-
World Journal of Clinical Cases Jul 2022Neonatal hyperbilirubinemia is a common problem faced by pediatricians. The role of genetic factors in neonatal jaundice has been gradually recognized. This study aims...
BACKGROUND
Neonatal hyperbilirubinemia is a common problem faced by pediatricians. The role of genetic factors in neonatal jaundice has been gradually recognized. This study aims to identify genetic variants that influence the bilirubin level in five patients using next-generation sequencing (NGS).
CASE SUMMARY
Five neonates with severe hyperbilirubinemia were retrospectively studied. They exhibited bilirubin encephalopathy, hypothyroidism, ABO blood type incompatibility hemolysis, glucose-6-phosphate dehydrogenase () deficiency and premature birth, respectively. A customized 22-gene panel was designed, and NGS was carried out for these neonates. Eight variations ( c.G1388A, c.C369G, c.C3825G, c.G211A, c.A1729G, c.G520A, c.1213-4T>G and c.A1474G) were identified in these five neonates. Genetic mutations of these genes are associated with deficiency, thalassemia, Dubin-Johnson syndrome, Gilbert syndrome, hereditary spherocytosis, and hereditary elliptocytosis. One of the neonates was found to have compound variants of the splice site c.1213-4T>G and c.G520A (p.E174K), but no elliptocyte was seen on his blood smear of 4 years old.
CONCLUSION
Pathological factors of severe neonatal hyperbilirubinemia are complicated. Genetic variants may play an important role in an increased risk of neonatal hyperbilirubinemia, and severe jaundice in neonates may be related to a cumulative effect of genetic variants.
PubMed: 36051115
DOI: 10.12998/wjcc.v10.i20.6999 -
Experimental and Therapeutic Medicine Sep 2022Hereditary spherocytosis (HS) is an erythrocyte membrane disease with a non-specific phenotype, particularly occurring in neonatal patients, and its diagnosis is...
Hereditary spherocytosis (HS) is an erythrocyte membrane disease with a non-specific phenotype, particularly occurring in neonatal patients, and its diagnosis is challenging. The present study reports on a patient with neonatal HS and reviewed the genetic characteristics of reported neonatal HS cases in China. The patient was admitted only a few hours after birth with jaundice. Auxiliary examination indicated anemia and hyperbilirubinemia. Spherical erythrocytes were occasionally observed in peripheral blood smears. Genetic testing suggested that the patient harbored a novel frameshift mutation (p.Asp495fsTer78) in spectrum, β, erythrocytic (SPTB), which was carried by the father. Review of 160 cases of HS in China revealed 24 to be neonatal cases. In these neonatal cases, the frequency of ankyrin 1 (ANK1) mutations and loss-of-function mutations of pathogenic genes (including ANK1 and SPTB) was higher than that in the non-neonatal group. In conclusion, the present study further expanded the mutation spectrum of SPTB and reaffirms the diagnostic value of gene detection in neonatal HS.
PubMed: 35949318
DOI: 10.3892/etm.2022.11537 -
The Kaohsiung Journal of Medical... Aug 2022In the Asian general population, at least six single-nucleotide variants (SNVs) in the UDP-glucuronosyltransferase (UGT) 1A1 gene have been identified: -3279T>G,... (Review)
Review
In the Asian general population, at least six single-nucleotide variants (SNVs) in the UDP-glucuronosyltransferase (UGT) 1A1 gene have been identified: -3279T>G, -53A(TA) TAA>A(TA) TAA, 211G>A, 686C>A, 1091C>T, and 1456T>G. Each of these six SNVs was observed in at least four ethnic groups of the 12 Asian populations studied. In East Asian populations, the descending frequency of these six SNVs was as follows: -3279G>[-53A(TA) TAA, 211A]>(686A, 1091T)>1456G. Because of the presence of linkage disequilibrium and the expulsion phenomenon, when the SNVs -3279G, -53A(TA) TAA, 211A, and 686A were simultaneously involved, 15 instead of the estimated 81 genotypes were observed. Those carrying 686AA or 1456GG developed Gilbert's syndrome or Crigler-Najjar syndrome type 2. Both -53A(TA) TAA/A(TA) TAA and 211AA are the main causes of Gilbert's syndrome in East Asian populations. In East Asian populations, the 211AA genotype is the main cause of neonatal hyperbilirubinemia, whereas -53A(TA) TAA/A(TA) TAA exerts a protective effect on hyperbilirubinemia development in neonates fed with breast milk. Both 211A and -53A(TA) TAA are significantly associated with adverse drug reactions induced by irinotecan (one of the most widely used anticancer agents) in Asians. However, at least three common SNVs (-3279G, -53A(TA) TAA, and 211A) should be comprehensively analyzed. This study investigated the clinical significance of these six SNVs and demonstrated that examining UGT1A1 variants in Asian populations is considerably challenging.
Topics: Asian People; Bilirubin; Female; Genotype; Gilbert Disease; Glucuronosyltransferase; Humans; Infant, Newborn
PubMed: 35942604
DOI: 10.1002/kjm2.12579 -
BMC Pediatrics Aug 2022Glucose phosphate isomerase (GPI) deficiency is a rare autosomal recessive disorder that causes hereditary nonspherocytic hemolytic anemia (HNSHA). Homozygous or...
BACKGROUND
Glucose phosphate isomerase (GPI) deficiency is a rare autosomal recessive disorder that causes hereditary nonspherocytic hemolytic anemia (HNSHA). Homozygous or compound heterozygous mutation of the GPI gene on chromosome 19q13 is the cause of GPI deficiency. Fifty-seven GPI mutations have been reported at the molecular level.
CASE PRESENTATION
A 5-month-old boy was presented with repeated episodes of jaundice after birth. He suffered from moderate hemolytic anemia (hemoglobin levels ranging from 62 to 91 g/L) associated with macrocytosis, reticulocytosis, neutropenia, and hyperbilirubinemia. Whole-exome sequencing showed that he has a missense mutation c.301G > A (p.Val101Met) in exon 4 and a frameshift mutation c.812delG (p.Gly271Glufs*131) in exon 10. Mutation p.Gly271Glufs*131 is a novel frameshift null mutation in GPI deficiency.
CONCLUSION
In a patient with recurrent jaundice since birth, mutations in the GPI gene associated with HNSHA should be evaluated. The c.812delG (p.Gly271Glufs*131) variant may be a novel mutation of the GPI gene. Compound heterozygous mutations c.301G > A (p.Val101Met) and c.812delG (p.Gly271Glufs*131) are not relevant to neurological impairment.
Topics: Anemia, Hemolytic; Anemia, Hemolytic, Congenital Nonspherocytic; China; Glucose-6-Phosphate Isomerase; Homozygote; Humans; Infant; Male; Metabolism, Inborn Errors
PubMed: 35915427
DOI: 10.1186/s12887-022-03522-9 -
United European Gastroenterology Journal Sep 2022Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated... (Review)
Review
Bilirubin, a breakdown product of heme, is normally glucuronidated and excreted by the liver into bile. Failure of this system can lead to a buildup of conjugated bilirubin in the blood, resulting in jaundice. Hyperbilirubinemia is an important clinical sign that needs to be investigated under a stepwise evaluation. Inherited non-hemolytic conjugated hyperbilirubinemic conditions include Dubin-Johnson syndrome (caused by mutations affecting ABCC2 gene) and Rotor syndrome (caused by the simultaneous presence of mutations in SLCO1B1 and SLCO1B3 genes). Although classically viewed as benign conditions requiring no treatment, they lately gained an increased interest since recent studies suggested that mutations in the responsible genes leading to hyperbilirubinemia, as well as minor genetic variants, may result in an increased susceptibility to drug toxicity. This article provides a comprehensive review on the pathophysiology of Dubin-Johnson and Rotor syndromes, presenting the current knowledge concerning the molecular details and basis of these conditions.
Topics: Bilirubin; Heme; Humans; Hyperbilirubinemia; Hyperbilirubinemia, Hereditary; Jaundice, Chronic Idiopathic; Liver-Specific Organic Anion Transporter 1
PubMed: 35860851
DOI: 10.1002/ueg2.12279 -
Internal Medicine (Tokyo, Japan) Jan 2023Most patients with hereditary spherocytosis (HS) have a family history of disease, while those without such a history are difficult to diagnose. We herein report a case...
Most patients with hereditary spherocytosis (HS) have a family history of disease, while those without such a history are difficult to diagnose. We herein report a case of HS with no family history harboring a novel heterozygous mutation of SPTA1, c.2161G>A (p.E721K), and a homozygous polymorphism of UGT1A1*6. In silico analyses suggested that the mutation might contribute to the pathogenesis of HS. The coexistence of HS and Gilbert's syndrome increases the risk of gallstones. Therefore, splenectomy, alone or in combination with cholecystectomy, is recommended. The determination of genetic diathesis provides useful information for the management of hemolytic anemia.
Topics: Humans; Gilbert Disease; Mutation; Spherocytosis, Hereditary; Heterozygote; Glucuronosyltransferase; Polymorphism, Genetic; Cytoskeletal Proteins
PubMed: 35650129
DOI: 10.2169/internalmedicine.9478-22 -
The Application of Clinical Genetics 2022To explore the clinical value of newborn genomic screening (nGS) for neonatal intensive care units (NICU) infants (taking neonatal hyperbilirubinemia as an example).
OBJECTIVE
To explore the clinical value of newborn genomic screening (nGS) for neonatal intensive care units (NICU) infants (taking neonatal hyperbilirubinemia as an example).
METHODS
Dried blood spots (DBSs) were collected after 72 hours of birth. The tandem mass spectrometry (TMS) screening and Angel Care genomic screening (GS, based on Targeted next-generation sequencing) were performed at the same time.
RESULTS
Ninety-six hyperbilirubinemia newborns were enrolled in this study and none was identified with inborn errors of metabolism (IEM) by TMS, while 6 infants (6.25%, 6/96) were suspected to have a genetic disorder by Angel Care, including 2 cases of glucose-6-phosphate dehydrogenase deficiency (G6PD), and 1 case of maple syrup urine disease type 1B (MSUD1B), autosomal recessive deafness 1A (DFNB1A), Leber hereditary optic neuropathy (LHON), thyroid dyshormonogenesis 6 (TDH6) each. In addition, 44 infants (45.8%) were detected having at least one variant which conferred a carrier status for a recessive childhood-onset disorder. A total of 33 out of 60 variants (55.0%) reported for carrier status were pathogenic (P), 24 (40.0%) were likely pathogenic (LP), and 3 variants were variant of uncertain significance (VUS). Top six common genes of carrier status were . Two newborns showed abnormalities in elementary screening of TMS, but were confirmed as false positive after recall. Their results of Angel Care did not found abnormality.
CONCLUSION
Using neonatal hyperbilirubinemia as an example, genome sequencing screening can find more evidence of genetic variation in NICU newborns, and "Angel Care" is an effective method.
PubMed: 35611242
DOI: 10.2147/TACG.S362148 -
Journal of Clinical Laboratory Analysis Jun 2022Uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), which is the major UGT1 gene product, is located on chromosome 2q37. The expression of UGT1A1 is relatively...
BACKGROUND
Uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), which is the major UGT1 gene product, is located on chromosome 2q37. The expression of UGT1A1 is relatively managed by a polymorphic dinucleotide repeat inside the promoter TATA box consisting of 5-8 copies of a TA repeat. A (TA) 6TAA is considered as the wild type. The A (TA) 7TAA allele has been identified as the most frequent allele in the Caucasian populations while A (TA) 8TAA allele remains the rarest allele worldwide in North Africa, including the Arab populations.
METHODS
The spectrum of UGT1A1 genetic mutations in seventeen Tunisian children affected by persistent unconjugated hyperbilirubinemias is represented in addition to their relatives, notably parents, sisters, and brothers. Tunisian children, from 16 unrelated families as well as a 17 family without CN1 affected child, were originated from the West Center of Tunisia. The promoter region and coding exons of the UGT1A1 were PCR amplified, subsequently subjected to Sanger sequencing.
RESULTS
The frequencies of genotypes in CN1 patients were as follows (TA) (7/7) (12/17: 70.6%) and (TA) (8/8) (5/17: 29.4%). All patients harbored the c.1070A>G mutation of exon 3 (UGT1A1*16) in the homozygous state. Among relatives of our patients (n = 16), who were all heterozygotes for UGT1A1*16, 13/16 (81.25%) had a heterozygous state for UGT1A1∗1/UGT1A1∗28 or (TA) (6/7) and, 18.75% (3/16) were heterozygous for UGT1A1∗28/UGT1A1∗37 or (TA) (7/8) of the promoter polymorphisms.
CONCLUSION
UGT1A1*16 accompanied with UGT1A1*28 or UGT1A1*37 had a specific geographic and ethnic distribution for CN pathogenesis in this Tunisian cohort.
Topics: Child; Crigler-Najjar Syndrome; Exons; Genotype; Glucuronosyltransferase; Humans; Male; Mutation; Polymorphism, Genetic
PubMed: 35527687
DOI: 10.1002/jcla.24482 -
Italian Journal of Pediatrics Apr 2022Several mutations of bilirubin uridine diphosphate-glucuronosyltransferase gene (UGT1A1) have been reported in patients with unconjugated hyperbilirubinemia. Few reports...
BACKGROUND
Several mutations of bilirubin uridine diphosphate-glucuronosyltransferase gene (UGT1A1) have been reported in patients with unconjugated hyperbilirubinemia. Few reports are available about the p.Pro364Leu mutation (P364L, c.1091C > T) in homozygous newborns. We describe the clinical, laboratory and therapeutic approach in two Chinese neonates with severe jaundice, homozygous for the P364L mutation.
CASE PRESENTATION
Two Chinese breastfed female infants presented prolonged unconjugated hyperbilirubinemia at the age of 1 month. Total bilirubin was higher than 15 mg/dl (D < 1). An exhaustive etiological work-up to detect possible causes of hyperbilirubinemia (notably hemolytic ones) was negative. The promoter and coding regions of UGT1A1 were amplified by polymerase chain reaction (PCR) from genomic DNA isolated from leukocytes. Both patients resulted homozygous for a variant site within the coding region of the gene in the 4 exon, c.1091C > T, p.Pro364Leu. In front of the persistently high level of unconjugated bilirubin, phototherapy was performed without persistent results. A treatment with phenobarbital was then begun and bilirubin level progressively decreased, with a complete and persistent normalization. The therapy was stopped.
CONCLUSION
UGT1A1 enzyme activity associated with the P364L mutation has been described as 35.6% of the wild-type enzyme activity. Photo-therapy and phenobarbital can be useful in front of persistently high level of unconjugated bilirubin. Our cases presented high bilirubin values, overlapping between Gilbert syndrome (GS) and Crigler-Najjar syndrome type II (CNS), but the complete normalization of bilirubin makes GS more likely. Homozygous P364L variant can be associated with severe neonatal unconjugated hyperbilirubinemia in Chinese infants, but jaundice can completely resolve in a few months, contrary to what happens in Crigler-Najjar syndrome type II.
Topics: Bilirubin; Crigler-Najjar Syndrome; Female; Gilbert Disease; Glucuronosyltransferase; Humans; Hyperbilirubinemia; Hyperbilirubinemia, Neonatal; Infant; Infant, Newborn; Mutation; Phenobarbital
PubMed: 35436954
DOI: 10.1186/s13052-022-01251-4 -
Molecular Genetics & Genomic Medicine Jul 2022Genetic testing of UGT1A1 was used to facilitate the diagnosis of Gilbert syndrome, and analyze the distribution features of pathogenic variants in the Chinese...
BACKGROUND
Genetic testing of UGT1A1 was used to facilitate the diagnosis of Gilbert syndrome, and analyze the distribution features of pathogenic variants in the Chinese population.
METHODS
DNA was extracted from whole blood samples of patients with unconjugated hyperbilirubinemia, and sequencing of the UGT1A1 gene was performed after PCR amplification. After alignment with reference sequences, the known pathogenic variants were identified, the variant spectrum was analyzed, and the pathogenicity of novel variants was predicted using online mutation prediction tools.
RESULTS
A total of 117 patients were confirmed with Gilbert syndrome by UGT1A1 genetic diagnosis, where the most common pathogenic variants included promoter A(TA) TAA insertion and p.Gly71Arg missense variant. Following novel variants were also identified: p.Ala61Gly, p.Tyr67Phe, p.Leu166Alafs*16, p.Arg240Lys, p.Ser306Phe, p.Arg341Gln, and p.Glu424* variants.
CONCLUSIONS
Genetic testing of UGT1A1 in clinical practices could facilitate confirming Gilbert syndrome and performing differential diagnosis. The pathogenic variant spectrum in the Chinese population was similar to other Asian populations. The novel pathogenic variants identified in this study require further investigation.
Topics: Adolescent; Adult; Asian People; Bilirubin; Diagnosis, Differential; Female; Gilbert Disease; Glucuronosyltransferase; Humans; Male; Middle Aged; Pedigree; Protein Isoforms; Young Adult
PubMed: 35426266
DOI: 10.1002/mgg3.1958