Use of a Comprehensive 66-Gene Cholestasis Sequencing Panel in 2171 Cholestatic Infants, Children, and Young Adults

Karpen, Saul J.; Kamath, Binita M.; Alexander, John J.; Ichetovkin, Ilia; Rosenthal, Philip; Sokol, Ronald J.; Dunn, S. Terrence; Thompson, Richard J.; Heubi, James E.

doi:10.1097/mpg.0000000000003094

Cited by 21 publications

(28 citation statements)

References 44 publications

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“…An early diagnosis in these patients may offer more specific therapeutics, delay invasive diagnostic procedures (biliary tree opacification, LB), and help clinicians with genetic counseling. Thus, NGS seems to be a first choice tool in the diagnostic process of these diseases [3,15].…”

Section: Discussionmentioning

confidence: 99%

Targeted-Capture Next-Generation Sequencing in Diagnosis Approach of Pediatric Cholestasis

Almes

Spraul

Ruiz³

et al. 2022

Diagnostics

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Background: Cholestasis is a frequent and severe condition during childhood. Genetic cholestatic diseases represent up to 25% of pediatric cholestasis. Molecular analysis by targeted-capture next generation sequencing (NGS) has recently emerged as an efficient diagnostic tool. The objective of this study is to evaluate the use of NGS in children with cholestasis. Methods: Children presenting cholestasis were included between 2015 and 2020. Molecular sequencing was performed by targeted capture of a panel of 34 genes involved in cholestasis and jaundice. Patients were classified into three categories: certain diagnosis; suggested diagnosis (when genotype was consistent with phenotype for conditions without any available OMIM or ORPHANET-number); uncertain diagnosis (when clinical and para-clinical findings were not consistent enough with molecular findings). Results: A certain diagnosis was established in 169 patients among the 602 included (28.1%). Molecular studies led to a suggested diagnosis in 40 patients (6.6%) and to an uncertain diagnosis in 21 patients (3.5%). In 372 children (61.7%), no molecular defect was identified. Conclusions: NGS is a useful diagnostic tool in pediatric cholestasis, providing a certain diagnosis in 28.1% of the patients included in this study. In the remaining patients, especially those with variants of uncertain significance, the imputability of the variants requires further investigations.

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Section: Discussionmentioning

confidence: 99%

Targeted-Capture Next-Generation Sequencing in Diagnosis Approach of Pediatric Cholestasis

Almes

Spraul

Ruiz³

et al. 2022

Diagnostics

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“…The advent of rapid molecular testing and readily available cholestasis genetic panels is already altering the timing and utility of liver biopsy for diagnostic purposes and, with further clinical experience, will likely become an essential component of the workup. [ 55 ]…”

Section: The Role Of Liver Biopsymentioning

confidence: 99%

“…Results were diagnostic in 12%, with the most common genetic diagnoses being ALGS, BSEP deficiency, alpha‐1‐antitrypsin (AAT) deficiency, MDR3 deficiency, and mitochondrial disease (DNA polymerase gamma [ POLG ]). [ 55 ] In a single‐center cohort of 50 cholestatic infants with suspected genetic etiology, the diagnostic rate was 60%. [ 58 ] Another study of 109 cholestatic infants tested on a custom 18‐gene panel showed an overall diagnostic yield of 26%, increased to 71% in the patients with the highest likelihood of a genetic etiology.…”

Section: Identifying Genetic Causes Of Cholestasismentioning

confidence: 99%

Cholestatic liver diseases of genetic etiology: Advances and controversies

et al. 2022

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With the application of modern investigative technologies, cholestatic liver diseases of genetic etiology are increasingly identified as the root cause of previously designated “idiopathic” adult and pediatric liver diseases. Here, we review advances in the field enhanced by a deeper understanding of the phenotypes associated with specific gene defects that lead to cholestatic liver diseases. There are evolving areas for clinicians in the current era specifically regarding the role for biopsy and opportunities for a “sequencing first” approach. Risk stratification based on the severity of the genetic defect holds promise to guide the decision to pursue primary liver transplantation versus medical therapy or nontransplant surgery, as well as early screening for HCC. In the present era, the expanding toolbox of recently approved therapies for hepatologists has real potential to help many of our patients with genetic causes of cholestasis. In addition, there are promising agents under study in the pipeline. Relevant to the current era, there are still gaps in knowledge of causation and pathogenesis and lack of fully accepted biomarkers of disease progression and pruritus. We discuss strategies to overcome the challenges of genotype–phenotype correlation and draw attention to the extrahepatic manifestations of these diseases. Finally, with attention to identifying causes and treatments of genetic cholestatic disorders, we anticipate a vibrant future of this dynamic field which builds upon current and future therapies, real‐world evaluations of individual and combined therapeutics, and the potential incorporation of effective gene editing and gene additive technologies.

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“…The discovery of blood-based diagnostics and dissemination of rapid, sensitive and specific clinical assays have lowered the barrier for testing and accelerated diagnosis [19][20][21][22]. In addition, the availability of molecular diagnostics (e.g., next generation sequencing) and phenotype-specific gene panels has further increased recognition of NPC disease in at-risk patient populations (e.g., neonates with cholestasis) [4,[23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Advancing diagnosis and treatment of Niemann-Pick C disease through biomarker discovery

Jiang

Ory

2021

Explor Neuroprot Ther

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Niemann-Pick C disease is a rare neurodegenerative, lysosomal storage disease caused by accumulation of unesterified cholesterol. Diagnosis of the disease is often delayed due to its rarity, the heterogeneous presentation, and the early non-specific symptoms. The discovery of disease-specific biomarkers—cholestane-3β,5α,6β-triol (C-triol), trihydroxycholanic acid glycinate (TCG) and N-palmitoyl-O-phosphocholineserine [PPCS, initially referred to as lysosphingomyelin-509 (lysoSM-509)]—has led to development of non-invasive, blood-based diagnostics. Dissemination of these rapid, sensitive, and specific clinical assays has accelerated diagnosis. Moreover, the superior receiver operating characteristic of the TCG bile acid biomarker and its detection in dried blood spots has also facilitated development of a newborn screen for NPC, which is currently being piloted in New York state. The C-triol, TCG and PPCS biomarkers have also been proved useful for monitoring treatment response in peripheral tissues, but are uninformative with respect to treatment efficacy in the central nervous system (CNS). A major gap for the field is the lack of a validated, non-invasive biomarker to monitor the course of disease and CNS response to therapy.

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Use of a Comprehensive 66-Gene Cholestasis Sequencing Panel in 2171 Cholestatic Infants, Children, and Young Adults

Cited by 21 publications

References 44 publications

Targeted-Capture Next-Generation Sequencing in Diagnosis Approach of Pediatric Cholestasis

Targeted-Capture Next-Generation Sequencing in Diagnosis Approach of Pediatric Cholestasis

Cholestatic liver diseases of genetic etiology: Advances and controversies

Advancing diagnosis and treatment of Niemann-Pick C disease through biomarker discovery

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