Combining Panel-Based Next-Generation Sequencing and Exome Sequencing for Genetic Liver Diseases - 05/07/23

Doi : 10.1016/j.jpeds.2023.113408

Chi-Bo Chen, MD ^1,^{^{∗
Contributed equally.}}, Jacob Shujui Hsu, PhD ^2,^{^{∗
Contributed equally.}}, Pei-Lung Chen, MD, PhD ^2,^3,⁴, Jia-Feng Wu, MD, PhD ¹, Huei-Ying Li, PhD ⁵, Bang-Yu Liou, PhD ¹, Mei-Hwei Chang, MD ¹, Yen-Hsuan Ni, MD, PhD ^1,^5,⁶, Wuh-Liang Hwu, MD, PhD ^1,^2,³, Yin-Hsiu Chien, MD, PhD ^1,^2,³, Yen-Yin Chou, MD ⁷, Yao-Jong Yang, MD, PhD ⁷, Ni-Chung Lee, MD, PhD ^1,^3,^{^{†
Contributed equally as co-corresponding authors.}}, Huey-Ling Chen, MD, PhD ^1,^6,^8,^{^{†
Contributed equally as co-corresponding authors.},}^⁎
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 Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
⁴ Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
⁵ Medical Microbiome Center, National Taiwan University College of Medicine, Taipei, Taiwan
⁶ Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
⁷ Department of Pediatrics, National Cheng Kung University Hospital, Taipei, Taiwan
⁸ Department of Medical Education & Bioethics, National Taiwan University College of Medicine, Taipei, Taiwan

^∗Reprint requests: Huey-Ling Chen, MD, PhD, Department of Pediatrics, National Taiwan University College of Medicine and Children’s Hospital, 17F, No. 8, Chung-Shan South Rd, Taipei 100, Taiwan.Department of PediatricsNational Taiwan University College of Medicine and Children’s Hospital17F, No. 8, Chung-Shan South RdTaipei100Taiwan

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.

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Keywords : children, infant, jaundice, cholestasis, progressive familial intrahepatic cholestasis

Abbreviations : NGS, NICCD, PCR, PFIC, WES

Plan

Variant Prioritization and Interpretation

Genetic Diagnosis

Results

Patients and Yield Rates of Genetic Diagnosis

Disease Spectrum and Distribution

Stepwise Approach and Increased Yield of Diagnosis with Advancement of Genetic Tools

Clinical Phenotype and Patient Management

Disease Spectrum by Functional Categories

Discussion

Data Statement

This study was financially supported through grants from the Ministry of Science and Technology, Taiwan (109-2314-B-002-159-MY3), and National Taiwan University Hospital (107-S3917, 108-S4392). The authors have no conflicts of interest to disclose.

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Article 113408- juillet 2023 Retour au numéro

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Combining Panel-Based Next-Generation Sequencing and Exome Sequencing for Genetic Liver Diseases - 05/07/23

Abstract

Objectives

Study design

Results

Conclusions

Plan

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