Genetic predisposition to porto‐sinusoidal vascular disorder: A functional genomic‐based, multigenerational family study

Shan, Jingxuan; Mégarbané, André; Chouchane, Aziz; Karthik, Deepak; Temanni, Ramzi; Romero, Atilio Reyes; Hua, Huiying; Pan, Chun Ming; Chen, Xixi; Mahadevan, Subramanian; Saad, Chadi; Mbarek, Hamdi; Mehawej, Cybel; Chouery, Éliane; Abuaqel, Sirin W. J.; Dömling, Alexander; Remadi, Sami; Yaghi, César; Li, Pu; Chouchane, Lotfi

doi:10.1002/hep.32735

Cited by 12 publications

(7 citation statements)

References 43 publications

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“…88 Furthermore, introduction of the genetic variant in mice led to PH development, confirming the causal role in determining the phenotype, although the mechanism remains to be clarified. 88 Finally, PSVD may be associated with other rare genetic diseases, such as Adams-Oliver syndrome, 89 cystic fibrosis-related liver disease (CFLD) 90 and Alagille syndrome (ALGS). 91 Although the genetic basis of these disorders, in particular for CFLD and ALGS, is well established and all these conditions affect the development of the biliary tree, suggesting it may secondarily affect liver vascular development, the detailed molecular mechanisms linking genetic variations to PSVD development remains to be clarified.…”

Section: Proposed Methodologymentioning

confidence: 91%

“…88 The variant may increase both messenger RNA (mRNA) and protein stability and its interaction with MTOR-associated protein, LST8 homologue, a key protein of the mechanistic target of rapamycin (mTOR pathway), resulting in increased mTORC1 activity. 88 Furthermore, introduction of the genetic variant in mice led to PH development, confirming the causal role in determining the phenotype, although the mechanism remains to be clarified. 88 Finally, PSVD may be associated with other rare genetic diseases, such as Adams-Oliver syndrome, 89 cystic fibrosis-related liver disease (CFLD) 90 and Alagille syndrome (ALGS).…”

Section: Proposed Methodologymentioning

confidence: 99%

“…Lastly, Shan and coworkers identified a homozygous rare variant of FCH and double SH3 domains 1 ( FCHSD1 , p.R183W), an uncharacterized gene, as the likely cause of PSVD in a Lebanese family 88 . The variant may increase both messenger RNA (mRNA) and protein stability and its interaction with MTOR‐associated protein, LST8 homologue, a key protein of the mechanistic target of rapamycin (mTOR pathway), resulting in increased mTORC1 activity 88 . Furthermore, introduction of the genetic variant in mice led to PH development, confirming the causal role in determining the phenotype, although the mechanism remains to be clarified 88 …”

Section: Genetic Alterations In Patients With Psvdmentioning

confidence: 99%

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The genetics of portal hypertension: Recent developments and the road ahead

Shalaby,

Ronzoni,

Hernandez‐Gea

et al. 2023

Liver International

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Portal hypertension (PH), defined as a pathological increase in the portal vein pressure, has different aetiologies and causes. Intrahepatic PH is mostly secondary to the presence of underlying liver disease leading to cirrhosis, characterized by parenchymal changes with deregulated accumulation of extracellular matrix and vascular abnormalities; liver sinusoidal endothelial cells and hepatic stellate cells are key players in PH progression, able to influence each other. However, PH may also develop independently of parenchymal damage, as occur in portosinusoidal vascular disorder (PSVD), a group of clinical and histological entities characterized by portal vasculature dysfunctions. In this particular group of disorders, the pathophysiology of PH is still poorly understood. In the last years, several genetic studies, based on genome‐wide association studies or whole‐exome sequencing analysis, have highlighted the importance of genetic heritability in PH pathogenesis, both in cirrhotic and non‐cirrhotic cases. The common PNPLA3 p.I148M variant, one of the main determinants of the susceptibility to steatotic liver disease, has also been associated with decompensation in patients with PH. Genetic variations at loci influencing coagulation, mainly the ABO locus, may directly contribute to the pathogenesis of PH. Rare genetic variants have been associated with familiar cases of progressive PSVD. In this review, we summarize the recent knowledges on genetic variants predisposing to PH development, contributing to better understand the role of genetic factors in PH pathogenesis.

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Section: Proposed Methodologymentioning

confidence: 91%

Section: Proposed Methodologymentioning

confidence: 99%

Section: Genetic Alterations In Patients With Psvdmentioning

confidence: 99%

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The genetics of portal hypertension: Recent developments and the road ahead

Shalaby,

Ronzoni,

Hernandez‐Gea

et al. 2023

Liver International

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“… 115 These include rare biallelic variants in DGUOK , GIMAP5 , and TRMT5 , as well as heterozygous variants in KCNN3 , FOPV (C4ORF54) , and FCHSD1 . 82 , 83 , 116 – 119 GIMAP5 , KCNN3 , and FOPV have been suggested to contribute to maintaining the integrity of the liver vasculature, while DGUOK and TRMT5 play a role in mitochondrial DNA maintenance. While these discoveries continue to enhance our understanding of PSVD, further research is required to disentangle the mechanisms among these heterogeneous disorders, for which we expect to illuminate innovative therapeutics.…”

Section: Rare Genetic Variants Underlying Liver Disease Pathogenesismentioning

confidence: 99%

Genetics of liver disease in adults

Konkwo,

Chowdhury,

Vilarinho

2024

Hepatology Communications

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Chronic liver disease stands as a significant global health problem with an estimated 2 million annual deaths across the globe. Combining the use of next-generation sequencing technologies with evolving knowledge in the interpretation of genetic variation across the human genome is propelling our understanding, diagnosis, and management of both rare and common liver diseases. Here, we review the contribution of risk and protective alleles to common forms of liver disease, the rising number of monogenic diseases affecting the liver, and the role of somatic genetic variants in the onset and progression of oncological and non-oncological liver diseases. The incorporation of genomic information in the diagnosis and management of patients with liver disease is driving the beginning of a new era of genomics-informed clinical hepatology practice, facilitating personalized medicine, and improving patient care.

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“…This mutation is transmitted in an autosomal recessive manner [ 35 ]. A recent study that sequenced the genome of four affected members of a Lebanese family with PSVD and two healthy members revealed an aberrant structure of the FCHSD1 (FCH and double SH3 domains 1) gene, leading to excessive expression of the FCHSD1 protein and enhanced activation of the mTOR signaling pathway [ 36 ]. Other genetic diseases associated with the development of PSVD include Adams-Oliver syndrome, Turner syndrome, familial obliterative portal venopathy, and cystic fibrosis [ 5 ].…”

Section: Pathophysiology and Etiology Of The Diseasementioning

confidence: 99%

Porto-sinusoidal vascular disease: a new definition of an old clinical entity

Barisic-Jaman,

Milosevic,

Pastrovic

et al. 2023

ceh

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Porto-sinusoidal vascular disease (PSVD) is defined as a vascular liver disease characterized by the absence of cirrhosis and the presence of characteristic histological features, with or without the presence of portal hypertension (PH). Half of the patients with PSVD also have associated disease that may contribute to the development of PSVD. Patients usually remain asymptomatic until complications of PH arise. Variceal bleeding and portal vein thrombosis are major complications associated with PSVD. The treatment is focused on managing complications of PH, mainly through primary prophylaxis of variceal bleeding and treatment of portal vein thrombosis. Currently, there is insufficient evidence to support the use of anticoagulants for thrombosis prevention in these patients. Despite the increase of recognition of PSVD, further research is needed to enable early disease diagnosis, establish optimal screening methods, and develop strategies to slow down disease progression.

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Genetic predisposition to porto‐sinusoidal vascular disorder: A functional genomic‐based, multigenerational family study

Cited by 12 publications

References 43 publications

The genetics of portal hypertension: Recent developments and the road ahead

The genetics of portal hypertension: Recent developments and the road ahead

Genetics of liver disease in adults

Porto-sinusoidal vascular disease: a new definition of an old clinical entity

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