Genetic polymorphisms in Thai neonates with hyperbilirubinemia

Aim:  Polymorphisms of the UGT1A1 gene, SLCO1B1 gene and GST gene have been associated with significant hyperbilirubinemia. We would like to determine whether the variation of UGT1A1 gene, SLCO1B1 gene and GST gene may play a significant role in neonatal hyperbilirubinemia in Thai infants.
Methods:  Ninety-one study subjects (hyperbilirubinemic group) and 86 control subjects were studied.
Results:  The cause of neonatal hyperbilirubinemia could not be identified in 64 infants (70.3%), ABO blood group incompatibility in 14.3% and Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency in 8.8%. In the hyperbilirubinemic group, 23 of 91 (25.3%) infants demonstrated variant of UGT1A1 at nucleotides (nt) 211 as compared to 6 of 86 (7%) in the control group (p = 0.001). There were no significant differences between groups in the variants UGT1A1 at nt 686, SLCO1B1 gene at nt 388, 463 and the GST gene. Male infants with G-6-PD deficiency were associated with hyperbilirubinemia (21.2% vs. 4.8% in the control group) with an odds ratio (OR) of 5.37 (p =0.02). The relationship between G-6-PD and variant in UGT1A1 gene at nt 211 could not be determined.
Conclusion:  Thai infants with variant in the UGT1A1 at nt 211 or with G-6-PD deficiency are at higher risk for developing neonatal hyperbilirubinemia.     

新生儿高胆红素血症与有机阴离子转运体1B1 T521C/A388G多态性的相关性研究

目的 有机阴离子转运体1B1(OATP 1B1)跨膜转运体内非结合胆红素(UCB),其基因变异能显著影响体内胆红素水平.此课题即为研究OATP 1B1基因多态性与新生儿高胆红素血症的相关性.方法 用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)方法分析220例高胆红素血症新生儿及200名对照者OATP 1B1 T521/A388G基因型,观察基因突变频率及基因型分布、基因多态性与疾病的相关性及对患儿血清总胆红素、结合胆红素、非结合胆红素水平的影响.结果 在高胆红素血症新生儿中,OATP 1B1 T521C等位基因突变频率显著下降,仅为8.2%.野生型的患者比例要显著高于对照组中野生型个体比例,达到84.1%.携带C等位基因的个体患病风险下降(OR=0.530,95%CI=0.328～0.857).血清总胆红素、结合胆红素、非结合胆红素水平在OATP 1B1A388G野生型患者中最高,杂合子次之,突变纯合子最低.结论 OATP 1B1 T521C多态性在新生儿高胆红素血症患儿中存在明显差异,OATP 1B1 A388G多态性显著影响新生儿高胆红素血症患儿血清胆红素水平.OATP 1B1 T521C/A388G是和新生儿高胆红素血症相关的重要基因多态位点.     

Clinical characteristics and mutation analysis of propionic acidemia in Thailand

Background

Propionic acidemia (PA) is caused by a deficiency of propionyl CoA carboxylase. A characteristic urine organic acid profile includes 3-hydroxypropionate, methylcitrate, tiglylglycine, and propionylglycine. The diagnosis of PA is confirmed by detection of mutations in the PCCA or PCCB genes. We herein report the clinical and molecular findings of four Thai patients with PA.

Methods

Clinical findings of four Thai patients with PA were retrospectively reviewed. Urine organic acids were analyzed by gas chromatography-mass spectrometry. PCR-sequencing analyses of encoding exons and intron/exon boundaries of the PCCA and PCCB genes were performed.

Results

All patients had neonatal onset of PA. One patient died of cardiomyopathy, and another one of pneumonia and metabolic decompensation. The remainder experienced significant neurocognitive impairment. Mutation analysis of the PCCA gene identified homozygous c.1284+1G>A in patient 1, c.230G>A (p.R77Q) and c.1855C>T (p.R619X) in patient 2, homozygous c.2125T>C (p.S709P) in patient 3, and only one mutant allele, c.231+1G>T in patient 4. No PCCB mutation was identified. Four mutations including c.230G>A, c.231+1G>T, c.1855C>T, and c.2125T>C have not been reported previously.

Conclusions

The clinical and molecular study of these Thai patients provided additional knowledge of the genotype and phenotype characteristics of PA. The results of the study suggested that PCCA mutations in Asian populations were distinct from those of other populations.     

3例Fanconi-Bickel综合征SLC2A2基因分析

Fanconi-Bickel 综合征(FBS, OMIM 227810)是一种常染色体隐性遗传的罕见糖代谢异常疾病,致病基因为SLC2A2。该文报道3 例经SLC2A2 基因分析确诊的FBS 病例。3 例患儿表现为典型的糖原累积症及近端肾小管功能障碍表现。基因测序显示1 例为纯合剪接突变IVS8+5G>C(c.1068+5 G>C);1 例为纯合无义突变c.1194T>A(p.Tyr398X);1 例为错义突变c.380C>A(p.Ala127Asp)和重复突变c.970dupT(p.324TyrfsX392),其中c.970dupT(p.324TyrfsX392)非经父母遗传,为新生突变。该4 种突变中,除IVS8+5G>C 外,其余3 种为中国人种FBS 新突变,而c.970dupT(p.324TyrfsX392)可能为世界首例FBS 新生突变报道。     

Clinical features and mutation analysis of X-linked agammaglobulinemia in 20 Chinese patients

Background

X-linked agammagobulinemia (XLA) is a primary immunodeficiency caused by Bruton’s tyrosine kinase (BTK) gene mutation. XLA patients have an extremely small amount of peripheral B cells and profound deficiency in all immunoglobulin isotypes. We analyzed the clinical, immunologic, and molecular characteristics of children with XLA in an attempt to improve the diagnosis and treatment of XLA in China.

Methods

Twenty children with XLA-compatible phenotypes from 18 unrelated families were enrolled in this study. The BTK gene was amplified and sequenced, followed by mutation analysis in these children and their female relatives.

Results

Eighteen different mutations of the BTK gene were identified in the 20 patients. Eleven mutations had been reported previously including eight missense mutations (c.994C>T, c.1987C>A, c.1885G>T, c.502T>C, c.1085C>T, c.1816C>T, c.214C>T, c.1912G>A) and three nonsense mutations (c.1267T>A, c.1793C>G, c.1618C>T). Seven novel mutations of the BTK gene were also presented and included five missense mutations (c.134T>A, c.1646T>A, c.1829C>G, c.711G>T, c.1235G>A), one splice-site mutation (c.523+1G>A) and one insertion mutation (c.1024-1025in sTTGCTAAAGCAACTGCTAAAGCAAG). Eight out of 18 mutations of the BTK gene were located in the TK domain, 4 in the PH domain, 4 in the SH2 domain and 2 in the TH domain. Genetic study for carrier status was carried out in 18 families with definite BTK gene mutations. Nine carriers with BTK gene mutations were identified. Six families without carriers were detected, and 3 patients were not tested in this study.

Conclusion

Our results support that molecular genetic testing represents an important tool for early confirmed diagnosis of congenital agammaglobulinemia and may allow accurate carrier detection and prenatal diagnosis.     

Neonatal hyperbilirubinemia and the bilirubin uridine diphosphate-glucuronosyltransferase gene: The common −3263T > G mutation of phenobarbital response enhancer module is not associated with the neonatal hyperbilirubinemia in Japanese

BACKGROUND: Neonatal hyperbilirubinemia is frequent and severe in Japanese newborns. Previously, it has been reported that half of the Japanese neonates with severe hyperbilirubinemia carried the 211G > A (p.G71R) mutation of the bilirubin uridine diphosphate-glucuronosyltransferase (UGT1A1) gene causing Gilbert syndrome. Recently, it was reported that the -3263T > G mutation in the phenobarbital response enhancer module in UGT1A1 was associated with the majority of cases of Gilbert syndrome. The gene frequency of the -3263T > G mutation was determined and the relation with neonatal hyperbilirubinemia in Japanese was studied. METHODS: UGT1A1 in 119 neonates born at Yamagata University Hospital, Yamagata, Japan, and 26 subjects who had undergone phototherapy due to severe hyperbilirubinemia at four other hospitals were studied. The gene frequency of -3263T > G mutation in Japanese, Korean, Chinese and German healthy adult controls was also determined. Hyperbilirubinemia was assessed with a Jaundice Meter and UGT1A1 was analyzed by sequence determination or restriction enzyme method. RESULTS: The gene frequency of the -3263T > G mutation was 0.26 in Japanese subjects and was similar to the prevalence in Korean, Chinese and German populations. However, there was no significant increase in the gene frequency of the mutation in the neonates who required phototherapy for hyperbilirubinemia compared to that in the neonates without severe hyperbilirubinemia. In addition, neonates with or without the mutation did not show a significant change in the level of bilirubin and the mutation also did not show a synergic effect with the 211G > A mutation on the level of bilirubin. CONCLUSION: The -3263T > G mutation is not likely to be associated with the neonatal hyperbilirubinemia in Japanese.     

Phenotypic and mutation spectrums of Thai patients with isovaleric acidemia

Background: Isovaleric acidemia (IVA) is an autosomal recessive disorder caused by deficiency of isovaleryl‐CoA dehydrogenase (IVD). Clinical features include vomiting, lethargy, metabolic acidosis, and “sweaty feet” odor. The pathognomonic metabolite, isovalerylglycine, is detected on urine organic acid analysis. Clinical diagnosis of IVA can be confirmed on mutation analysis of the IVD gene. Methods: The cases of five unrelated Thai patients with IVA, identified on urine organic acid analysis, are described. Mutation analysis of the IVD gene was performed using polymerase chain reaction sequencing of the entire coding regions. Results: Four out of the five IVA patients had an acute neonatal form. The hematologic abnormalities were common and thus could be presenting symptoms in the absence of metabolic acidosis. As for the neurological outcome, only one patient had normal intelligence. Mutation analysis of the IVD gene identified the mutations c.457–3_2CA>GG, c.1199A>G (p.Y371C), c.281C>G (p.A65G), c.358G>A (p.G91R), and c.827T>C (p.L247P). The poor outcome in most patients might be explained by the delayed diagnosis and initial unavailability of the metabolic formulas and medications in Thailand. The c.457–3_2CA>GG mutation was identified in all of the present patients. This suggests that it is the most common mutation in the Thai population. Therefore, it could be a founder mutation in Thai subjects. One of the present Thai IVA patients also had the p.Y371C mutation, which is common in Han Chinese subjects. In addition, two novel mutations, p.A65G and p.L247P, were identified. Conclusion: The present study provides additional knowledge on the genotype–phenotype of IVA, suggesting that IVD mutations in Asian populations are distinct from these in Western populations.     

广西黑衣壮族高胆红素血症新生儿UGT1A1基因突变分析

目的 探讨广西黑衣壮族高胆红素血症新生儿尿苷二磷酸葡萄糖醛酸转移酶1A1（UGT1A1）基因的突变分布特点及其与高胆红素血症的关系。方法 提取黑衣壮族高胆红素血症新生儿（病例组）及对照组新生儿血液基因组DNA各100例,对UGT1A1 启动子TATA盒及所有外显子进行PCR扩增及直接测序。结果 检测到UGT1A1 启动子TATA盒（TA）7插入突变、第1外显子G71R错义突变及第5外显子中4个SNP位点（rs199539868、rs114982090、rs1042640、rs8330）。病例组的G71R等位基因频率显著高于对照组（PP>0.05）。Logistic回归分析显示UGT1A1 TATA盒、G71R、rs1042640及rs8330对新生儿高胆红素血症发生的OR值（95%CI）分别为0.846（0.440,1629）、3.932（1.745,8.858）、0.899（0.364,2.222）。结论 UGT1A1基因（TA）7插入突变与G71R错义突变是广西黑衣壮族高胆红素血症新生儿的常见突变类型,4个SNP 位点（rs199539868、rs114982090、rs1042640、rs8330）为国内首次报道。UGT1A1 G71R错义突变是广西黑衣壮族新生儿高胆红素血症的危险因素。     

遗传因素在广西新生儿高胆红素血症中的作用

目的探讨UGT1A1 G71R突变、OATP2A388G突变和G-6-PD缺乏对在广西新生儿高胆红素血症发病的作用。方法用四氮唑蓝定量法（NBT法）测定G-6-PD酶活性。聚合酶链反应-等位基因特异性寡核苷酸探针点杂交（PCR-ASO）法确定G71R基因型。限制性片段长度多态性分析（RFLP）检测A388G基因型。测定109例新生儿脐血的G-6-PD活性及G71R基因型,其中101例同时检测了A388G基因型。据G-6-PD活性及G71R或A388G基因型分组,分析UGT1A1G71R突变、OATP2A388G突变和G-6-PD缺乏与足月新生儿高胆红素血症之间关系。结果G71R等位基因频率在G-6-PD缺乏组为22．03％,在G-6-PD正常组为28．00％。G-6-PD缺乏共存有G71R突变纯合子或杂合子的新生儿高胆红素血症发生率（95．50％）高于G-6-PD正常且G71R为野生型的新生儿（53．90％）,x^2=10．45,P=0．0012,前者发生高胆红素血症的机会比（95％可信区间）[OR（95％CI）]为18．00（2．12,152．9）。A388G等位基因频率在G-6-PD缺乏组为20．O％,在G-6-PD正常组为18．5％。G-6-PD缺乏共存有A388G突变新生儿的高胆红素血症发生率（90．0％）高于G-6-PD正常且A388G为野生型的新生）L（44．80％）,X2=10．39,P=0．0013,前者发生高胆红素血症的伽（95％CT）为11．08（2．15,56．48）。结论G71R突变与G-6-PD缺乏共存或A388G突变与G-6-PD缺乏共存对广西足月新生儿高胆红素血症的发生有协同作用。     

有机阴离子转运体1B1基因与新生儿黄疸关系的研究进展

有机阴离子转运体2(OATP2)是一种肝细胞膜上转运胆红素等物质的转运体,影响胆红素的代谢.OATP2 由有机阴离子转运体1B1(SLCO1B1)基因编码,该基因突变可抑制OATP2 的转运功能,致胆红素清除减慢,引起高胆红素血症.近年的研究显示,SLCO1B1 基因多态性可能与新生儿黄疸发生相关.该文综述了SLCO1B1 基因结构、功能及SLCO1B1 基因突变与新生儿黄疸的关系.     

UGT1A1基因G71R突变与新生儿不明原因严重高胆红素血症相关

目的探讨尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1)基因G71R突变与新生儿严重高胆红素血症的相关性。方法采用病例对照研究的方法,病例组为复旦大学附属儿科医院(我院)收治的不明原因严重高胆红素血症(血清总胆红素水平≥342μmol·L-1)新生儿,采用PCR对外周血UGT1A1基因进行检测。对照组为我院新生儿出生缺陷生物样本数据库中血清总胆红素水平221μmol·L-1病例。病例组及对照组新生儿均要求胎龄≥35周,出生体重≥2 500 g。结果病例组和对照组各65例。UGT1A1 G71R是病例组中最常见的突变类型(73.8%,48/65)。对照组UGT1A1 G71R突变位点与既往Meta分析中提取的中国健康新生儿对比,在基因型分布及等位基因频率上差异均无统计学意义(P0.05)。病例组和对照组UGT1A1基因G71R突变中A等位基因频率分别为0.5和0.15,差异有统计学意义(P0.001),把握度为0.993。与携带G/G基因型新生儿相比,UGT1A1 G71R突变(A/A+G/A基因)可增加新生儿严重高胆红素血症的发病风险(OR=7.373,95%CI:3.395~16.008),把握度为1.0。结论 UGT1A1基因G71R突变与新生儿不明原因严重高胆红素血症相关。     

Frequencies of A(TA)7TAA, G71R, and G493R mutations of the UGT1A1 gene in the Malaysian population

BACKGROUND: Gilbert syndrome is caused by defects in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene. These mutations differ among different populations and many of them have been found to be genetic risk factors for the development of neonatal jaundice. OBJECTIVES: The objective was to determine the frequencies of the following mutations in the UGT1A1 gene: A(TA)7TAA (the most common cause of Gilbert syndrome in Caucasians), G71R (more common in the Japanese and Taiwanese population), and G493R (described in a homozygous Malay woman with Crigler-Najjar syndrome type 2) in a group of Malaysian babies with hyperbilirubinemia and a group of normal controls. METHODS: The GeneScan fragment analysis was used to detect the A(TA)7TAA variant. Mutation screening of both G71R and G493R was performed using denaturing high performance liquid chromatography. RESULTS: Fourteen out of fifty-five neonates with hyperbilirubinemia (25%) carried the A(TA)7TAA mutation (10 heterozygous, 4 homozygous). Seven out of fifty controls (14%) carried this mutation (6 heterozygous, 1 homozygous). The allelic frequencies for hyperbilirubinemia and control patients were 16 and 8%, respectively (p=0.20). Heterozygosity for the G71R mutation was almost equal among both groups (5.5% for hyperbilirubinemia patients and 6.0% for controls; p=0.61). One subject (1.8%) in the hyperbilirubinemia group and none of the controls were heterozygous for the G493R mutation (p=0.476). CONCLUSIONS: The A(TA)7TAA seems more common than the G71R and G493R mutations in the Malaysian population.     

A genome‐wide analysis of colorectal cancer in a child with Noonan syndrome

Noonan syndrome (NS) is a developmental syndrome caused by germline mutations in the Ras signaling pathway. No association has been shown between NS and pediatric colorectal cancer (CRC). We report the case of CRC in a pediatric patient with NS. The patient underwent whole genome sequencing. A germline SOS1 mutation c.1310T>C (p. Ile437Thr) confirmed NS diagnosis. No known hereditary cancer syndromes were identified. Tumor analysis revealed two mutations: a TP53 missense mutation c.481G>A (p. Ala161Tyr) and NCOR1 nonsense mutation c.6052C>T (p. Arg2018*). This report highlights the complexity of Ras signaling and the interplay between developmental syndromes and cancer.     

伴皮层下囊肿的巨脑性白质脑病一家系MLC1基因突变分析

收集伴皮层下囊肿的巨脑性白质脑病(MLC)先证者及其父母的临床资料,采用聚合酶链反应和DNA 直接测序法进行MLC1 基因突变检测。患儿临床表现为运动发育迟缓、巨颅,头颅MRI 扫描显示弥漫性脑白质肿胀,伴双侧额顶部皮层下囊肿。基因测序结果发现患儿携带MLC1 基因2 个杂合突变:第3 外显子的错义突变c.217G>A(p.Gly73Arg)和第9 内含子的剪接位点突变c.772-1G>C in IVS9-1。患儿的父母均为c.772-1G>C in IVS9-1 杂合突变携带者,无临床症状。可推测患儿c.772-1G>C in IVS9-1 突变来源于父母;c.217G>A(p.Gly73Arg)为新生突变,为国内外首次报道。     

Severe phenotypes of SMARD1 associated with novel mutations of the IGHMBP2 gene and nuclear degeneration of muscle and Schwann cells

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a very rare autosomal recessive form of spinal muscular atrophy manifested in low birth weight, diaphragmatic palsy and distal muscular atrophy. Caused by a mutation in the IGHMBP2 gene, the disease is addressed here by reference to five Polish patients in which SMARD1 has been confirmed genetically. All presented a severe form of the disease and had evident symptoms during the second month of life; with four displaying weak cries, feeding difficulties and hypotonia from birth. Two were afflicted by severe dysfunction of the autonomic nervous system. Ultrastructural analysis of a muscle biopsy revealed progressive degeneration within the nuclei of the muscle cells and Schwann cells. Neuromuscular junctions were also defective. It proved possible to identify in our patients 6 novel IGHMBP2 mutations: three missense (c.595G>C, c.1682T>C and c.1794C>A), two nonsense (c.94C>T and c.1336C>T) and one in-frame deletion (c.1615_1623del). One nonsense mutation (c.429C>T) that had been described previously was also identified. Observation of our patients makes it clear that clinical picture is still the most important factor suggesting diagnosis of SMARD1, though further investigations concerning some of the symptoms are required. As the IGHMBP2 gene is characterized by significant heterogeneity, genetic counseling of affected families is rendered more complex. IGHMBP2 protein deficiency can lead to the degeneration of nuclei, in both muscle and Schwann cells.     

Heme oxygenase-1 gene variants and hyperbilirubinemia risk in North Indian newborns

Heme oxygenase-1 (HO-1) is a rate-limiting enzyme in bilirubin metabolism, and its genetic variant may modulate hyperbilirubinemia risk in neonates. The aim of the present study was to assess the association between heme oxygenase-1 gene variants and hyperbilirubinemia risk in Indian newborns. In a prospective case–control study, we analyzed (GT)_n repeats and g.-413A>T variant of HO-1 gene and UGT1A1 gene variants in 100 case newborns with total serum bilirubin (TSB) levels exceeding 95th percentile and 100 control newborns with TSB levels below 75th percentile on the hour-specific bilirubin nomogram of the American Academy of Pediatrics. Study population consisted of term (37–41 weeks) and late preterm (34–36 weeks) newborns during the first 2 weeks of age. In our analysis, the (GT)_n allele was highly polymorphic, ranging in number from 15 to 40. The incidence of short (GT)_n allele (≤20) was significantly higher in neonates with hyperbilirubinemia than in controls. Although g.-413A>T variant was widely prevalent in the study population, no difference was noted in its prevalence between cases and controls. Short (GT)_n repeats of HO-1 gene, c.211G>A variant of UGT1A1 gene, and excessive weight loss were independent risk factors for neonatal hyperbilirubinemia. In the presence of two or more risk factors, the odds of developing neonatal hyperbilirubinemia were high. Shorter (GT)_n genotype in the promoter region of HO-1 gene is significantly associated with hyperbilirubinemia risk in Indian newborns. This genotype may interact with other genetic and clinical risk factors to further potentiate hyperbilirubinemia risk in newborns.     

胆红素-尿苷二磷酸葡萄糖醛酸基转移酶G71R基因型对广西地区新生儿黄疸程度的影响

目的 探讨胆红素-尿苷二磷酸葡萄糖醛酸基转移酶1A1(UGT 1A1)基因突变对广西新生儿黄疸的影响.方法 收集73例高胆红素血症新生儿及31例健康新生儿外周血,应用突变特异性扩增系统(amplification refractory mutation system,ARMS)法及直接测序法对所有新生儿行UGT1A1基因G71R突变检测,分析胆红素脑病发生率,胆红素峰值及总胆红素(total serum bilirubin,TSB)>20 mg/dl的机会比.结果 (1)本研究人群G71R等位基因频率为0.1915,病例组为0.2329,健康对照组为0.097,病例组的G71R等位基因频率显著高于健康对照组(P<0.05).(2)G71R纯合子的胆红素脑病发病率及72 h的TSB浓度(28.57%,23.12±4.58 mg/dl)均高于野生型组(0%,17.68±2.69 mg/dl),差异有统计学意义(P<0.001).(3)G71R纯合子组中5例的TSB>20 mg/dl,G71R纯合子TSB>20 mg/dl的机会比(odds ratio,OR)为7.955,总体机会比95%可信区间(confidence interval,CI)为(1.349,46.899).结论 G71R突变与本地新生儿黄疸的发病存在相关性.G71R纯合子的胆红素脑病发病率及生后72 h的TSB较对照组及野生型增高.G71R纯合子发生TSB>20 mg/dl的危险性是野生型的7.955倍.     

Homozygous variant of UGT1A1 gene mutation and severe neonatal hyperbilirubinemia

Background: The aim of the present study was to compare, in a case–control study, the prevalence of nucleotide 211 guanine to adenine (G→A) mutation of uridine diphosphoglucuronosyl transferase (UGT1A1) gene in Malaysian Chinese newborns with and without severe hyperbilirubinemia (total serum bilirubin >250 µmol/L during first 48 h of life or ≥300 µmol/L thereafter), and to determine whether this mutation was a significant risk factor associated with severe hyperbilirubinemia. Methods: Seventy‐four term infants of Chinese descent admitted with severe hyperbilirubinemia were recruited. Infants without severe hyperbilirubinemia (n = 125) were randomly selected from among healthy Chinese term infants. UGT1A1 nucleotide 211 polymorphism was assayed using the Taqman single nucleotide polymorphism genotyping method. Using gestational age, types of feeds, G6PD mutation, G6PD enzyme levels, and UGT1A1 gene mutation status as independent variables, logistic regression analysis was carried out to determine the significant risk factors associated with severe hyperbilirubinemia. Results: UGT1A1 gene mutation was significantly more common among hyperbilirubinemic infants (39.2%) than controls (25.6%; P = 0.04). Gestational age (adjusted odds ratio [OR], 0.7; 95% confidence intervals [CI]: 0.5–0.9; P = 0.01), G6PD mutation (adjusted OR, 7.2; 95%CI: 2.7–19.0; P < 0.0001), exclusive breast‐feeding (adjusted OR, 11.7; 95%CI: 2.7–49.9; P = 0.001), and homozygous variant of UGT1A1 gene mutation (adjusted OR, 32.2; 95%CI: 3.8–273.2; P = 0.001) were significant risk factors. Heterozygous variant of UGT1A1 gene mutation, actual levels of G6PD enzyme, and mixed feeding were not. Conclusion: Homozygous variant of nucleotide 211 G→A mutation of UGT1A1 gene is a significant risk factor associated with severe hyperbilirubinemia among Malaysian Chinese newborns.     

广西三江县侗族新生儿UGT1A1基因变异分析北大核心CSCD

目的探讨广西柳州三江县侗族新生儿UGT1A1基因变异特点及其与侗族新生儿高胆红素血症发生的关系。方法前瞻性选取2021年1月至2022年1月于三江县人民医院新生儿科诊断不明原因高胆红素血症的新生儿84例为研究对象;另选取同期健康新生儿60例纳入健康对照组。提取两组新生儿外周血基因组DNA,对UGT1A1启动子区TATA盒和外显子1进行PCR扩增并进行基因测序。结果病例组检测出33例G71R错义突变,突变率为39%,A等位基因频率(21%)显著高于健康对照组(10%)(P<0.05)。携带G71R错义突变基因型的侗族新生儿发生高胆红素血症的风险是携带野生型的健康新生儿的2.588倍(P<0.05)。Hardy-Weinberg遗传平衡检验结果提示两组新生儿UGT1A1 G71R位点基因型符合遗传平衡(P>0.05)。结论UGT1A1 G71R突变是三江县侗族新生儿高频基因变异类型,且G71R错义突变与侗族新生儿发生高胆红素血症相关。     

Relationship between bilirubin UDP-glucuronosyl transferase 1A1 gene and neonatal hyperbilirubinemia

The variation rate within the coding region of UDP-glucuronosyl transferase 1A1 (UGT1A1) gene in Taiwan Chinese was found to be 29.3%. This study sought to determine whether that high variation rate of UGT1A1 gene is a risk factor for neonatal hyperbilirubinemia. The study subjects consisted of 123 newborn infants suffering from unconjugated hyperbilirubinemia who had no known risk factors for hyperbilirubinemia and 218 healthy control neonates. The promoter area, exons 1 to 4, coding region of exon 5, and the flanking intronic regions in UGT1A1 gene were determined by the PCR in all subjects. Wild UGT1A1 gene, variation in the promoter, variation at nucleotide 211, variation at nucleotide 1091, and compound heterozygous variation of UGT1A1 gene were found. The percentage of neonates with wild UGT1A1 gene and the percentage of neonates with variation at nucleotide 211 were significantly different between the study subjects and controls. The percentages with bilirubin >or=342 micro M (20.0 mg/dL) and with persistent hyperbilirubinemia in the subjects carrying homozygous variation at nucleotide 211 (Gly71Arg) were significantly higher than the neonates carrying wild type or other genotypes. In conclusion, this study has demonstrated that variation at nucleotide 211 of the UGT1A1 gene is a risk factor for the development of neonatal hyperbilirubinemia. Pediatricians should closely follow hyperbilirubinemic newborn infants who carry homozygous 211 G to A variation in UGT1A1 gene.