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Journal of Pediatric Genetics Dec 2021In this article, we reported a patient with Crigler-Najjar syndrome type II with high-unconjugated bilirubin levels that decreased after phenobarbital treatment. The...
In this article, we reported a patient with Crigler-Najjar syndrome type II with high-unconjugated bilirubin levels that decreased after phenobarbital treatment. The patient had two novel missense mutations in the gene and a promoter variant in one allele. One mutation was c.1001T > C, that predicted leucine to proline substitution at position 334 (p.Leu334Pro). The other, c.1139A > G, predicted glutamic acid to glycine replacement at position 380 (p.Glu380Gly). In silico analysis indicated that both mutations are likely pathogenic.
PubMed: 34849280
DOI: 10.1055/s-0040-1714361 -
World Journal of Clinical Cases May 2020Both Gilbert's syndrome (GS) and hereditary spherocytosis (HS) are common genetic disorders. However, comorbidity of GS with HS has always been considered a rare...
BACKGROUND
Both Gilbert's syndrome (GS) and hereditary spherocytosis (HS) are common genetic disorders. However, comorbidity of GS with HS has always been considered a rare phenomenon, and it can impede accurate diagnoses in the presence of isolated unconjugated hyperbilirubinemia.
CASE SUMMARY
In a study on Levitt's carbon monoxide (CO) breath test for the differential diagnosis of isolated hyperbilirubinemia, we found six GS patients with HS in 6 mo. The patients, including five males and one female, aged 25-58 years, were from four families and generally in good health. Their chronic fluctuating jaundice and/or hyperbilirubinemia had been diagnosed as simple constitutional jaundice for 6-30 years. Liver function tests showed isolated unconjugated hyperbilirubinemia with serum total bilirubin ranging from 20.7-75.4 μmol/L. Blood hemoglobin was normal in five cases, and slightly decreased in one (11.5 g/dL). Overt hemolytic signs were absent, while erythrocyte lifespan determined by the newly developed Levitt's CO breath test was significantly short (15-50 d), definitely demonstrating the presence of hemolysis. Given that their unconjugated hyperbilirubinemia compared inappropriately with hemolytic severity, as indicated by the hemoglobin level, further combined genetic tests for both and hereditary erythrocyte deficiencies were conducted. These tests confirmed, at last, the coexistence of GS with HS.
CONCLUSION
Comorbidity of GS and HS might not be uncommon in isolated unconjugated hyperbilirubinemia. While CO breath test would sensitively detect the hemolysis, the discordance between the hyperbilirubinemia and hemoglobin level could strongly indicate the coexistence of GS and HS.
PubMed: 32518793
DOI: 10.12998/wjcc.v8.i10.2001 -
Scientific Reports May 2020UDP-glucuronosyltransferases 1 A (UGT1A) enzymes are capable of detoxifying a broad range of endo- and xenobiotic compounds, which contributes to antioxidative...
UDP-glucuronosyltransferases 1 A (UGT1A) enzymes are capable of detoxifying a broad range of endo- and xenobiotic compounds, which contributes to antioxidative effects, modulation of inflammation and cytoprotection. In the presence of low-function genetic UGT1A variants fibrosis development is increased in various diseases. This study aimed to examine the role of common UGT1A polymorphisms in NASH. Therefore, htgUGT1A-WT mice and htgUGT1A-SNP mice (carrying a common human haplotype present in 10% of the white population) were fed a high-fat Paigen diet for 24 weeks. Serum aminotransferase activities, hepatic triglycerides, fibrosis development and UGT1A expression were assessed. Microscopic examination revealed higher hepatic fat deposition and a significant induction of UGT1A gene expression in htgUGT1A-WT mice. In agreement with these observations, lower serum aminotransferase activities and lower expression levels of fibrosis-related genes were measured in htgUGT1A-SNP mice. This was accompanied by reduced PPARα protein levels in htgUGT1A-WT but not in SNP mice. Our data demonstrate a protective effect of a UGT1A SNP haplotype, leading to milder hepatic steatosis and NASH. Higher PPARα protein levels in animals with impaired UGT1A activity are the likely result of reduced glucuronidation of ligands involved in PPARα-mediated fatty acid oxidation and may lead to the observed protection in htgUGT1A-SNP mice.
Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Diet, High-Fat; Fibrosis; Gilbert Disease; Glucuronosyltransferase; Haplotypes; Humans; Liver; Mice; Mice, Inbred C57BL; Mice, Transgenic; Non-alcoholic Fatty Liver Disease; PPAR alpha; Polymorphism, Single Nucleotide; Protein Isoforms; Triglycerides
PubMed: 32457304
DOI: 10.1038/s41598-020-65481-4 -
Cureus Mar 2020We describe a case of hereditary spherocytosis in a neonate with pyloric stenosis requiring laparoscopic pyloromyotomy. Hereditary spherocytosis is the most commonly...
We describe a case of hereditary spherocytosis in a neonate with pyloric stenosis requiring laparoscopic pyloromyotomy. Hereditary spherocytosis is the most commonly inherited hemolytic anemia causing hyperbilirubinemia and mild anemia. Anesthetic management for laparoscopic pyloromyotomy is challenging. Multiple factors involved, such as anemia, hyperbilirubinemia, and the effect of drugs, play an important role in anesthetic management.
PubMed: 32300497
DOI: 10.7759/cureus.7277 -
Molecular Syndromology Feb 2020Heterozygous pathogenic variants in cause autosomal dominant hereditary spherocytosis, an important cause of neonatal nonimmune hemolytic anemia. Biallelic mutations...
Heterozygous pathogenic variants in cause autosomal dominant hereditary spherocytosis, an important cause of neonatal nonimmune hemolytic anemia. Biallelic mutations are rarely reported, all with severe neonatal presentation. We describe rapid (68 h) genomic diagnosis of homozygous β-spectrin deficiency in a newborn with severe transfusion-dependent hemolytic anemia, conjugated hyperbilirubinemia, and progressive liver failure. Trio whole-exome sequencing identified a novel biallelic variant (c.6119C>T; p.Thr2040Ile) located in the critical spectrin repeat region. Pretransfusion blood film showed marked spherocytosis including microspherocytes and nucleated erythrocytes, and eosin-5-maleimide (E5M) staining was markedly reduced, supporting pathogenicity. Both asymptomatic heterozygous parents demonstrated mildly reduced E5M staining, with occasional spherocytes and elliptocytes. Early molecular diagnosis facilitated hypertransfusion to suppress ineffective erythropoiesis and reverse hepatic dysfunction. This report broadens the genotypic and phenotypic spectrum of spectrin deficiency and highlights the utility of rapid genomic testing in facilitating early diagnosis and informing targeted therapy in critically ill patients.
PubMed: 32256302
DOI: 10.1159/000505886 -
Frontiers in Genetics 2020A large fraction of DNA variants impairs pre-mRNA splicing in human hereditary disorders. Crigler-Najjar syndrome (CNS) is characterized by a severe unconjugated...
A large fraction of DNA variants impairs pre-mRNA splicing in human hereditary disorders. Crigler-Najjar syndrome (CNS) is characterized by a severe unconjugated hyperbilirubinemia caused by variants in the gene. We previously reported one CNS-type II patient with two splice-site variants in trans (c.864+5G>T and c.996+2_996+5del). According to MaxEntScan, both disrupt their corresponding donor sites (c.864+5G>T: 6.99 → 2.28; c.996+2_996+5del: 5.96 → -11.02), so they were selected for subsequent functional tests. Given the unavailability of patient RNA, we constructed an splicing-reporter minigene with exons 1-4 to characterize the underlying splicing anomaly. The variant c.996+2_996+5del generated two aberrant transcripts, Δ(E2) (exon 2 skipping/64%) and ▼(E2q135) (intron retention of 135-nt/36%), which lead to the loss of 18 conserved amino-acids and the gain of 45 new ones of a critical functional domain, respectively. The c.864+5G>T variant mainly produced the aberrant transcript Δ(E1q141) (141-nt deletion/70.4%) and the full-length isoform (29.6%). Δ(E1q141) would provoke the loss of 47 amino-acids of the N-terminal domain that encodes for substrate specificity. Thus, the three anomalous transcripts are likely to inactivate . Moreover, this patient is also homozygous for the promoter variant A(TA)7TAA that decreases expression by 70%, so the full-length transcript produced by c.864+5G>T would be even more reduced (<9%), thus supporting the diagnosis of CNS-type II. Therefore, minigenes represent valuable tools for the functional and clinical classifications of genetic variants.
PubMed: 32211025
DOI: 10.3389/fgene.2020.00169 -
Orphanet Journal of Rare Diseases Mar 2020Dubin-Johnson syndrome (DJS) is a rare autosomal recessive disorder characterized by predominantly conjugated hyperbilirubinemia that is caused by pathogenic mutations...
BACKGROUND
Dubin-Johnson syndrome (DJS) is a rare autosomal recessive disorder characterized by predominantly conjugated hyperbilirubinemia that is caused by pathogenic mutations in the adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2) gene, which encodes multidrug resistance-associated protein 2 (MRP2). However, little is known about the causative mutation of DJS in China. Recently, we have reported ABCC2 p.G693R mutation in two unrelated cases. In the present study, we investigated the pathogenicity of the ABCC2 p.G693R mutation in DJS in China.
METHODS
Clinical and genetic analysis was conducted for the two patients with the ABCC2 p.G693R mutation. Whole exome sequencing for mutations in other known hyperbilirubinemia-related genes was conducted for the cases with ABCC2 p.G693R. Expression and cellular localization of the mutant MRP2 p.G693R were analyzed by Western blotting and immunofluorescence assay, respectively. Organic anion transport activity was evaluated by the analysis of glutathione-conjugated-monochlorobimane.
RESULTS
The two DJS patients with ABCC2 p.G693R mutation, which was conserved among different species, showed typical hyperbilirubinemia phenotype. No pathogenic mutation was identified in the other known hyperbilirubinemia related genes. Functional studies in three cell lines showed that the expression, localization and the organic anion transport activity were significantly compromised by MRP2 p.G693R mutation compared with wild-type MRP2.
CONCLUSIONS
The recurrent ABCC2 p.G693R mutation is associated with loss of function of the MRP2 protein and may result in hyperbilirubinemia in DJS in China.
Topics: China; Humans; Hyperbilirubinemia; Jaundice, Chronic Idiopathic; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Mutation
PubMed: 32183854
DOI: 10.1186/s13023-020-1346-4 -
Molecular Genetics & Genomic Medicine May 2020Congenital dyserythropoiesis anemia type Ia (OMIM:224120), is a rare hereditary anemia. The diagnosis is difficult to make and usually delayed in part due to its rarity...
BACKGROUND
Congenital dyserythropoiesis anemia type Ia (OMIM:224120), is a rare hereditary anemia. The diagnosis is difficult to make and usually delayed in part due to its rarity and nonspecific clinical manifestations.
METHODS
Whole exome sequencing was applied for the genetic diagnosis of a 12-year-old boy who has suffered from hemolytic anemia since birth and who requires regular transfusions. Sanger sequencing of the variants detected in whole exome sequencing was performed in the patient and his parents.
RESULTS
Compound heterozygous mutations of CDAN1 gene, including one previously reported and one novel mutation, which is a splicing change, were detected in the whole exome sequencing and confirmed by Sanger sequencing. The autosomal recessive inheritance was confirmed by pedigree analysis.
CONCLUSION
To our knowledge, this is the first case report of congenital dyserythropoiesis anemia type Ia with genetic diagnosis to be located in Taiwan. Because of the rarity of CDA Ia and the overlapping of the clinical manifestations with other hereditary anemias, the next-generation sequencing approach is effective for conclusive diagnosis of CDA Ia.
Topics: Anemia; Child; Erythrocytes, Abnormal; Genes, Recessive; Glycoproteins; Humans; Male; Mutation; Nuclear Proteins; Exome Sequencing
PubMed: 32160409
DOI: 10.1002/mgg3.1220 -
BMC Gastroenterology Mar 2020Crigler Najjar type 1 is a rare autosomal recessive condition caused by the absence of UDPGT enzyme due to mutations in the UGT1A1 gene. This enzyme is responsible for...
BACKGROUND
Crigler Najjar type 1 is a rare autosomal recessive condition caused by the absence of UDPGT enzyme due to mutations in the UGT1A1 gene. This enzyme is responsible for elimination of unconjugated bilirubin from the body by glucuronidation. Affected individuals are at risk for kernicterus and require lifelong phototherapy. Liver transplant is the only definitive treatment.
CASE PRESENTATION
Here we report a case of a 6 month old Sudanese female infant with CN1 whose molecular analysis revealed a novel homozygous 22 base pair duplication (c.55_76dup) in the coding exon 1 of the UGT1A1 gene. This 22 bp duplication causes a frame shift leading to a premature stop codon. She underwent a successful liver transplant at 7 months of age and is doing well at 1 year follow-up.
CONCLUSION
This study shows that molecular diagnosis helps in precise diagnosis of CN1 and in prognosis, prompt medical intervention and appropriate therapy. This particular 22 bp duplication within the coding region of UGT1A1 can be a founder mutation in the Sudanese population.
Topics: Consanguinity; Crigler-Najjar Syndrome; Exons; Female; Gene Duplication; Glucuronosyltransferase; Humans; Infant; Liver Transplantation; Pedigree; Sudan
PubMed: 32143638
DOI: 10.1186/s12876-020-01192-4