Variants in ATP8B1, ABCB11, and ABCB4 underlie the most prevalent forms of progressive familial intrahepatic cholestasis. We aim to describe variants in these genes in a cohort of patients with ...adult‐onset liver disease, and explore a genotype–phenotype correlation. Patients with onset of liver disease aged above 18 who underwent sequencing of cholestasis genes for clinical purposes over a 5‐year period were identified. Bioinformatic analysis of variants was performed. Liver histology was evaluated in patients with variants. Of the 356 patients tested, at least one variant was identified in 101 (28.4%): 46 ABCB4, 35 ABCB11, and 28 ATP8B1. Patients with ABCB4 variants had chronic liver disease (71.7%) and pregnancy‐associated liver dysfunction (75%), with a younger age of onset in more severe genotypes (p = 0.046). ABCB11 variants presented with pregnancy‐associated liver dysfunction (82.4%) and acute/episodic cholestasis (40%), with no association between age of onset and genotype severity. ATP8B1 variants were associated with chronic liver disease (75%); however, they were commonly seen in patients with an alternate etiology of liver disease and variants were of low predicted pathogenicity. In adults with suspected genetic cholestasis, variants in cholestasis genes were frequently identified and were likely to contribute to the development of liver disease, particularly ABCB4 and ABCB11. Variants were often in heterozygous state, and they should no longer be considered recessive Mendelian traits. Sequencing cholestasis genes in selected patients with adult‐onset disease should be considered, with interpretation in close collaboration with histopathologists and geneticists.
Variants in cholestasis genes were found in patients with adult‐onset liver disease. ABCB4 variants are associated with chronic biliary disease, variants in ABCB11 are seen in patients with acute cholestasis, and the clinical significance of ATP8B1 variants is not clear.
Mutations in the transaldolase 1 (TALDO1) gene have been described in a limited number of cases. Several organs can be affected and clinical manifestations are variable, but often include liver ...dysfunction and/or hepatosplenomegaly. We report 4 patients presenting with liver disease: 2 with early‐onset hepatocellular carcinoma (HCC). Patients with cholestasis and mutations in TALDO1 were identified by next‐generation sequencing. Clinical, laboratory, and histological data were collected. Four (1 male) patients were identified with variants predicted to be damaging in TALDO1. Three patients were homozygous (two protein truncating/one missense mutations), 1 one was compound heterozygous (two missense mutations). Median age at presentation was 4 months (range, 2‐210 days) with jaundice (3), hepatosplenomegaly (3), and pancytopaenia (1). The diagnosis was corroborated by detection of minimal transaldolase enzyme activity in skin fibroblasts in two cases and raised urine polyols in the third. Three patients underwent liver transplantation (LT), 2 of whom had confirmed HCC on explanted liver. One patient suddenly died shortly after LT. The nontransplanted case has a chronic liver disease with multiple dysplastic liver nodules, but normal liver biochemistry and alpha‐fetoprotein. Median follow‐up was 4 years (range, 1‐21). Conclusion: Transaldolase deficiency can include early‐onset normal gamma‐glutamyltransferase liver disease with multisystem involvement and variable progression. Patients with this disease are at risk of early‐onset HCC and may require early LT.
Wilson disease (WD) is caused by biallelic pathogenic variants in adenosine triphosphatase copper‐transporting beta (ATP7B); however, genetic testing identifies only one or no pathogenic ATP7B ...variant in a number of patients with WD. Synonymous single‐nucleotide sequence variants have been recognized as pathogenic in individual families. The aim of the present study was to evaluate the prevalence and disease mechanism of the synonymous variant c.2292C>T (p.Phe764=) in WD. A cohort of 280 patients with WD heterozygous for a single ATP7B variant was investigated for the presence of c.2292C>T (p.Phe764=). In this cohort of otherwise genetically unexplained WD, the allele frequency of c.2292C>T (p.Phe764=) was 2.5% (14 of 560) compared to 7.1 × 10−6 in the general population (2 of 280,964 in the Genome Aggregation Database; p < 10−5; Fisher exact test). In an independent United Kingdom (UK) cohort, 2 patients with WD homozygous for p.Phe764= were identified. RNA analysis of ATP7B transcripts from patients homozygous or heterozygous for c.2292C>T and control fibroblasts showed that this variant caused high expression of an ATP7B transcript variant lacking exon 8. Conclusion: The synonymous ATP7B variant c.2292C>T (p.Phe764=) causes abnormal messenger RNA processing of ATP7B transcripts and is associated with WD in compound heterozygotes and homozygotes.
Wilson disease is caused by recessive pathogenic variants in ATP7B. In a subgroup of patients no or only one genetic defect can be identified. The present study shows that one in 100 patients with WD have a synonymous (silent) genetic variant, which had not been previously recognized as disease‐causing. This variant causes alternative splicing resulting, predicted to result in an in‐frame deletion of 78 residues of the ATP7B protein.
Although a good genotype-phenotype correlation has not been established in Wilson disease (WD), patients with loss-of-function (LOF) ATP7B variants demonstrate different clinical and biochemical ...characteristics. We aim to describe long-term treatment outcomes in the chronic liver disease (CLD) phenotype and evaluate an association with LOF variants.
This was a single-center retrospective review of WD patients with at least 1 variant in ATP7B. Demographic, biochemical, genetic, and clinical parameters were obtained. The composite clinical endpoint of liver transplantation or death was used for probands with CLD phenotype on chelators.
Of 117 patients with hepatic WD: 71 had CLD, 27 had fulminant hepatic failure requiring urgent liver transplantation, and 19 were diagnosed through family screening. Median age at diagnosis was 13.1 (interquartile range, 9.7–17.6) years. In total, 91 variants in ATP7B were identified in the study population. At least 1 LOF variant was present in 60 (51.3%) patients. During median follow-up of 10.7 (interquartile range, 6.7–18.9) years, 10 (14.1%) of the probands with CLD reached the composite endpoint. There was a worse transplant-free survival for patients prescribed chelation therapy in patients with at least 1 LOF variant (P = .03).
Patients with WD and CLD phenotype on chelators, who have at least 1 LOF variant in ATP7B, have a worse prognosis during long-term follow up. This subgroup of patients requires close monitoring for signs of progressive liver disease. Sequencing of ATP7B may be used in the diagnosis of WD, and in addition, it may provide useful prognostic information for patients with hepatic WD.
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Cholestasis Due to USP53 Deficiency Bull, Laura N.; Ellmers, Rebecca; Foskett, Pierre ...
Journal of pediatric gastroenterology and nutrition,
20/May , Letnik:
72, Številka:
5
Journal Article
Recenzirano
Odprti dostop
ABSTRACT
Objectives:
Although a number of genetic forms of cholestasis have been identified, the genetic etiology of disease remains unidentified in a subset of cholestasis patients.
Methods:
Whole ...exome sequencing (WES) was performed in DNA from patients diagnosed with cholestasis, at different points on the continuum from progressive familial intrahepatic cholestasis to benign recurrent intrahepatic cholestasis, in whom no disease mutations in known cholestasis genes had been identified. Candidate genes were then assessed in a larger patient sample, by targeted next‐generation sequencing (NGS). Disease features at presentation and follow‐up were collected from available medical records.
Results:
By WES, we identified 3 patients with homozygous mutations in USP53. Screening of USP53 in a larger set of patients identified 4 additional patients with homozygous mutations in USP53. Six of the 7 patients had deletion mutations, and 1 had a missense mutation; 3 of the patients were siblings, all bearing a deletion that also disrupted neighboring MYOZ2. Age of onset ranged from early infancy to adolescence. Cholestasis tended to be biochemically mild and intermittent, and responsive to medication. Liver fibrosis was, however, present in all 4 patients who were biopsied, and splenomegaly was apparent in 5 of 7 at last ultrasound.
Conclusions:
Two groups recently identified patients with liver disease and mutation in USP53. We have now identified biallelic mutation in USP53 in 7 further patients with cholestasis, from 5 families. Most individuals had evidence of chronic liver disease, and long‐term follow‐up is recommended.
Summary
Targeted therapy for chronic myeloid leukaemia (CML) has allowed for a near‐normal patient life‐expectancy; however, quality of life and aggravation of existing co‐morbidities have posed new ...treatment challenges. In clinical practice, TKI dose reduction occurs frequently, often on multiple occasions, because of intolerance. We conducted a retrospective ‘real‐world practice’ review of 246 patients receiving lower than standard dose (LD) TKI after the achievement of major molecular response (MR3), because of intolerable adverse events. In 274 of 298 cases of dose reduction (91·9%), MR3 was maintained at median follow‐up of 27·3 months. One patient progressed to blast crisis while on LD TKI. Two patients developed two new ABL kinase domain mutations (T315I and V299L), of whom one had achieved deep molecular response on an alternative LD TKI at last follow‐up. Seventy‐six patients eventually discontinued LD TKI and the two‐year treatment‐free remission (TFR) rate in these patients was 74·1%. The majority of patients with CML in at least MR3 appear to be safely managed with LD TKI, although three of 246 patients had new events (progression and new mutation), indicating that this approach requires vigilance. TKI LD does not prevent the achievement of TFR in this patient population.
Aims
Both homozygous and heterozygous α1‐antitrypsin (AAT) deficiency patients are at risk of developing hepatocellular carcinoma (HCC), but also of developing cholangiocarcinoma and combined HCC and ...cholangiocarcinoma. The aim of our study is to report a series of bile duct adenomas (BDAs) and intrahepatic cholangiocarcinoma (ICCs) in adult AAT deficiency patients, observed in our institution over a 5‐year period. Our observational study includes a detailed investigation of their immunohistochemical profile and BRAF V600E mutation status.
Methods and results
Eleven biliary lesions from five AAT deficiency patients (six BDAs from three cirrhotic patients with other concurrent liver diseases; three BDAs and two ICCs from two non‐cirrhotic patients) were identified between 2010 and 2015 during routine histological investigation. Most BDAs expressed CD56, EpCAM, CD133, and CA19‐9, similarly to hepatic progenitor cells (HPCs), and carried the BRAF V600E mutation (87.5%). One ICC showed a similar immunohistochemical profile but no evidence of the BRAF V600E mutation.
Conclusions
Most of the biliary proliferations in AAT deficiency patients have an appearance of BDA with an HPC‐related immunohistochemical profile. Their frequent BRAF V600E mutations support their neoplastic nature, but not necessarily their progression to ICC. We believe that this may depend on the patient genotype, or require a different pathway or a second mutational hit for malignant transformation. We postulate that BDA represents a heterogeneous group of biliary lesions, and that those associated with AAT deficiency may constitute a group of their own.
An 18-year-old man underwent liver transplantation due to an Abernethy malformation associated with multiple hepatocellular nodules including one which was rapidly enlarging and was suspicious for ...malignant transformation. Analysis of the explanted liver showed a spectrum of multiple hepatocellular nodules ranging in appearance from focal nodular hyperplasia, hepatocellular adenoma and to a well-differentiated hepatocellular neoplasm borderline for hepatocellular carcinoma. Mutational analysis revealed wild-type β-catenin expression in the background liver and some nodules, whilst different variants were present in other lesions irrespective of their morphological appearance. No telomerase reverse transcriptase (TERT) promoter mutation was identified. Abernethy malformations can lead to independent genetic events which can result in β-catenin mutations associated with malignant transformation of hepatocellular nodules. When following up such patients, one must therefore have a high index of suspicion, particularly if radiological surveillance reveals a change in the nature of hepatic lesions.
To use next generation sequencing (NGS) technology to identify undiagnosed, monogenic diseases in a cohort of children who suffered from acute liver failure (ALF) without an identifiable etiology.
We ...identified 148 under 10 years of age admitted to King's College Hospital, London, with ALF of indeterminate etiology between 2000 and 2018. A custom NGS panel of 64 candidate genes known to cause ALF and/or metabolic liver disease was constructed. Targeted sequencing was carried out on 41 children in whom DNA samples were available. Trio exome sequencing was performed on 4 children admitted during 2019. A comparison of the clinical characteristics of those identified with biallelic variants against those without biallelic variants was then made.
Homozygous and compound heterozygous variants were identified in 8 out of 41 children (20%) and 4 out of 4 children (100%) in whom targeted and exome sequencing were carried out, respectively. The genes involved were NBAS (3 children); DLD (2 children); and CPT1A, FAH, LARS1, MPV17, NPC1, POLG, SUCLG1, and TWINK (1 each). The 12 children who were identified with biallelic variants were younger at presentation and more likely to die in comparison with those who did not: median age at presentation of 3 months and 30 months and survival rate 75% and 97%, respectively.
NGS was successful in identifying several specific etiologies of ALF. Variants in NBAS and mitochondrial DNA maintenance genes were the most common findings. In the future, a rapid sequencing NGS workflow could help in reaching a timely diagnosis and facilitate clinical decision making in children with ALF.
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