Advancing diagnosis and management of liver disease in adults through exome sequencing

Zheng, Melanie; Hakim, Aaron; Konkwo, Chigoziri; Deaton, Aimée M.; Ward, Lucas D.; Silveira, Marina G.; Liapakis, AnnMarie; Jaffe, Ariel; Jiang, Z. Gordon; Curry, Michael P.; Lai, Michelle; Cho, Michael H.; Dykas, Daniel; Bale, Allen E.; Mistry, Pramod K.; Vilarinho, Sílvia

doi:10.1016/j.ebiom.2023.104747

Cited by 10 publications

(6 citation statements)

References 55 publications

(69 reference statements)

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“…In particular, WES has been instrumental in the genetic diagnosis of idiopathic liver diseases. 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 Herein, we investigated a total of 20 paediatric cases with rELT or ALF of unknown aetiology using WES. While there was no candidate morbid variation found in ALF patients, we established a genetic diagnosis in four out of 10 rELT patients (40%) using a liver gene panel.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, there is an urgent necessity for enhanced diagnostic approaches to enable earlier and more precise interventions in affected children. In particular, WES has been instrumental in the genetic diagnosis of idiopathic liver diseases 12–23 . Herein, we investigated a total of 20 paediatric cases with rELT or ALF of unknown aetiology using WES.…”

Section: Discussionmentioning

confidence: 99%

“… 9 , 10 , 11 Recent studies have highlighted the utility of whole‐exome sequencing (WES) in the identification of genetic causes underlying liver diseases of unknown aetiology in both paediatric and adult patients. 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 However, genetic studies focusing on children and, in particular, patients with different ethnic backgrounds are still limited. The identification of inborn monogenic causes of indeterminate liver diseases holds significant clinical importance, as it may facilitate familial testing for earlier diagnosis, prognosis prediction and more precise management in high‐risk family members.…”

Section: Introductionmentioning

confidence: 99%

“…Next‐generation sequencing technologies, such as whole‐exome and ‐genome sequencing, are now widely used in clinics as powerful genome‐wide scanning tools in the search for genetic variants responsible for phenotypes of interest 9–11 . Recent studies have highlighted the utility of whole‐exome sequencing (WES) in the identification of genetic causes underlying liver diseases of unknown aetiology in both paediatric and adult patients 12–23 . However, genetic studies focusing on children and, in particular, patients with different ethnic backgrounds are still limited.…”

Section: Introductionmentioning

confidence: 99%

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Whole‐exome sequencing for genetic diagnosis of idiopathic liver injury in children

Lülecioğlu,

Yazıcı,

Baran

et al. 2024

J Cellular Molecular Medi

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Genome‐wide approaches, such as whole‐exome sequencing (WES), are widely used to decipher the genetic mechanisms underlying inter‐individual variability in disease susceptibility. We aimed to dissect inborn monogenic determinants of idiopathic liver injury in otherwise healthy children. We thus performed WES for 20 patients presented with paediatric‐onset recurrent elevated transaminases (rELT) or acute liver failure (ALF) of unknown aetiology. A stringent variant screening was undertaken on a manually‐curated panel of 380 genes predisposing to inherited human diseases with hepatobiliary involvement in the OMIM database. We identified rare nonsynonymous variants in nine genes in six patients (five rELT and one ALF). We next performed a case‐level evaluation to assess the causal concordance between the gene mutated and clinical symptoms of the affected patient. A genetic diagnosis was confirmed in four rELT patients (40%), among whom two carried novel mutations in ACOX2 or PYGL, and two had previously‐reported morbid variants in ABCB4 or PHKA2. We also detected rare variants with uncertain clinical significance in CDAN1, JAG1, PCK2, SLC27A5 or VPS33B in rELT or ALF patients. In conclusion, implementation of WES improves diagnostic yield and enables precision management in paediatric cases of liver injury with unknown aetiology, in particular recurrent hypertransaminasemia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Whole‐exome sequencing for genetic diagnosis of idiopathic liver injury in children

Lülecioğlu,

Yazıcı,

Baran

et al. 2024

J Cellular Molecular Medi

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“…Although great progress has been made in hepatitis B vaccines, antiviral drugs and surgery, the global burden of liver disease is still increasing, and the morbidity and mortality of liver disease are increasing year by year, especially in less developed regions 1 – 5 . According to incomplete statistics, 120 million people worldwide suffer from end-stage liver disease, resulting in more than 2 million deaths each year 1 , 2 . Not only that, liver disease increases the risk of cardiovascular disease, and has substantial effects on pre-adolescent health 6 , 7 .…”

Section: Introductionmentioning

confidence: 99%

Prediction of early recovery of graft function after living donor liver transplantation in children

Tan,

Yang,

et al. 2024

Sci Rep

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For end-stage liver disease in children, living donor liver transplantation (LDLT) is often the important standard curative treatment. However, there is a lack of research on early recovery of graft function after pediatric LDLT. This is a single-center, ambispective cohort study. We collected the demographic and clinicopathological data of donors and recipients, and determined the risk factors of postoperative delayed recovery of hepatic function (DRHF) by univariate and multivariate Logistic analyses. 181 cases were included in the retrospective cohort and 50 cases in the prospective cohort. The incidence of DRHF after LDLT in children was 29.4%, and DRHF could well evaluate the early recovery of graft function after LDLT. Through Logistic analyses and AIC score, preoperative liver function of donors, ischemia duration level of the liver graft, Ln (Cr of recipients before operation) and Ln (TB of recipients on the 3rd day after operation) were predictive indicators for DRHF after LDLT in children. Using the above factors, we constructed a predictive model to evaluate the incidence of postoperative DRHF. Self-verification and prospective internal verification showed that this prediction model had good accuracy and clinical applicability. In conclusion, we pointed many risk factors for early delayed recovery of graft function after LDLT in children, and developed a visual and personalized predictive model for them, offering valuable insights for clinical management.

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The contribution of genetics and epigenetics to MAFLD susceptibility

Moretti,

Romeo,

Valenti

2024

Hepatol Int

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Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease worldwide. The risk of developing MAFLD varies among individuals, due to a combination of environmental inherited and acquired genetic factors. Genome-wide association and next-generation sequencing studies are leading to the discovery of the common and rare genetic determinants of MAFLD. Thanks to the great advances in genomic technologies and bioinformatics analysis, genetic and epigenetic factors involved in the disease can be used to develop genetic risk scores specific for liver-related complications, which can improve risk stratification. Genetic and epigenetic factors lead to the identification of specific sub-phenotypes of MAFLD, and predict the individual response to a pharmacological therapy. Moreover, the variant transcripts and protein themselves represent new therapeutic targets. This review will discuss the current status of research into genetic as well as epigenetic modifiers of MAFLD development and progression.

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Advancing diagnosis and management of liver disease in adults through exome sequencing

Cited by 10 publications

References 55 publications

Whole‐exome sequencing for genetic diagnosis of idiopathic liver injury in children

Whole‐exome sequencing for genetic diagnosis of idiopathic liver injury in children

Prediction of early recovery of graft function after living donor liver transplantation in children

The contribution of genetics and epigenetics to MAFLD susceptibility

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