Targeted Next-Generation Sequencing in Diagnostic Approach to Monogenic Cholestatic Liver Disorders—Single-Center Experience

Lipiński, Patryk; Ciara, Elżbieta; Jurkiewicz, Dorota; Pollak, Agnieszka; Wypchło, Maria; Płoski, Rafał; Cielecka-Kuszyk, Joanna; Socha, Piotr; Pawłowska, Joanna; Jankowska, Irena

doi:10.3389/fped.2020.00414

Cited by 19 publications

(19 citation statements)

References 25 publications

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“…Biliary diversion can be successful if there is no fully developed cirrhosis of the liver and the disease is diagnosed early after the onset of symptoms in infancy [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Long-Term Outcome after Liver Transplantation for Progressive Familial Intrahepatic Cholestasis

et al. 2021

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Background and Objectives: Progressive familial intrahepatic cholestasis (PFIC) is a rare autosomal recessive inherited disease divided into five types (PFIC 1-5). Characteristic of all types is early disease onset, which may result clinically in portal hypertension, fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and extrahepatic manifestations. Liver transplantation (LT) is the only successful treatment approach. Our aim is to present the good long-term outcomes after liver transplantation for PFIC1, focusing on liver function as well as the occurrence of extrahepatic manifestation after liver transplantation. Materials and Methods: A total of seven pediatric patients with PFIC1 underwent liver transplantation between January 1999 and September 2019 at the Department of Surgery, Charité Campus Virchow Klinikum and Charité Campus Mitte of Charité-Universitätsmedizin Berlin. Long-term follow-up data were collected on all patients, specifically considering liver function and extrahepatic manifestations. Results: Seven (3.2%) recipients were found from a cohort of 219 pediatric patients. Two of the seven patients had multilocular HCC in cirrhosis. Disease recurrence or graft loss did not occur in any patient. Two patients (male, siblings) had persistently elevated liver parameters but showed excellent liver function. Patient and graft survival during long-term follow-up was 100%, and no severe extrahepatic manifestations requiring hospitalization or surgery occurred. We noted a low complication rate during long-term follow-up and excellent patient outcome. Conclusions: PFIC1 long-term follow-up after LT shows promising results for this rare disease. In particular, the clinical relevance of extrahepatic manifestations seems acceptable, and graft function seems to be barely affected. Further multicenter studies are needed to analyze the clinically inhomogeneous presentation and to better understand the courses after LT.

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“…Biliary diversion can be successful if there is no fully developed cirrhosis of the liver and the disease is diagnosed early after the onset of symptoms in infancy [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Long-Term Outcome after Liver Transplantation for Progressive Familial Intrahepatic Cholestasis

et al. 2021

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“…Santos Silva et al used evoluting gene panels (from 54 genes to 95 genes) to 13 paediatric patients, and the diagnostic rate is 2/13(15.4%) 38 . Moreover, Lipiński et al implemented a panel with 1000 clinically relevant genes, and the sequencing on patients with chronic cholestatic liver disease of an unknown aetiology led to a molecular diagnosis in 15/22 patients (68%) 39 …”

Section: Discussionmentioning

confidence: 99%

The utility of hierarchical genetic testing in paediatric liver disease

Wang

Zhao

et al. 2022

Liver International

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Background & Aims Genetic factors underlie a substantial proportion of paediatric liver diseases. 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. Methods 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. Results 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‐four 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‐typical 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. Conclusions 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.

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“…In our country these techniques are not routinely available ( 2 ). The introduction of NGS allowed us to diagnose CTX and other disorders which have not been recognized yet ( 21 ). Molecular biology constitutes an useful diagnostic tool, especially when mass spectrometry data may be inconclusive, such as during the early neonatal period, or if the patient had been treated with bile acid before analysis ( 13 , 17 ).…”

Section: Discussionmentioning

confidence: 99%

Sterol 27-Hydroxylase Deficiency as a Cause of Neonatal Cholestasis: Report of 2 Cases and Review of the Literature

et al. 2021

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Introduction: Inborn errors of primary bile acid (BA) synthesis are rare autosomal recessive disorders responsible for 1–2% of cases of neonatal cholestasis. Among them, cerebrotendinous xanthomatosis (CTX) is caused by mutations in the CYP27A1 gene resulting in the impairment of sterol 27-hydroxylase enzyme activity.Patients and Methods: Here we present the study on two siblings with neonatal cholestasis diagnosed with sterol 27-hydroxylase deficiency. The clinical, biochemical, histological, and molecular presentation at the time of diagnosis and detailed follow-up were described. An extensive overview of the literature regarding patients with sterol 27-hydroxylase deficiency presenting with neonatal cholestasis was also provided.Results: Patient 1 presented with cholestatic jaundice since 10 weeks of age and developed the end-stage liver disease requiring liver transplantation at 8 months of age but finally succumbed 3 years post-transplantation due to autoimmune hemolytic anemia and multiorgan failure development. Next-generation sequencing performed post mortem, revealed him to be homozygous for the known pathogenic splicing variant c.1184+1G>A in the CYP27A1 gene. Patient 2 (sibling) presented with cholestatic jaundice since the first day of life. Sanger sequencing of CYP27A1 revealed the same results. Chenodeoxycholic acid treatment was introduced just after diagnosis, at 4 months of age. Fourteen patients with sterol 27-hydroxylase deficiency presenting with neonatal cholestasis were reported in the literature, in most of them presenting as a self-limiting disease.Conclusions: An early recognition and treatment initiation in CTX is essential.

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Targeted Next-Generation Sequencing in Diagnostic Approach to Monogenic Cholestatic Liver Disorders—Single-Center Experience

Cited by 19 publications

References 25 publications

Long-Term Outcome after Liver Transplantation for Progressive Familial Intrahepatic Cholestasis

Long-Term Outcome after Liver Transplantation for Progressive Familial Intrahepatic Cholestasis

The utility of hierarchical genetic testing in paediatric liver disease

Sterol 27-Hydroxylase Deficiency as a Cause of Neonatal Cholestasis: Report of 2 Cases and Review of the Literature

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