Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
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- On the discovery of cholestasis-related genes;
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- On pathological pathways of mutations in these loci;
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- On epidemiology and clinical features of patients with hereditary cholestatic diseases, focusing on the dysregulation of BAs in the liver gut axis concerning the development of primary biliary and liver cancers.
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- Abstracts or posters of congresses and meetings;
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- Editorials;
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- Studies that included patients with intrahepatic cholestasis without a genetic or histological diagnosis;
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- Articles focused on patients with other causes of autoimmune or acquired cholestasis, increased BAs such as primary biliary cholangitis, primary sclerosing cholangitis, IgG4 cholangitis, alcoholic and nonalcoholic steatohepatitis.
3. From Rare Pediatric Cholestatic Diseases to Adult Cryptogenic Cholestasis: An Overview of Different Features of Familial Intrahepatic Cholestasis
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- ATP8B1 gene (PFIC1): it is responsible for the synthesis of a lipid flippase, able to maintain the asymmetry of the cell membrane by the translocation of phospholipids from the exoplasmic to the cytoplasmic leaflet, having a protective role against excessive concentrations of BAs [14];
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- ABCB11 gene (PFIC2): coding for the bile export pump (BSEP), ABCB11 regulates the excretion of monovalent BAs from hepatocytes to bile canaliculi against a concentration gradient. The accumulation of BAs in hepatocytes is induced by a less expression or a malfunction of BSEP, resulting in cellular injury and alterations of the enterohepatic pathway of BAs [14];
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- ABCB4 gene (PFIC3): alterations of the MDR3 glycoprotein, a phosphatidylcholine flippase sited in the canalicular membrane of hepatocytes, lead to the disease; MDR3 protein carries phosphatidylcholine from the hepatocytes into the bile canaliculus, protecting the cholangiocytes from the detergent activity of BAs and reducing cellular injury. Patients with PFIC3 have, in fact, late onset of disease, and present high levels of gamma-glutamyl transferase (GGT) compared to PFIC1 and PFIC2, in which GGT is low or in the normal range [14];
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- TJP2 gene (PFIC4): TJP2 encodes an essential protein in the structure of tight junctions, establishing connections between the transmembrane tight junction proteins and the actin cytoskeleton. PFIC4 usually affects pediatric patients with low GGT levels [12];
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- NR1H4 gene (PFIC5): NR1H4 produces the farnesoid x receptor (FXR), bile acid-activated nuclear hormone receptor, the primary regulator of BAs metabolism and homeostasis [14];
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- SLC51A (PFIC6): this gene is responsible for the synthesis of the alpha subunit of the alpha-beta heteromeric organic solute transporter (OSTα-OSTβ), having the central role in the intestinal BA reabsorption in the setting of enterohepatic circulation: the pump exports BA across the basolateral membrane and OSTα deficiency causes a pediatric clinical picture with elevated liver transaminases, high GGT-cholestasis, normal serum BAs and congenital diarrhoea [15,16];
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- USP53 (PFIC7): USP53 encodes a nonprotease homolog of the ubiquitin-specific peptidase family; mutations in this gene are responsible for an autosomal recessive liver disorder characterized by infantile-onset jaundice and itching associated with cholestasis, elevated transaminases, normal GGT, hepatocellular and canalicular cholestasis with fibrotic changes at liver histology. In many cases, resolution of the liver injury is observed with age, although some patients have persistent hepatitis or splenomegaly. A subset of patients develops hearing loss since the USP53 locus interacts with the tight junction proteins TJP1 and TJP2 in polarized epithelial cells. Mutations in USP53 alter auditory hair cells modifying the stability of tight junctions [17];
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- KIF12 (PFIC8): mutations in KIF12 are characterized by cholestasis and high GGT presenting in the infantile period; liver immuno-staining of patients with KIF12 mutations resulted in changes in MRP2 (ABCC2 gene) trafficking with its strong cytoplasmic signal leading to change in cell polarity [18].
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- Benign recurrent intrahepatic cholestasis (BRIC): BRIC is an inherited disease characterized by almost two episodes of intermittent cholestasis with jaundice. Two types of BRIC are fully known, BRIC1 having mutations in the ATP8B1 gene and BRIC2 having mutations in the ABCB11 gene. The clinical presentation is usually less aggressive than PFIC since the protein function is only partially injured; pregnancy, infections, or drugs can trigger the attacks, while liver tests are normal between two episodes [19]. In the last years also, defects in the MYO5B gene have been described in patients with recurrent and transient forms of intrahepatic cholestasis [20,21]. Bull et al. reported BRIC-like phenotypes in a patient with USP53 mutations: age-onset was between infancy and 15 years, and patients had recurrent attacks of cholestasis with low GGT, hyperbilirubinemia and variably increased transaminases [22].
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- Intrahepatic cholestasis of pregnancy (ICP): the disease is the most common liver disorder of pregnancy, historically ascribed to the heterozygous mutations in ATP8B1, ABCB11 and ABCB4 genes. There are also associations with NR1H4 e TJP2 genes [23,24]. The main features are transient cholestasis and itching during the pregnancy that resolve after childbirth. Serious fetal complications are rare and occur when levels of BAs are higher than 40 µmol/L with ursodeoxycholic acid (UDCA) as the first-line therapy.
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- Low-phospholipid-associated cholelithiasis (LPAC): gallstone disease is linked to mutations in the ABCB4 gene in young people (younger than 40 years old) with symptomatic intrahepatic biliary lithiasis before and later even after cholecystectomy. A worsened secretion of phospholipids in the bile decreases the solubility of cholesterol, promoting gallstone formation. For this reason, long-term therapy with UDCA prevents several complications, especially after cholecystectomy, such as secondary sclerosing cholangitis [27].
4. Progressive Familial Intrahepatic Cholestasis-Related Genes
4.1. Role of Next-Generation Sequencing
4.2. Hepatobiliary Cancers and Cholestasis-Related Genes: An Underestimated Association
4.3. Hepatobiliary and Nor Cancers in Patients with Mutations in Cholestasis-Related Genes: PFIC Genes History and Cholestasis-Cancer Links
4.3.1. ATP8B1
4.3.2. ABCB11
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- BSEP1, if carrying at least one of the two common European mutations associated with residual BSEP function (c.1445A>G or c.890A>G);
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- BSEP2, if carrying at least one missense mutation, different to (c.1445A>G or c.890A>G);
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- BSEP3, if carrying mutations causing non-functional protein.
4.3.3. ABCB4
4.3.4. TJP2
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- Nine patients required LT;
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- One child died at 13 months;
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- Two had stable liver disease with mild portal hypertension at the ages of 4 and 7 years.
4.3.5. NR1H4
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- The increase in the synthesis of fibroblast growth factor-19 (FGF-19);
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- The CY7A1 inhibition through the fibroblast growth factor receptor 4 (FGFR4) pathway in the hepatocytes (Figure 1);
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- The downregulation of sodium taurocholate cotransporting polypeptide (NTCP) blocking the uptake of BAs by the liver;
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- The upregulation of the synthesis of BSEP and MDR3;
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- The increase of BAs efflux from the liver to the lumen of bile canaliculus;
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- The synthesis of organic solute transporter alpha/beta (OSTα/β) via enhancement of BAs output from the liver to the portal vein [80].
4.3.6. MYO5B
4.3.7. SLC51A
4.3.8. USP53
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- In clear cell renal cell carcinoma inhibits the occurrence and development of cancer through NF-κB pathway inactivation [93];
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- In cervical squamous cell carcinoma correlated with the sensitivity to radiotherapy [94];
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- In oesophagal carcinoma, USP53 suppresses cancer progression by regulating cell growth and metabolism [95];
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- In lung adenocarcinoma, USP53 regulates cell apoptosis and glycolysis through the AKT1 pathway acting as a tumour suppressor [96].
4.3.9. KIF12
4.3.10. SLC25A13
4.3.11. JAG1 and NOTCH2
4.3.12. HNF1B
4.4. Other DNA Changes
5. Bile Acids and Liver Cancer: Pathophysiology
5.1. Structural and Functional Hepatocyte Polarity and Liver Disease
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- Claudin 1 (NISCH syndrome) and TJP2 (involved in PFIC4 and familial hypercholanaemia) in the group of tight junction proteins;
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- VPS33B (ARC syndrome) and Myosin 5B (involved in MVID and PFIC) in the intracellular trafficking protein;
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- ATP8B1 (PFIC1), ABCB11 (PFIC2), ABCB4 (PFIC3), and ABCC2 (involved in Dubin Johnson syndrome) in the canalicular membrane transporters;
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- SLCO1B1 and SLCO1B3 among the basolateral membrane transporters (Rotor syndrome), localized to the sinusoidal membrane of hepatocytes and able to control sodium-independent cellular uptake of bilirubin glucuronide, BAs, steroids and drugs;
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- KIF12 is able to impair the hepatocyte polarity by interacting with MRP2 protein (ABCC2 gene), which has a strong cytoplasmic signal, in PFIC8-affected liver [17].
5.2. The Gut Microbiome–Bile Acid Axis in Hepatocarcinogenesis
6. Discussion
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
A | Arabic |
AFP | alpha-phetoprotein |
ARE | apical recycling endosome |
ASBT | apical sodium-dependent bile acid transporter |
AP | amino-phospholipids |
BAs | bile acids |
BD | biliary diversion |
BSEP | bile salt export pump protein |
BRIC | benign recurrent intrahepatic cholestasis |
C | Caucasian |
CA | Central Asian |
CAC | Central Asian Caucasian |
CCA | cholangiocarcinoma |
Ch | Chinese |
Cho | cholestasis |
Cir | cirrhosis |
CFTR | cystic fibrosis transmembrane conductance regulator |
CNVs | copy number variants |
CTLDN2 | adult-onset type II citrullinemia |
CYP7A1 | cholesterol 7α-monooxygenase |
del | deletion |
DIC | drug-induced cholestasis |
DILI | drug-induced liver injury |
DSBs | double-strand breaks |
ER | endoplasmic reticulum |
FGF19 | fibroblast growth factor 19 |
FGFR14 | fibroblast growth factor receptor 4 |
FIC | familial intrahepatic cholestasis |
FIC 1 | familial intrahepatic cholestasis deficiency type 1 protein |
FXR | farnesoid X receptor |
FTTDCD | failure to thrive and dyslipidemia caused by citrin deficiency |
GGT | gamma-glutamyl transferase |
GWAS | genome-wide association study |
H | hepatomegaly |
Hi | Hispanic |
HBCs | hepatobiliary cancers |
HCC | hepatocellular carcinoma |
HNF-1B | hepatocyte nuclear factor-1beta |
I | itching |
IBAT | ileal bile acid transporter |
ICP | intrahepatic cholestasis of pregnancy |
INDELs | DNA insertions and deletions |
J | jaundice |
Ja | Japanese |
JAG-2 | jagged canonical notch ligand-2 |
KIF12 | kinesin family member 12 |
LF | liver failure |
LT | liver transplantation |
MODY | maturity-onset diabetes of the young |
MVID | microvillus inclusion disease |
LPAC | low-phospholipid-associated cholelithiasis |
LT | liver transplantation |
MB | megabases |
MDR | multidrug resistance protein |
mo | months |
MRP | multidrug resistance protein |
NEC | Northern European Caucasian |
NGS | next-generation sequencing |
mo | months |
MDR | multidrug resistance protein |
ng | nanograms/mL |
NKT | natural killer T |
nf | not found |
NICD | notch intracellular domain |
NLT | normalized liver tests |
NOTCH-1,2 | notch homolog-1,2 translocation-associated |
NTCP | sodium taurocholate cotransporting polypeptide |
OMIM | Online Mendelian Inheritance in Man |
OR | odd ratio |
OATP | organic anion transporting polypeptide |
OST α/β | organic solute transporter alpha/beta |
PC | phosphatidylcholine |
PE | phosphatidylethanolamine |
PELD PFIC | paediatric end-stage liver disease progressive familial intrahepatic cholestasis |
PGS | panel gene sequencing |
PMID | PubMed-Indexed for MEDLINE |
PS | phosphatidylserine |
RBPjk | recombining binding protein suppressor of hairless |
RCAD | renal cysts and diabetes syndrome |
ROS | reactive oxygen species |
SA | South Asian |
SL25A13 | solute carrier family 25 member 13 |
STRs | short tandem repeats |
SVs | structural variants |
T | Taiwanese |
TGR5 | G-protein-coupled bile acid receptor |
TJP2 | tight junction protein 2 gene |
THBA | tetrahydroxylated bile acids |
UDCA | ursodeoxycholic acid |
USP53 | ubiquitin-specific peptidase 53 |
VIPAR | VPS33B interacting protein, apical–basal polarity regulator |
VPS33B | vacuolar protein sorting associated protein 33B |
WES | whole-exome sequencing |
WGS | whole-genome sequencing |
wk | weeks |
wt | wild type |
y | year |
yrs | years |
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Year | Gene | Protein | Phenotypes | Hepatobiliary Cancers |
---|---|---|---|---|
1998 | ATP8B1 | ATP8B1 | ICP BRIC PFIC 1 | Not reported |
1998 | ABCB11 | BSEP | ICP DIC LPAC BRIC PFIC 2 | HCC CCA |
1996 | ABCB4 | MDR3 | ICP DIC LPAC PFIC 3 | HCC CCA Gallbladder cancer |
2014 | TJP2 | TJP2 | ICP PFIC 4 | HCC CCA |
2016 | NR1H4 | FXR | ICP PFIC 5 | Not reported |
2017 | MYO5B | MYO5B | BRIC MVID MYO5B-PFIC | Not reported |
2019 | USP53 | USP53 protein | BRIC PFIC 7 | Not reported |
2019 | KIF12 | KIF12 | PFIC 8 | Not reported |
2020 | SLC51A | OSTα-OSTβ | PFIC 6 | Not reported |
Patient †/Gender/Origins | Age, PFIC Onset | Age, HBC Type and Liver Histology | Gene | Nucleotide Changes | Predicted Consequences | PMID |
---|---|---|---|---|---|---|
A/M/NEC | Cho from 3 wk | 21 mo (incidental in explant; AFP 199 ng), at LT | ABCB11 | c.1939delA/c.2012-8T>G | p.G648Vfs*6/splice site disruption | 16871584 |
B/F/NEC | Cho from 2 wk, hospitalized for evaluation aged 12 wk | 28 mo, at open biopsy; AFP not determined | ABCB11 | c.2178 + 1G>A/c.74C>A | Splice site disruption/p.S25* | 16871584 |
C/M/NEC | Cho from birth | 23 mo (AFP 30k ng; liver mass); histologic diagnosis at necropsy, 24 mo | ABCB11 | c.1445A>G/c.3691C>T | p.D482G/p.R1231W | 16871584 |
D/M/NEC | Cho from 3 wk | 22 mo (AFP 158k ng); liver mass; lung and bone lesions; chemotherapy given; histologic diagnosis at LT, 25 mo | ABCB11 | c.890A>G/c.890A>G | p.E297G/p.E297G | 16871584 |
E/M/NEC | Growth failure from 6 mo; diagnosed 9.5 mo | 29 mo (incidental in explant; AFP 6.4k ng), at LT | ABCB11 | c.611 + 1G>A/c.890A>G | Splice site disruption/p.E297G | 16871584 |
F/M/NEC | Cho from 6 wk | 16 mo (clinically unsuspected), at necropsy; AFP not determined | ABCB11 | c.908 + 1G>A/not known | Splice site disruption/not known | 16871584 |
G/F/A | Cho from 6 wk | 15 mo, HCC (AFP 11k ng); histologic diagnosis at LT, 16 mo | ABCB11 | c.1416T>A/c.1416T>A | p.Y472*/p.Y472* | 16871584 |
H/M/NEC | Evaluation at 6 mo for J and growth failure | 52 mo (marked increase in abdominal size; tumour metastasized at diagnosis; AFP 2 × 106 ng), at open biopsy | ABCB11 | c.890A>G/IVS13del-13ˆ-8 | p.E297G/splice site disruption | 16871584 |
I/M/CAC | Cho from birth | 13 mo (incidental in explant; AFP 831 ng), at LT | ABCB11 | c.2343 + 2T>C/c.2343 + 2T>C | Splice site disruption | 16871584 |
J/M/CAC | Cho from 1 wk | 14 mo (AFP 4k ng; liver mass), at biopsy; confirmed at LT, 15 mo | ABCB11 | c.2316T>G/c.2316T>G | p.Y772*/p.Y772* | 16871584 |
K/M/NEC | Cho from 3 mo | 26 mo; HCC metastasized at diagnosis (AFP not reported); at biopsy | ABCB11 | None sought | None predicted | 16871584 |
A/F/Hi | 2 mo | Giant cell hepatitis and mild portal-tract fibrosis, biliary Cir (3 years), CCA at 4/6/12 yrs | ABCB11 | c.1723C>T/12.5 Mb del | p.R575*/12.5 Mb del | 17452236 |
B/F/C | J and I in infancy | Giant cell hepatitis (2 mo), hepatic resection revealed advanced biliary Cir with left-lobe peripheral CCA | ABCB11 | c.890A>G/c.2343 + 1G>T | p.Q297G/splice site disruption | 17452236 |
1/-/CA-A * | ABCB11 | c.379delA/c.379delA | p.T127Hfs*6/p.T127Hfs*6 | 18395098 | ||
7/-/CA-A * | ABCB11 | c.3213 + 1delG/c.3213 + 1delG | Splice defect | 18395098 | ||
65 | ABCB11 | c.3382C>T/c.3382C>T | p.R1128C/p.R1128C | 18395098 | ||
45a/-/EU | ABCB11 | c.1238T>G/c.1238T>G | p.L413W/p.L413W | 18395098 | ||
45b/-/EU | ABCB11 | c.1238T>G/c.1238T>G | p.L413W/p.L413W | 18395098 | ||
47a/-/EU | ABCB11 | c.149T>C/c.149T>C | p.L50S/p.L50S | 18395098 | ||
47b/-/EU | ABCB11 | c.149T>C/c.149T>C | p.L50S/p.L50S | 18395098 | ||
83/-/EU | ABCB11 | c.937C>A/c.1445A>G | p.R313S/p.D482G | 18395098 | ||
105/-/EU | ABCB11 | c.1445A>G/not identified | p.D482G/not identified | 18395098 | ||
5a/-/- | 10 mo | 4 yrs; H, S, I, J, LF; trifocal HCC, AFP 931 ng | ABCB11 | Not reported | p.Y354*/p.G982R | 20232290 |
16/-/- | 1 mo | H, I, recurrent J, LF, AFP 1500 ng (17 mo) | ABCB11 | Not reported | p.R1231W/p.I528* | 20232290 |
24/-/- | 1 mo | H, S, permanent J, I, bifocal HCC, normal values of AFP (10 yrs), LF (12 yrs) | ABCB11 | Not reported | p.R1153C/c.3213 + 4A>G | 20232290 |
27/-/- | 3 wk | H, I, decreased J, AFP 5000 ng (10 yrs), HCC (1 nodule resected) | ABCB11 | Not reported | p.G982R/p.R1001R (predicted to affect splicing) | 20232290 |
32/-/- | 1 mo | H, pemanent J, I, HCC (2 nodules), AFP 3600 ng, LF (7 mo) | ABCB11 | Not reported | p.R698H/nf | 20232290 |
33/-/- | 1 wk | H, permanent J, DS, I AFP 124752 (2mo) and 19770 ng (5mo), no nodule, LF (4 mo) | ABCB11 | Not reported | p.R698H/nf | 20232290 |
1/F/- | P at the age of 8 mo | 8 mo | ABCB11 | Not reported | p.A389P/p.R1226H | 25016225 |
10/F/EU | 54 yrs | Periportal fibrosis, mild ductular reaction, steatosis, biliary dysplasia, CCA | ABCB4 | c.1005 + 5G>A/wt | Splicing/wt | 22331132 |
13/F/EU | 55 yrs | Biliary Cir, macronodule with well-differentiated HCC | ABCB4 | c.959C>T/wt | p.S320F/wt | 22331132 |
GWAS Icelandic population | <40 yrs | Liver, gallbladder and gallways cancer OR 2.42 | ABCB4 | c.1865G>A | p.G622E | 25807286 |
GWAS Icelandic population | <40 yrs | Liver, gallbladder and gallways cancer OR 3.07 | ABCB4 | c.1333_1334delCT | p.L445Gfs*22 | 25807286 |
GWAS Icelandic population | <40 yrs | Liver, gallbladder and gallways cancer OR 4.75 | ABCB4 | c.1529A>G | p.N510S | 25807286 |
GWAS Icelandic population | <40 yrs | Liver, gallbladder and gallways cancer OR 0.99 | ABCB4 | c.711A>T | p.I237= | 25807286 |
1/-/EU | LPAC | CCA diagnosed | ABCB4 | c.1405A>T/wt | p.R469W/wt | 32893960 |
2/-/EU | LPAC | CCA diagnosed | ABCB4 | c.1268A>C/wt | p.Q423P/wt | 32893960 |
3/-/EU | LPAC | HCC diagnosed | ABCB4 | c.760G>A/wt; c.1546A>G/wt; c.2363G>A/wt | p.A254T/wt; p.M516V/wt; p.R788Q/wt | 32893960 |
1/F/C | Neonatal onset, 26 mo | At liver biopsy moderately differentiated HCC in a chronic Cho with Cir | TJP2 | c.2668-1G>T/c.2438dupT | Splice defect/p.N814Qfs*28 | 25921221 |
2/M/C | Neonatal onset, 6 mo | Liver biopsy at 6 mo showed C, giant cell transformation, and micronodular Cir | TJP2 | c.817delG/c.817delG | p.A273Pfs*38/p.A273Pfs*38 | 25921221 |
1/F/- | 1 month | 7 yrs | TJP2 NM_001170416.1 | c.(2659 + 1_2660-1)_(2760 + 1_2761-1)del/c.(2659 + 1_2660-1)_(2760 + 1_2761-1)del | Skipping exon 18/skipping exon 18 | 28733884 |
P2.5/M/- | 20 yrs | 23 yrs | TJP2 | c.3334C>T/c.3334C>T | p.Q1112*/p.Q1112* | 32089630 |
1/M/- | ALGS at 13 wk of age | 3 yrs | JAG1 | De novo mutation of the protein-encoding JAG1-region of chr. 20 (not shown by the authors) | 20714715 | |
-/F/- | ALGS around age 35 yrs | JAG1 | c.693_694del state not specified | p.Arg231Serfs*10 | 33369123 | |
1/-/- | Cir, 1.5 y | JAG1 | c.551G>A/wt | p.R184H/wt | 32180165 | |
2/-/- | Cir, 2 yrs | NOTCH2 | c.5830G>A/c.5830G>A | p.G1944S/p.G1944S | 32180165 | |
1/F/Ja | CTLDN2; 40 yrs, after her first baby | 40 yrs | SLC25A13 | c.1180 + 1G>A/c.1180 + 1G>A | Splice site disruption | 14606711 |
1/M/- | No symptoms | 50 yrs, HCC and intrahepatic CCA | SLC25A13 | c.1180 + 1G>A/c.1180 + 1G>A | Splice site disruption | 18385606 |
1/M/T | CTLDN2; 34 yrs | HCC at 48 yrs | SLC25A13 | c.852_855del/c.852_855del | p.M285Pfs*2/p.M285Pfs*2 | 17000460 |
1/M/Ch | After birth | HCC at 6 yrs | SLC25A13 | c.852_855del/c.852_855del | p.M285Pfs*2/p.M285Pfs*2 | 30591617 |
1/M/- | After birth | HCC at 16 mo | HNF1B | 1.5 Mb deletion of chr. 17/wt | No protein/wt | 29727438 |
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Vitale, G.; Mattiaccio, A.; Conti, A.; Turco, L.; Seri, M.; Piscaglia, F.; Morelli, M.C. Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature. Cancers 2022, 14, 3421. https://doi.org/10.3390/cancers14143421
Vitale G, Mattiaccio A, Conti A, Turco L, Seri M, Piscaglia F, Morelli MC. Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature. Cancers. 2022; 14(14):3421. https://doi.org/10.3390/cancers14143421
Chicago/Turabian StyleVitale, Giovanni, Alessandro Mattiaccio, Amalia Conti, Laura Turco, Marco Seri, Fabio Piscaglia, and Maria Cristina Morelli. 2022. "Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature" Cancers 14, no. 14: 3421. https://doi.org/10.3390/cancers14143421