Evidence map›Paper›PMID 37314652›Full record

ArticleHepatology international2024

Diagnostic yield and novel candidate genes by next generation sequencing in 166 children with intrahepatic cholestasis.

Yucan Zheng, Hongmei Guo, Leilei Chen, Weixia Cheng, Kunlong Yan, Zhihua Zhang, Mei Li, Yu Jin, Guorui Hu, Chunli Wang and 5 more

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In one paragraph

Article in Hepatology international, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
3.2field-weighted citation impact, top 8% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed, 10 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors at 2 institutions in 1 country.

Yucan ZhengDepartment of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China.
Hongmei GuoDepartment of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China.
Leilei ChenDepartment of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China.
Weixia ChengDepartment of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China.
Kunlong YanDepartment of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China.
Zhihua ZhangDepartment of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China.
Mei LiDepartment of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China.
Yu JinDepartment of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China.
Guorui HuDepartment of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China.
Chunli WangNanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China.
Chunlei ZhouDepartment of Pathology, Children's Hospital of Nanjing Medical University, Nanjing, China.
Wei ZhouNanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China.
Zhanjun JiaNanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China.
Bixia Zheng *Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China. bixia.zheng@njmu.edu.cn.ORCID http://orcid.org/0000-0003-3457-6545
Zhifeng Liu *Department of Gastroenterology, Children's Hospital of Nanjing Medical University, Nanjing, China. zfliu@njmu.edu.cn.
Second Affiliated Hospital of Nanjing Medical University · CNNanjing Children's Hospital · CN

Funding

National Natural Science Foundation of China 81873542
6 · The paper itself

Abstract

BACKGROUND AND

aimsCholestatic liver disease is a leading referral to pediatric liver transplant centers. Inherited disorders are the second most frequent cause of cholestasis in the first month of life.

methodsWe retrospectively characterized the genotype and phenotype of 166 participants with intrahepatic cholestasis, and re-analyzed phenotype and whole-exome sequencing (WES) data from patients with previously undetermined genetic etiology for newly published genes and novel candidates. Functional validations of selected variants were conducted in cultured cells.

resultsOverall, we identified disease-causing variants in 31% (52/166) of our study participants. Of the 52 individuals, 18 (35%) had metabolic liver diseases, 9 (17%) had syndromic cholestasis, 9 (17%) had progressive familial intrahepatic cholestasis, 3 (6%) had bile acid synthesis defects, 3(6%) had infantile liver failure and 10 (19%) had a phenocopy of intrahepatic cholestasis. By reverse phenotyping, we identified a de novo variant c.1883G > A in FAM111B of a case with high glutamyl transpeptidase (GGT) cholestasis. By re-analyzing WES data, two patients were newly solved, who had compound heterozygous variants in recently published genes KIF12 and USP53, respectively. Our additional search for novel candidates in unsolved WES families revealed four potential novel candidate genes (NCOA6, CCDC88B, USP24 and ATP11C), among which the patients with variants in NCOA6 and ATP11C recapitulate the cholestasis phenotype in mice models.

conclusionsIn a single-center pediatric cohort, we identified monogenic variants in 22 known human intrahepatic cholestasis or phenocopy genes, explaining up to 31% of the intrahepatic cholestasis patients. Our findings suggest that re-evaluating existing WES data from well-phenotyped patients on a regular basis can increase the diagnostic yield for cholestatic liver disease in children.

Indexed as

CholestasisCholestasis, IntrahepaticMembrane Transport ProteinsAdenosine TriphosphatasesAnimalsCell Cycle ProteinsChildHigh-Throughput Nucleotide SequencingHumansKinesinsMiceMutationRetrospective StudiesUbiquitin-Specific ProteasesUbiquitin ThiolesteraseAdenosine TriphosphatasesATP11C protein, humanATP11C protein, mouseCell Cycle ProteinsFAM111B protein, humanKIF12 protein, humanKinesinsMembrane Transport ProteinsUbiquitin-Specific ProteasesUbiquitin ThiolesteraseUSP24 protein, humanUSP53 protein, humanATP11CCholangiocytesExome sequencingHepatocytesIntrahepatic cholestasisNCOA6Reverse phenotyping

Identifiers

PMID37314652
OpenAlexW4380550536

What Socratic holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.