Molecular Genetic Dissection and Neonatal/Infantile Intrahepatic Cholestasis Using Targeted Next-Generation Sequencing

Togawa, Takao; Sugiura, Tetsuro; Ito, Koichi; Endo, Takeshi; Aoyama, Kohei; Ohashi, Kei; Negishi, Yutaka; Kudo, Takako; Ito, Reiko; Kikuchi, Atsuo; Arai-Ichinoi, Natsuko; Kure, Shigeo; Saitoh, Shinji

doi:10.1016/j.jpeds.2016.01.006

Cited by 95 publications

(97 citation statements)

References 31 publications

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“…In this largest study of its kind, we made a number of important clinically important observations. Alpha‐1 anti‐trypsin‐related liver disease is notably absent in our population, which is similar to what has been observed for other Asian countries . We also note that Wilson's disease is over diagnosed where it was the referral diagnosis in six of cases and yet only 50% were found to have mutations consistent with the disease; in the remaining half of such referrals, an alternate diagnosis identified genotypically and changed clinical management.…”

Section: Discussionsupporting

confidence: 85%

“…However, the remaining 32% were founder based on their detection in apparently unrelated individuals and the cumulative carrier frequency was 0.0115 (1 in 87). This translates into a minimum disease burden of cholestatic liver disease in Saudi Arabia of 1:7246, a very high estimate even when compared with countries with high burden of cholestatic liver disease in children like Japan .…”

Section: Resultsmentioning

confidence: 99%

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Genetic profiling of children with advanced cholestatic liver disease

et al. 2017

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Advanced cholestatic liver disease is a leading referral to pediatric liver transplant centers. Recent advances in the genetic classification of this group of disorders promise a highly personalized management although the genetic heterogeneity also poses a diagnostic challenge. Using a next-generation sequencing-based multi-gene panel, we performed retrospective analysis of 98 pediatric patients who presented with advanced cholestatic liver disease. A likely causal mutation was identified in the majority (61%), spanning many genes including ones that have only rarely been reported to cause cholestatic liver disease, e.g. TJP2 and VIPAS39. We find no evidence to support mono-allelic phenotypic expression in the carrier parents despite the severe nature of the respective mutations, and no evidence of oligogenicity. The high-carrier frequency of the founder mutations identified in our cohort (1 in 87) suggests a minimum incidence of 1:7246, an alarmingly high disease burden that calls for the primary prevention through carrier screening.

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Section: Discussionsupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Genetic profiling of children with advanced cholestatic liver disease

et al. 2017

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“…A second ATP8B1 variant was not detected. Patients with neonatal cholestasis but only a heterozygous pathogenic variant in ATP8B1 and also in other PFIC/BRIC genes have been reported previously . Interestingly, we also observed typical disease related symptoms in another patient with phenotypical PFIC3 and heterozygous pathogenic variant in ABCB4 [c.1769G>A, p.(Arg590Gln)] and in a patient with phenotypical WD and heterozygous pathogenic variant in ATP7B [c.2304dupC, p.(Met769Hisfs*26)].…”

Section: Discussionsupporting

confidence: 85%

Diagnosis of monogenic liver diseases in childhood by next‐generation sequencing

et al. 2017

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Next-generation sequencing (NGS) has opened up novel diagnostic opportunities for children with unidentified, but suspected inherited diseases. We describe our single-center experience with NGS diagnostics in standard clinical scenarios in pediatric hepatology. We investigated 135 children with suspected inherited hepatopathies, where initially no causative pathogenic variant had been identified, with an amplicon-based NGS panel of 21 genes associated with acute and chronic hepatopathies. In 23 of these patients, we detected pathogenic or likely pathogenic variants in 10 different genes. We present 6 novel variants. A total of 14 of these patients presented with the characteristic phenotype of the related hepatopathy. Nine patients showed only few or atypical clinical symptoms or presented with additional signs. In another 13 out of 135 cases, we detected variants of unknown significance (VUS) in 9 different genes. Only 2 of these patients showed characteristic phenotypes conclusive with the detected variants, whereas 11 patients showed unspecific or atypical phenotypes. Our multi-gene panel is a fast and comprehensive tool to diagnose inherited pediatric hepatopathies. We also illustrate the challenge of dealing with genetic variants and highlight arising clinical questions, especially in patients with atypical phenotypes.

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“…In all, 1,372 children with liver disease who underwent genetic study were enrolled, and 697 of them with only elevated transferase activities were further excluded. This left 675 with icteric cholestasis, defined by (a) a serum direct bilirubin (DB) >20% of the total bilirubin (TB) if TB >5 mg/dl or (b) a serum DB >1 mg/dl if TB <5 mg/dl (Togawa et al, ). Other biomarkers (serum alkaline phosphatase, γ‐glutamyl transpeptidase [GGT], and 5′‐ribonucleotidase activity values) were not used as selection criteria to cast our net as widely as possible.…”

Section: Methodsmentioning

confidence: 99%

TJP2 hepatobiliary disorders: Novel variants and clinical diversity

et al. 2019

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To assess the spectrum of pediatric clinical phenotypes in TJP2 disease, we reviewed records of our seven patients in whom intrahepatic cholestasis was associated with biallelic TJP2 variants (13; 12 novel) and correlated clinical manifestations with mutation type. The effect of a splicing variant was analyzed with a minigene assay. The effects of three missense variants were analyzed with protein expression in vitro. Our patients had both remitting and persistent cholestasis. Three exhibited growth retardation. Six responded to treatment with cholestyramine, ursodeoxycholic acid, or both. Two had cholecystolithiasis. None required liver transplantation or developed hepatocellular or cholangiocellular malignancy. None manifested extrahepatic disease not attributable to effects of cholestasis. The variant c.2180-5T>G resulted in exon 15 skipping with in-frame deletion of 32 amino acid residues in TJP2. The three missense variants decreased but did not abolish TJP2 expression. Patients with truncating or canonical splice-site variants had clinically more severe disease. TJP2 disease in children includes a full clinical spectrum of severity, with mild or intermittent forms as well as the severe and minimal forms hitherto described. Biallelic TJP2 variants must be considered in children with clinically intermittent or resolved intrahepatic cholestasis.

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Molecular Genetic Dissection and Neonatal/Infantile Intrahepatic Cholestasis Using Targeted Next-Generation Sequencing

Cited by 95 publications

References 31 publications

Genetic profiling of children with advanced cholestatic liver disease

Genetic profiling of children with advanced cholestatic liver disease

Diagnosis of monogenic liver diseases in childhood by next‐generation sequencing

TJP2 hepatobiliary disorders: Novel variants and clinical diversity

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