Abstract

Background and Aims: The multiple renal cysts (MRC) occur in some patients with noncirrhotic portal hypertension (NCPH) could be a subset of ciliopathy. However, the potential genetic influencers and/or determinants in NCPH with MRC are largely unknown. The aim of this study was to explore the potential candidate variants/genes associated with those patients. Methods: 8,295 cirrhotic patients with portal hypertension were enrolled in cohort 1 and 267 patients affected with NCPH were included in cohort 2. MRC was defined as at least two cysts in both kidneys within a patient detected by ultrasonography or computed tomography. Whole-genome sequencing (WGS) was performed in nine patients (four from cohort 1 and five from cohort 2). Then we integrated WGS and publicly available single-cell RNA sequencing (scRNA-seq) to prioritize potential candidate genes. Genes co-expressed with known pathogenic genes within same cell types were likely associated NCPH with MRC. Results: The prevalence of MRC in NCPH patients (19.5%, 52/267) was significantly higher than cirrhotic patients (6.2%, 513/8,295). Further, the clinical characteristics of NCPH patients with MRC were distinguishable from cirrhotic patients, including late-onset, more prominent portal hypertension however having preserved liver functions. In the nine whole genome sequenced patients, we identified three patients with early onset harboring compound rare putative pathogenic variants in the known disease gene PKHD1. For the remaining patients, by assessing cilia genes profile in kidney and liver scRNA-seq data, we identified CRB3 was the most co-expressed gene with PKHD1 that highly expressed in ureteric bud cell, kidney stromal cell and hepatoblasts. Moreover, we found a homozygous variant, CRB3 p.P114L, that caused conformational changes in the evolutional conserved domain, which may associate with NCPH with MRC. Conclusion: ScRNA-seq enables unravelling cell heterogeneity with cell specific gene expression across multiple tissues. With the boosting public accessible scRNA-seq data, we believe our proposed analytical strategy would effectively help disease risk gene identification.

Highlights

  • Cirrhotic portal hypertension complicated esophageal-gastric variceal bleeding (EGVB), ascites, hepatic encephalopathy (HE), acute kidney injury (AKI) or hepatorenal syndrome (HRS) and splenomegaly accompanied by severe liver disfunctions, is almost accounted for 80–85%

  • Two hundred sixty-seven patients with non-cirrhotic portal hypertension (NCPH) in cohort 2, confirmed by radiologists, hepatologists and pathologists based on enhanced computed tomography (CT) or nuclear magnetic resonance imaging (MRI) and/or pathology according to guidelines on the management of NCPH of EASL (Khanna and Sarin, 2014)

  • The prevalence of multiple renal cysts (MRC) in NCPH patients accounted for 19.5% (52/267)

Read more

Summary

Introduction

Cirrhotic portal hypertension complicated esophageal-gastric variceal bleeding (EGVB), ascites, hepatic encephalopathy (HE), acute kidney injury (AKI) or hepatorenal syndrome (HRS) and splenomegaly accompanied by severe liver disfunctions, is almost accounted for 80–85%. We speculate that liver disease in multiple renal cysts (MRC) present as NCPH, except for a subset of patients with ciliopathy affected by hepatorenal fibrocystic diseases (HFDs), such as autosomal recessive polycystic kidney disease (ARPKD) or Caroli syndrome (Abdul Majeed et al, 2020; McConnachie et al, 2021). HFDs are a group of ciliopathies and genetic disorders that involve developmental abnormalities in the portobiliary system in association with fibrocystic degeneration of the kidney (Lasagni et al, 2021). Patients with NCPH with MRC may be a non-classical genetic mutations or HFD phenotype. The multiple renal cysts (MRC) occur in some patients with noncirrhotic portal hypertension (NCPH) could be a subset of ciliopathy. The aim of this study was to explore the potential candidate variants/genes associated with those patients

Objectives
Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call