Panel-Based Next-Generation Sequencing for the Diagnosis of Cholestatic Genetic Liver Diseases: Clinical Utility and Challenges
Journal
Journal of Pediatrics
Journal Volume
205
Pages
153-159000000
Date Issued
2019
Author(s)
Li H.-Y.
Wu S.-H.
Chen H.-L.
Yang Y.-H.
Hsu Y.-H.
Liou B.-Y.
Abstract
Objective: To test the application of a target enrichment next-generation sequencing (NGS) jaundice panel in genetic diagnosis of pediatric liver diseases. Study design: We developed a capture-based target enrichment NGS jaundice panel containing 42 known disease-causing genes associated with jaundice or cholestasis and 10 pathway-related genes. During 2015-2017, 102 pediatric patients with various forms of cholestasis or idiopathic liver diseases were tested, including patients with initial diagnosis of cholestasis in infancy, progressive familial intrahepatic cholestasis, syndromic cholestasis, Wilson disease, and others. Results: Of the 102 patients, 137 mutations/variants in 44 different genes were identified in 84 patients. The genetic disease diagnosis rate was 33 of 102 (32.4%). A total of 79 of 102 (77.5%) of patients had at least 1 heterozygous genetic variation. Those with progressive intrahepatic cholestasis or syndromic cholestasis in infancy had a diagnostic rate of 62.5%. Disease-causing mutations, including ATP8B1, ABCB11, ABCB4, ABCC2, TJP2, NR1H4 (FXR), JAG1, AKR1D1, CYP7B1, PKHD1, ATP7B, and SLC25A13, were identified. Nine patients had unpredicted genetic diagnosis with atypical phenotype or novel mutations in the investigational genes. We propose an NGS diagnosis classification categorizing patients into high (n = 24), moderate (n = 9), or weak (n = 25) levels of genotype–phenotype correlations to facilitate patient management. Conclusions: This panel enabled high-throughput detection of genetic variants and disease diagnosis in patients with a long list of candidate causative genes. A NGS report with diagnosis classification may aid clinicians in data interpretation and patient management. ? 2018 Elsevier Inc.
SDGs
Other Subjects
alanine aminotransferase; alpha fetoprotein; aspartate aminotransferase; bilirubin glucuronide; gamma glutamyltransferase; ABCB11 protein, human; cell receptor; DNA; farnesoid X-activated receptor; abcb11 gene; abcb4 gene; abcc2 gene; akr1d1 gene; Article; atp7b gene; atp8b1 gene; child; cholestasis; cyp7b1 gene; diagnostic value; female; gene; gene library; gene mutation; genetic association; genetic disorder; genetic screening; genetic variation; genotype phenotype correlation; heterozygote; human; infant; intrahepatic cholestasis; jag1 gene; jaundice; liver disease; major clinical study; male; missense mutation; modifier gene; next generation sequencing; nr1h4 gene; patient care; phenotype; pkhd1 gene; polymerase chain reaction; preschool child; priority journal; pruritus; Sanger sequencing; slc25a13 gene; tjp2 gene; dna mutational analysis; genetic association study; genetics; high throughput sequencing; intrahepatic cholestasis; metabolism; mutation; newborn; retrospective study; ATP Binding Cassette Transporter, Subfamily B, Member 11; Child, Preschool; Cholestasis, Intrahepatic; DNA; DNA Mutational Analysis; Female; Genetic Association Studies; High-Throughput Nucleotide Sequencing; Humans; Infant; Infant, Newborn; Male; Mutation; Receptors, Cytoplasmic and Nuclear; Retrospective Studies
Publisher
Mosby Inc.
Type
journal article