Comprehensive analysis of gene mutation in neonatal hyperbilirubinemia caused by inherited diseases

doi:10.21203/rs.3.rs-4845629/v1

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Comprehensive analysis of gene mutation in neonatal hyperbilirubinemia caused by inherited diseases

https://doi.org/10.21203/rs.3.rs-4845629/v1

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We performed this study to explore the characteristics of genetic mutations associated with NH and analyze the correlation with genetic diseases. One hundred and five patients with NH were obtained between September 2020 and June 2023 from the second Affiliated Hospital of Xiamen Medical College. We analyzed gene mutations in NH caused by inherited diseases by a 25-gene panel. Seventeen frequently mutated genes were found in the 105 patients. UGT1A1 variants were identified among the 71 cases of neonatal Gilbert syndrome. In these patients with sodium taurocholate cotransporting polypeptide (NTCP) deficiency, the primary mutation identified is SLC10A1. ATP7B mutations primarily occur in patients with hepatolenticular degeneration (Wilson's disease). In addition, we found UGT1A1 and G6PD mutations were higher in the high-risk group than low-risk group, while mutations in SLC10A1, ATP7B, and SLC25A13 were more common in the low-risk group.

Conclusions: Gene mutations are significantly associated with NH. This study not only contributes to a deeper understanding of the pathogenesis of NH, but also provides new ideas for its prevention, diagnosis and treatment.

Hyperbilirubinemia

Gene mutation

Neonates

Genetic polymorphisms

NH is one of the most common clinical issues in newborns, with an incidence as high as 60% in healthy full-term infants [1, 2]. Most cases are physiological and mild, often not requiring treatment. However, it can also be associated with certain underlying conditions. Severe cases can lead to bilirubin encephalopathy without timely treatment, resulting in intellectual impairment, damage to the nervous and auditory systems, and even death[3].

The etiology of NH is complex and different cases of hyperbilirubinemia can have single or mixed causes. Known pathogenic factors include ABO or Rh blood group incompatibility, infections, and delayed meconium passage[4–6]. However, there are also cases where the cause of jaundice is unclear. For cases of NH with unknown causes, identifying the underlying etiology is crucial for timely diagnosis and effective treatment. In some instances, abnormally elevated bilirubin levels may indicate underlying genetic factors, where genetic mutations may play a crucial role[7, 8].

Some studies have shown that several genetic disorders can lead to hyperbilirubinemia, including Dubin-Johnson syndrome (DJS), Crigler-Najjar syndrome, Gilbert syndrome, and Lucey-Driscoll syndrome[9]. With the advancement of genetic testing technologies, the crucial role of genetic mutations in the occurrence of NH is increasingly recognized. Gilbert syndrome is a common genetic disorder characterized by elevated levels of bilirubin in the blood(10). Its main feature is mutations in the UGT1A1 gene, which is involved in bilirubin metabolism. Research has indicated that mutations in the UGT1A1 gene lead to decreased bilirubin metabolism capacity, thereby increasing the risk of NH[11]. Crigler-Najjar syndrome is a rare but severe genetic disorder characterized by high levels of bilirubin in the blood. Its etiology is also associated with mutations in the UGT1A1 gene[12]. In addition, there are other genetic mutations related to bilirubin metabolism that are associated with NH, such as SLCO1B1, SLC25A13, and BLVRA[13–15]. These findings indicate that genetic mutations play a significant role in the pathogenesis of NH, providing important clues for a deeper understanding of the genetic basis and pathological mechanisms of this disease. However, previous studies have mainly focused on exploring the correlation between specific gene variants and patients with hyperbilirubinemia, lacking systematic exploration of the association between more unknown genes and NH in large-scale populations.

Given the potential complexity and clinical significance of NH, a thorough understanding of the associated genetic mutations is crucial for elucidating the genetic basis of this condition, guiding clinical diagnosis, and formulating individualized treatment. Therefore, this study aims to comprehensively explore genetic mutations associated with NH and investigate the correlation between these mutations and the pathogenesis of the disease. These results will provide a foundation for future clinical practice and genetic counseling, offering a deeper understanding and guidance for the prevention and treatment of NH.

Study population and data collection

This study enrolled 105 newborn patients diagnosed with hyperbilirubinemia, with or without a family history, between September 2020 and June 2023 from the Second Affiliated Hospital of Xiamen Medical College. The Whole blood samples were collected from all patients and stored at -20°C for genetic sequencing. The study was conducted in accordance with the Helsinki Declaration and approved by the Clinical Research Ethics Committee of the Second Affiliated Hospital of Xiamen Medical College (Approval No: 2020039). The informed consent was obtained from all legal guardians of the study participants.

Targeted Panel Sequencing and Genetic analysis

Targeted panel sequencing of 24 genes including ABCB11, ABCC2, ABCD3, ACOX2, ATP7B, UGT1A1, CYP7B1, G6PD, HBB, HSD3B7, JAG1, NPC1, NPC2, NOTCH2, SMPD1, GBA, ABCB4, TJP2, NR1H4, AMACR, AKR1D1, ATP8B1, SLC10A1, SLC25A13, and SMPD1 was performed on each patient. Genomic DNA was extracted from whole-blood samples using a QIAamp DNA Blood Mini Kit (Qiagen) according to the manufacturer’s protocol. Genomic DNA fragments were enriched for targeted panel sequencing (Agilent ClearSeq Inherited Disease Kit; Agilent). DNA libraries after the enrichment underwent next-generation sequencing (Illumina HiSeq 2000/2500 platform). Sequencing data were first processed to remove low-quality reads and adapter sequences. The Burrows-Wheeler Aligner (BWA) software was then used to align the sequencing reads to the human reference genome (version hg19). Subsequently, the GATK software was employed to identify single nucleotide variants (SNVs) and insertions/deletions (INDELs) within the aligned reads. Annotation analysis was conducted using databases including the 1000 Genomes Project, ExAC, gnomAD, ClinVar, HGMD Professional, and local databases.

Statistical analysis

SPSS 20.0 was used for data analysis. The continuous variables in the data group were expressed as mean ± SD. Count data was described by frequency and percentage. The Pearson chi-square test was used, and P < 0.05 was considered as statistically significant.

General clinical characteristics

A total of 105 newborns with hyperbilirubinemia (38 males and 43 females) were collected in this study, 105 newborns had severe hyperbilirubinemia (32.20%, 128/149) (Table 1). In these patients, birth weight was 2.01 ~ 4.10 kg, with an average of 3.25kg ± 0.82kg, and gestational age was 36-41wk, with an average of 38 ± 2 wk; The occurrence of hyperbilirubinemia ranged from 1 day to 60 days, with an average of 16.5 days. There were 87 preterm infants, 9 were full-term infants, and 9 were of unknown status. 73 cases were full breastfeeding, 24 cases were mixed feeding and 8 cases were unknown. The peak value of total serum bilirubin (TSB) was 14.8-722.39 µmol/L, with an average of 398.07 ± 55.09 µmol/L. Among these 105 patients, 14 had TSB levels of less than 200 µmol/L, 25 patients had levels between 200 µmol/L and 300µmol/L, and 37 patients had levels greater than 300 µmol/L. Among them, there were 71 cases (67.6%) of Gilbert's syndrome, 14 cases (13.3%) of NTCP deficiency, and 9 cases (8.6%) of Citrin deficiency. There were five cases each of G6PD deficiency, Niemann-Pick disease, Wilson's disease, and congenital bile acid synthesis disorder(4.8%). There were four cases (3.8%) of progressive familial intrahepatic cholestasis and four cases (3.8%) of Alagille syndrome. Three cases (2.9%) of Dubin-Johnson syndrome, and two cases (1.9%) of thalassemia.

Table 1

Demographic and clinical racteristics of study population
	Patient cohorts (N = 105) n(%)
Sex
Female	43
Male	38
Gestational age (Weeks)	38 ± 2
birth weight(kg)	3.25 ± 0.82(2.01–4.10)
serum total bilirubin (umol/L)
<200	14
200–300	25
≥ 300	37
Age of onset(days)
1-3days	59
4-7days	11
≥ 8days	6
Feeding pattern
Full Breastfeeding	73
Mix feeding	24
Premature birth
Yes	9
No	87

Genetic spectrum in the study participants

We tested the samples through a 24-gene panel, variants defined as pathogenic or likely pathogenic were selected for analysis. Of 105 cases, 75 (71.4%) were pathogenic or likely pathogenic variant carriers. In a study of 82 patients, a total of 17 pathogenic mutation genes were detected, including ABCB11, ABCC2, ABCD3, ACOX2, ATP7B, UGT1A1, CYP7B1, G6PD, HBB, HSD3B7, JAG1, NPC1, NR1H4, ATP8B1, SLC10A1, SLC25A13, and SMPD1 (Fig. 1). Of these genes, UGT1A1 (77.3%) was the gene with the highest mutation frequency, comprising 67.2% (39/58) heterozygous mutations and 32.7% (19/58) homozygous mutations. The next highest frequency gene was SLC10A1 (18.7%), which included 92.9% (13/14) heterozygous mutations and 7.1% (1/14) homozygous mutations. This was followed by genes that were entirely heterozygous mutations: SLC25A13 (12%) and ATP7B (6.7%). The remaining were some low-frequency pathogenic genes including JAG1 (5.3%), NPC1 (5.3%), ABCC2 (4.0%), and G6PD 4.0%). These gene mutations are associated with the onset of neonatal hyperbilirubinemia caused by genetic diseases.

Analysis of genetic factors in NH

We analyzed the molecular genetic factors of hyperbilirubinemia caused by genetic diseases, and the list of gene mutations is shown in Table 2. Among the 17 detected genetic diseases, Gilbert Syndrome is the most common, and through diagnostic analysis, a total of 4 different UGT1A1 variants were identified among the 71 cases of neonatal Gilbert syndrome. The most common variant was p.Gly71Arg (84.5%), followed by p.Pro364Leu (9.9%) and p.Tyr486Asp (2.8%). The three known mutations were all classified as pathogenic according to the HGMD standards/guidelines, the p.Pro451Leu mutation is a variant of uncertain significance that was identified for the first time. In patients with NTCP deficiency, the primary mutation identified is SLC10A1 (p.Ser267Phe). ATP7B mutations primarily occur in patients with hepatolenticular degeneration (Wilson's disease), among which there are four variants of uncertain clinical significance: p.Asp1164Asn, p.Arg827Gln, p.Thr935Met, and p.Cys157Phe. Mutations in G6PD are associated with hemolytic anemia due to G6PD deficiency. When considering Niemann-Pick disease(NPD), the HSD3B7(p.Ser738Ter, p.Gln81His), SMPD1(p.Leu124Arg), and ABCD3 (p.Ala321Val) gene mutation rates were 12.2% (28/230) and 9.6% (22/230), respectively. In patients with Dubin-Johnson syndrome, the mutations occur in the ABCC2 gene. Among these mutations, p.Gln93Ter is classified as LP (Likely Pathogenic), and the other two novel variants (p.Arg1310Gly and p.Glu881del) were classified as VUS (Variants of Uncertain Significance). Additionally, we identified several rare mutations, including HBB mutations in patients with thalassemia, ACOX2 mutations in patients with type 1 congenital bile acid synthesis disorder, and SMPD1 mutations in patients with neonatal DJS.

Table 2

List of pathogenic/likely pathogenic variants in patients
Gene	Cytogenetic location	Mutation variant	Amino acid variant	Type of gene	Allele Frequency
UGT1A1	Chr2:234669144	c.211G > A	p.Gly71Arg	Het/Hom	0.152
	Chr2:234676872	c.1091C > T	p.Pro364Leu	Het	0.012
	Chr2:234681059	c.1456T > G	p.Tyr486Asp	PAT	0.001
	Chr2:234680955	c.1352C > T	p.Pro451Leu	Het	0.005
SLC10A1	Chr14:70245193	c.800C > T	p.Ser267Phe	Het/Hom	0.078
SLC25A13	Chr7:95818684	c.852_855delTATG	p.Met285ProfsTer2	Het	0.004
	Chr7:95813702	c.1064G > A	p.Arg355Gln	Het	3.48E-04
	Chr7:95775896*	c.1424G > A	p.Arg475Gln	Het	-
	Chr7:95751240	c.1638_1660dup	p.Ala554GlyfsTer17	Het	0.0013
ATP7B	Chr13:52515283	c.3490G > A	p.Asp1164Asn	Het	-
	Chr13:52524503*	c.2480G > A	p.Arg827Gln	Het	5.80E-4
	Chr13:52523859	c.2804C > T	p.Thr935Met	Het	0.002
	Chr13:52548886	c.470G > T	p.Cys157Phe	Het	-
	Chr13:52524515*	c.2468A > G	p.Glu823Gly	Het	1.16E-4
	Chr13:52534313	c.2092A > C	p.Ile698Leu	Het	-
G6PD	ChrX:153774276	c.185A > G	p.His62Arg	Hemi	0.002
	ChrX:153763476	c.482G > T	p.Gly161Val	Het	6.03E-4
	ChrX:153760484	c.1466G > T	p.Arg489Leu	Het	0.008
	ChrX:153760472	c.1478G > A	p.Arg493His	Hemi	0.005
HBB	Chr11:5246931	c.341T > A	p.Val114Glu	Het	2.32E-4
CYP7B1	Chr8:65536958	c.259 + 2T > C		Het	1.16E-4
ABCC2	Chr10:101552060*	c.277C > T	p.Gln93Ter	Het	1.16E-4
JAG1	Chr20:10622442	c.2671G > A	p.Ala891Thr	Het	-
NPC1	Chr18:21116653	c.3229C > T	p.Arg1077Ter	Het	-
NR1H4	Chr12:100926359*	c.569T > A	p.Met190Lys	Het	-
HSD3B7	Chr16:30998260*	c.631C > T	p.Arg211Cys	Het	-
	Chr18:21123451	c.2213C > A	p.Ser738Ter	Het	1.16E-4
	Chr18:21152082*	c.243G > C	p.Gln81His	Het	-
ATP8B1	Chr18:55351421*	c.1477G > A	p.Val493Ile	Het	7.11E-4
ATP8B1	Chr20:10629285*	c.1481A > G	p.Asn494Ser	Het	-
ACOX2	Chr3:58512313	c.1226G > A	p.Arg409His	Het	0.002
ACOX2	Chr3:58508322*	c.1533A > G	p.Ile511Met	Het	5.78E-4
SMPD1	Chr11:6412666*	c.371T > G	p.Leu124Arg	Het	3.47E-4
	Chr10:101604163*	c.3928C > G	p.Arg1310Gly	Het	-
	Chr12:100904723*	c.247C > G	p.Pro83Ala	Het	5.78E-04
	Chr10:101590078*	c.2643_2645delAGA	p.Glu881del	Het	-
ABCB11	Chr2:169830310*	c.1349T > C	p.Met450Thr	Het	4.65E-4
ABCB11	Chr11:5247153	c.316-197C > T		Het	-
ABCD3	Chr1:94933490*	c.262C > T	p.Leu88Phe	Het	0.001
	Chr18:21136571	c.962C > T	p.Ala321Val	Het	3.67E-4
	Chr20:10623197*	c.2511T > G	p.Asp837Glu	Het	-

Gene mutations and their distribution in high-risk patients

Based on a total bilirubin level of 342 µmol/L, cases were classified into high-risk and low-risk groups. First, we analyzed the correlation between clinical characteristics and TSB levels. Our bivariate analysis results of the clinical characteristics are shown in Table 3. The exclusive breastfeeding is shown to be associated with severe TSB (p < 0.05). Gender, feeding method, birth weight and gestational age are not related to TSB. An analysis of the frequency of genetic mutations in the high-risk and low-risk groups was conducted. The results showed that the proportions of UGT1A1 and G6PD mutations were higher in the high-risk group, while mutations in SLC10A1, ATP7B, and SLC25A13 were more common in the low-risk group(Fig. 2). Otherwise, The bivariate analysis results of gene mutation and TSB are shown in Table 4. None of the genes showed any association with severe TSB.

Table 3

Demographic and clinical racteristics of study population
	Hyperbilirubinemia
Factors	(TSB ≥ 342µmol/L)	(TSB <342 µmol/L)	P-value
Gender
Female	17	26	0.67
Male	18	36	0.67
Exclusive breastfeeding
Yes	31	42	0.027
No	4	20	0.027
Gestational age
(Mean ± SD, wk)	38.9 ± 1.26	38.6 ± 1.43	0.170
Birth weight
(Mean ± SD, kg)	3.19 ± 0.41	3.16 ± 0.41	0.38
premature birth
Yes	2	7	0.48
No	33	54	0.48

Table 4

Gene mutation analysis between high and low TSB groups
	Hyperbilirubinemia
Mutation	(TSB ≥ 342 µmol/L)	(TSB <342 µmol/L)	P-value
UGT1A1
G/A	32	11	0.32
C/T	4	3
T/G	1	1
SLC10A1
C/T	6	7	NA
SLC25A13
c.852_855delTATG	2	3	0.57
c.1638_1660dup	0	1
G/A	0	1
ATP7B
G/T	1	0	0.26
A/C	1	0
G/A	0	1
C/T	0	1
G6PD
G/T	1	2	0.32
G/A	1	0
A/G	0	1

Neonatal hyperbilirubinemia is a common condition in newborns, and its pathogenesis involves abnormalities in the bilirubin metabolism pathway[16]. In recent years, an increasing number of studies have shown a close association between hyperbilirubinemia and genetic mutations[17]. These mutations affect the function of related genes, leading to abnormalities in bilirubin metabolism. In this study, we explored the relationship between hyperbilirubinemia caused by inherited diseases and genetic mutations and analyzed their potential clinical significance.

UGT1A1 is an enzyme responsible for conjugating bilirubin with glucuronic acid. Genetic variants of UGT1A1 that result in reduced enzyme activity and expression are associated with non-hemolytic hyperbilirubinemia syndromes, such as Gilbert syndrome (GS) and Crigler-Najjar syndrome type I and type II (referred to as CN I and CN II, respectively)[18–20]. In previous studies, it has been confirmed that the prevalence of UGT1A1 gene mutations in patients with hyperbilirubinemia is significantly higher than that in healthy control groups, suggesting that UGT1A1 gene mutations play an important role in the pathogenesis of hyperbilirubinemia[21]. Additionally, research by Mazur-Kominek et al. has shown that UGT1A1 mutations are one of the key causes of neonatal hyperbilirubinemia[22]. These mutations lead to a decrease in the expression level of the UGT1A1 gene, thereby reducing the rate of bilirubin metabolism and increasing the concentration of bilirubin in the blood, ultimately leading to the occurrence of hyperbilirubinemia. In the current study, we found that UGT1A1 has the highest mutation frequency in patients with hyperbilirubinemia, consistent with previous research results. Furthermore, our study indicates that the mutation frequency of UGT1A1 in high-risk bilirubin patients is higher than that in low-risk groups. ATP7B gene is one of the genes encoding copper-transporting proteins in the human genome. The protein encoded by this gene is an ATPase, playing a critical role in maintaining the balance and metabolism of copper ions in the body. Previous studies have suggested that mutations in the ATP7B gene may affect the structure or function of the ATP7B protein, leading to abnormal copper accumulation in the liver and resulting in Wilson's disease[23, 24]. Wilson's disease may cause liver diseases such as liver fibrosis, cirrhosis, etc., which may interfere with the metabolism and excretion of bilirubin, ultimately leading to hyperbilirubinemia[25]. In our results, Our research results demonstrate that the mutation frequency of the ATP7B gene is higher in the high-risk bilirubin patient group. This suggests that ATP7B plays an important role in hyperbilirubinemia. Additionally, we observed common mutations in G6PD among patients with high bilirubin levels in our study. G6PD deficiency is caused by functional loss mutations in the G6PD gene. G6PD deficiency is a major risk factor for neonatal hyperbilirubinemia[26, 27]. Several studies have indicated that infants with G6PD deficiency are prone to severe neonatal jaundice[28–30]. Elevated levels of bilirubin in the blood and ineffective bilirubin clearance in the liver can also lead to the accumulation of serum bilirubin, resulting in neonatal hyperbilirubinemia. This condition is more common and severe in infants with G6PD deficiency[31]. Furthermore, studies have indicated that variations in the UGT1A1 gene are risk factors for neonatal hyperbilirubinemia in infants with G6PD deficiency[32]. The adenosine triphosphate-binding cassette subfamily C member 2 (ABCC2) gene is located on chromosome 10q24, encoding the multidrug resistance-associated protein 2 (MRP2). Studies have confirmed that the most obvious consequence of mutations in ABCC2 that lead to DJS is conjugate hyperbilirubinemia[33].

We identified several rare mutations, including HBB mutations in patients with beta-thalassemia, ACOX2 mutations in patients with type 1 congenital bile acid synthesis disorder, and SMPD1 mutations in patients with DJS. The HBB gene encodes the beta-globin chain of hemoglobin. Beta-thalassemia is an inherited blood disorder caused by mutations in the HBB gene, resulting in impaired synthesis of beta-globin, leading to hemolytic anemia and chronic anemia, and hemolysis may lead to hyperbilirubinemia[34]. The ACOX2 gene encodes acyl-coenzyme A oxidase 2, which plays a key role in the bile acid synthesis pathway. Defects in ACOX2 can block bile acid synthesis, leading to bile stasis and hyperbilirubinemia[35]. The SMPD1 gene encodes acid sphingomyelinase, which is involved in the maintenance of lysosomal function by degrading lysosomal membranes in the lysosome. Dubin-Johnson syndrome is a rare genetic disorder caused by mutations in the SMPD1 gene, resulting in impaired acid sphingomyelinase activity, leading to obstructed bilirubin excretion and resulting in hyperbilirubinemia[36]. The identification of these rare mutations emphasizes the genetic diversity of hyperbilirubinemia, where different gene mutations may lead to different types of hyperbilirubinemia. Further investigation of these rare mutations will help us better understand the pathogenesis of hyperbilirubinemia and provide new clues and methods for the diagnosis and treatment of related diseases.

This study has certain limitations. Firstly, the limited number of cases may restrict the reliability and generalizability of the study results. Secondly, there are challenges in collecting clinical data on neonatal hyperbilirubinemia, including issues related to the quality and completeness of case data, which may affect the reliability of the study results. Additionally, differences in the number of samples available for analysis between different groups may also lead to experimental biases. Therefore, in the future, larger sample sizes and more comprehensive studies are needed to determine the correlation between genomic variations and the severity of hyperbilirubinemia.

In conclusion, There is a close association between hyperbilirubinemia and genetic mutations, where genetic mutations affect the normal functioning of bilirubin metabolism pathways, leading to the occurrence of hyperbilirubinemia. Research on genetic mutations related to hyperbilirubinemia not only helps us understand the pathogenesis of hyperbilirubinemia in depth but also provides new insights for its prevention, diagnosis, and treatment. Future studies should continue to explore the relationship between hyperbilirubinemia and genetic mutations to promote advancements in clinical practice, ultimately improving the prognosis of infants with hyperbilirubinemia.

DJS Dubin-Johnson syndrome

GS Gilbert syndrome

NH Neonatal hyperbilirubinemia

NTCP Sodium taurocholate cotransporting polypeptide

NPD Niemann-Pick disease

TSB Total serum bilirubin

VUS Variants of Uncertain Significance

Authors’ contributions Jinying You conceived and designed the study; Lingyun Xiong wrote the manuscript; Junsong Fan, Minfang Wu,and Qihua Fu collected data and performed bioinformatics analysis; Jinying You and Lingyun Xiong edited and revised the manuscript. All authors read and approved the final manuscript.

Funding This study was supported by a grant from the Xiamen Municipal Science and Technology Bureau Project (project no.3502Z20209177)

Data availability Analyzed data are available from the corresponding author on reasonable request

Ethics approval and consent to participate This study was approved by the Ethics Committee of the Second Affiliated Hospital of Xiamen Medical College (Approval No: 2020039). Written informed consent was obtained from all subjects and/or their legal guardian(s)

Competing interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Comprehensive analysis of gene mutation in neonatal hyperbilirubinemia caused by inherited diseases

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Abstract

Figures

Introduction

Materials and methods

Study population and data collection

Targeted Panel Sequencing and Genetic analysis

Statistical analysis

Results

General clinical characteristics

Genetic spectrum in the study participants

Analysis of genetic factors in NH

Gene mutations and their distribution in high-risk patients

Discussion

Abbreviations

Declarations

References

Additional Declarations

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