https://pubmed.ncbi.nlm.nih.gov/37019333/ Genetic

J Pediatr. 2023 Apr 3;113408.
doi: 10.1016/j.jpeds.2023.113408. Online ahead of print.

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

Chi-Bo Chen 1, Jacob Shujui Hsu 2, Pei-Lung Chen 3, Jia-Feng Wu 1, Huei-Ying Li 4, Bang-Yu Liou 1, Mei-Hwei Chang 1, Yen-Hsuan Ni 5, Wuh-Liang Hwu 6, Yin-Hsiu Chien 6, Yen-Yin Chou 7, Yao-Jong Yang 7, Ni-Chung Lee 8, Huey-Ling Chen 9

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 6/19 (31.6%) who tested negative in Tier 2, and a higher detection rate in 14/22 (63.6%) patients with deteriorating/multi-organ disease receiving one-step WES (P=0.041). 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 two 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.