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Hereditary liver diseases have considerable genetic heterogeneity and variable clinical manifestations, which bring great challenges to clinical and molecular diagnoses. In this study, we investigated a group of paediatric patients with varying degrees of liver dysfunction using a hierarchical genetic testing strategy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We first applied a panel encompassing 166 known causal genes of liver disease. We then used exome sequencing (ES) in those patients whose cases remained undiagnosed to identify the genetic aetiology of their symptoms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In total, we enrolled 131 unrelated paediatric patients with liver disease of Chinese Han ethnicity. We first applied targeted gene sequencing of 166 genes to all patients and yielded a diagnostic rate of 35.9% (47 of 131). Eighty\u2010four patients who remained undiagnosed after target gene sequencing were subjected to ES. As a result, eight (8\/84, 9.5%) of them obtained molecular diagnoses, including four patients suspected of abnormal bilirubin metabolism and four idiopathic cases. Non\u2010typical genetic findings, including digenic inheritance and dual molecular diagnosis, were also identified. Through a comprehensive assessment of novel candidate variants of uncertain disease association, 11 patients of the remaining undiagnosed patients were able to obtain likely molecular diagnoses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our study presents evidence for the diagnostic utility of sequential genetic testing in a cohort of patients with paediatric liver disease. Our findings expand the understanding of the phenotypic and mutational spectrum underlying this heterogeneous group of diseases.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15235","type":"journal-article","created":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T09:44:31Z","timestamp":1646732671000},"page":"1097-1108","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The utility of hierarchical genetic testing in paediatric liver disease"],"prefix":"10.1111","volume":"42","author":[{"given":"Fuchuan","family":"Wang","sequence":"first","affiliation":[{"name":"Fifth Medical Center of Chinese PLA General Hospital  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6829-8208","authenticated-orcid":false,"given":"Yaqi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery State Key Laboratory of Complex Severe and Rare Diseases Peking Union Medical College Hospital Peking Union Medical College and Chinese Academy of Medical Sciences  Beijing China"},{"name":"Key Laboratory of Big Data for Spinal Deformities Chinese Academy of Medical Sciences  Beijing China"},{"name":"Beijing Key Laboratory for Genetic Research of Skeletal Deformity  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9418-4231","authenticated-orcid":false,"given":"Sen","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery State Key Laboratory of Complex Severe and Rare Diseases Peking Union Medical College Hospital Peking Union Medical College and Chinese Academy of Medical Sciences  Beijing China"},{"name":"Key Laboratory of Big Data for Spinal Deformities Chinese Academy of Medical Sciences  Beijing China"},{"name":"Beijing Key Laboratory for Genetic Research of Skeletal Deformity  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zefu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery State Key Laboratory of Complex Severe and Rare Diseases Peking Union Medical College Hospital Peking Union Medical College and Chinese Academy of Medical Sciences  Beijing China"},{"name":"Key Laboratory of Big Data for Spinal Deformities Chinese Academy of Medical Sciences  Beijing China"},{"name":"Beijing Key Laboratory for Genetic Research of Skeletal Deformity  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiqiang","family":"Xu","sequence":"additional","affiliation":[{"name":"Fifth Medical Center of Chinese PLA General Hospital  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lianlei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Orthopedic Surgery Qilu Hospital of Shandong University  Jinan Shandong P. 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