally, 7 individuals—who were not included in this study—have been reported in the literature with a comparable course of disease (Table 1, Supplementary Table 3) 3, 18, 26…”