Combining Panel-Based Next-Generation Sequencing and Exome Sequencing for Genetic Liver Diseases

Chi-Bo Chen; Jacob Shujui Hsu; Pei-Lung Chen; Jia-Feng Wu; Huei-Ying Li; Bang-Yu Liou; Mei-Hwei Chang; Yen-Hsuan Ni; Wuh-Liang Hwu; Yin-Hsiu Chien; Yen-Yin Chou; Yao-Jong Yang; Ni-Chung Lee; Huey-Ling Chen

doi:10.1016/j.jpeds.2023.113408

Combining Panel-Based Next-Generation Sequencing and Exome Sequencing for Genetic Liver Diseases

J Pediatr. 2023 Jul:258:113408. doi: 10.1016/j.jpeds.2023.113408. Epub 2023 Apr 3.

Authors

Affiliations

¹ Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan.
² Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan.
³ Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.
⁴ Medical Microbiome Center, National Taiwan University College of Medicine, Taipei, Taiwan.
⁵ Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan; Medical Microbiome Center, National Taiwan University College of Medicine, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
⁶ Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan; Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
⁷ Department of Pediatrics, National Cheng Kung University Hospital, Taipei, Taiwan.
⁸ Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan; Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
⁹ Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan; Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; Department of Medical Education & Bioethics, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: hueyling@ntu.edu.tw.

PMID: 37019333
DOI: 10.1016/j.jpeds.2023.113408

Abstract

Objectives: To determine how advanced genetic analysis methods may help in clinical diagnosis.

Study design: We report a combined genetic diagnosis approach for patients with clinical suspicion of genetic liver diseases in a tertiary referral center, using tools either tier 1: Sanger sequencing on SLC2SA13, ATP8B1, ABCB11, ABCB4, and JAG1 genes, tier 2: panel-based next generation sequencing (NGS), or tier 3: whole-exome sequencing (WES) analysis.

Results: In a total of 374 patients undergoing genetic analysis, 175 patients received tier 1 Sanger sequencing based on phenotypic suspicion, and pathogenic variants were identified in 38 patients (21.7%). Tier 2 included 216 patients (39 of tier 1-negative patients) who received panel-based NGS, and pathogenic variants were identified in 60 (27.8%). In tier 3, 41 patients received WES analysis, and 20 (48.8%) obtained genetic diagnosis. Pathogenic variants were detected in 6 of 19 (31.6%) who tested negative in tier 2, and a greater detection rate in 14 of 22 (63.6%) patients with deteriorating/multiorgan disease receiving one-step WES (P = .041). The overall disease spectrum is comprised of 35 genetic defects; 90% of genes belong to the functional categories of small molecule metabolism, ciliopathy, bile duct development, and membrane transport. Only 13 (37%) genetic diseases were detected in more than 2 families. A hypothetical approach using a small panel-based NGS can serve as the first tier with diagnostic yield of 27.8% (98/352).

Conclusions: NGS based genetic test using a combined panel-WES approach is efficient for the diagnosis of the highly diverse genetic liver diseases.

Keywords: children; cholestasis; infant; jaundice; progressive familial intrahepatic cholestasis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Exome Sequencing
Genetic Testing*
High-Throughput Nucleotide Sequencing / methods
Humans
Liver Diseases* / diagnosis
Liver Diseases* / genetics
Mutation