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Objective:To summarize the clinical and genetic characteristics of Potocki-Shaffer syndrome (PSS).Methods:A retrospective study was conducted to analyze the clinical data of 1 patient diagnosed with PSS in the Department of Pediatrics of the Sixth Affiliated Hospital, Sun Yat-Sen University at February 2021.The data analyzed included clinical manifestations, biochemical tests and gene tests.Meanwhile, studies were retrieved from the China National Knowledge Internet database, Wanfang database, and PubMed database from the establishment of the database to December 2021 by taking " Potocki-Shaffer syndrome" " EXT2 gene" " AlX4 gene" and " PHF21A gene" as key words.Besides, genes were searched from the Online Frontal Analysis Mendelian Inheritance in Man.The clinical and genetic features of PSS patients were summarized. Results:The patient was 5 months and 21 days old, male, who was admitted to the hospital due to excessive growth in body mass for the past 3 months.The patient showed mental and motor retardation, overgrowth, concealed penis, hearing loss, and hypotonia.Whole exon sequencing of this patient revealed heterozygous deletions in the Chr11: 44069455-48188946 region, including the deletions of 3 autosomal dominant genes: EXT2, ALX4, and PHF21A.The patient was diagnosed with PSS.A total of 14 articles published in English were collected, involving this boy and other 35 patients.In these patients, 14 cases had point mutations, and 22 cases had large deletions. PHF21A gene variation was detected in 23 cases (dysgnosia in 22 cases, dyskinesia in 21 cases, language development delay in 18 cases). EXT2 gene variation was observed in 22 cases (exostoses in 13 cases). ALX4 gene variation was found in 19 cases (bilateral parietal foramina in 15 cases). Of 36 cases, 27 cases had craniofacial anomalies. Conclusions:The main clinical symptoms of PSS are language and motor developmental delay, intellectual disability, exostoses, bilateral parietal foramina, and craniofacial anomalies, which are closely related to 3 autosomal dominant genes ALX4, EXT2 and PHF21A.Genetic testing facilitates the clinical diagnosis of PSS, and the mutation types are dominated by point mutations and large deletions.
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Objective:To detect the genes of common genetic diseases in newborns with the high-throughput sequencing technology based on target gene capture, to study the incidence rate of such diseases, the carrying rate and variant types of pathogenic mutations related to such diseases, and to explore the application value of the high-throughput sequencing technology in screening genetic diseases of newborns.Methods:The heel blood of 1 793 newborns born in Guangdong province from June 2019 to April 2020 were collected, and the exon regions of 138 common genetic disease-related genes in neonates were detected using the high-throughput sequencing technology based on target gene capture.The pathogenicity of the mutations was interpreted according to the " Classification Criteria and Guidelines for Genetic Variation(2017)" , in which known disease and probable disease were considered as positive mutations.The positive mutations were verified by Sanger sequencing technology, and the test results were analyzed with statistical methods.Results:Among the 1 793 newborns, 978 were male and 815 were female.A total of 158 positive cases were screened(8.81%), and 11 positive diseases were detected.Among the positive diseases, there were 41 cases(2.29%)of autosomal recessive deafness type 1A, 40 cases(2.23%)of Gilbert syndrome or Crigler-Najjar syndrome, and 33 cases(1.84%)of glucose-6-phosphate dehydrogenase deficiency(1.84%), 19 cases(1.06%)of familial hypercho-lesterolemia, 18 cases(1.00%) of sodium taurocholate cotransporter peptide deficiency disease, 2 cases(0.11%)of mitochondrial non-syndromic deafness, 2 cases(0.11%)of Citrin deficiency, 1 case(0.06%)of holocarboxylase synthase deficiency, 1 case(0.06%)of β-thalassemia and 1 case(0.06%)of metachromatic leukodystrophies.Of all studied cases, 972 carried one or more positive mutations, involving 85 kinds of diseases in total.The diseases with a high carrying rate were Gilbert syndrome or Crigler-Najjar syndrome(359 cases, 20.02%), autosomal recessive deafness type 1A(302 cases, 16.84%), and sodium taurocholate cotransport peptide deficiency disease(291 cases, 16.22%). The high-frequency mutation sites were UGT1A1 gene c. 211G> A, GJB2 gene c .109G> A and SLC10A1 gene c. 800C> T. Conclusions:The common genetic diseases detected in neonates from Guangdong province are autosomal recessive deafness type 1A, Gilbert syndrome or Crigler-Najjar syndrome, glucose-6-phosphate dehydrogenase deficiency, familial hypercholesterolemia, and sodium taurocholate cotransport peptide deficiency.There are high-frequency carrying mutation sites in the population.Preliminary genetic screening of common neonatal genetic diseases can accumulate data and experience for the development of newborn genetic screening.
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Objective@#To report on clinical characteristics and genetic findings in 15 Chinese patients with methylmalonic acidemia (MMA).@*Methods@#For the 15 MMA patients detected by tandem mass spectrometry, genetic analysis was carried out in twelve pedigrees. Clinical characteristics, genetic finding, treatment and outcomes were retrospectively analyzed.@*Results@#The main features of the patients included poor feeding, recurrent vomiting, lethargy, seizure and development retardation. Blood propionylcarnitine (except for 3 patients), its ratio with acetylcarnitine, and urine methylmalonic acid were increased in all patients. Twelve patients were diagnosed genetically, which included 7 with MUT variants, 4 with MMACHC variants, and 1 with MMAB variant. Nine MUT variants were detected, among which c. 1159A>C, 753+ 1delGinsTGGTTATTA and c. 504del were novel. Six known pathogenic MMACHC variants and two novel MMAB variants (c.289_290delGG, c. 566G>A) were also detected. Seven patients died of metabolic crises within a year, others had improved effectively following the treatment, but had mild to severe growth delay and/or developmental retardation.@*Conclusion@#The clinical manifestation of MMA are complex. Most patients have variants of the MUT and MMACHC genes. High mortality may occur before one year of age.
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OBJECTIVE@#To report on clinical characteristics and genetic findings in 15 Chinese patients with methylmalonic acidemia (MMA).@*METHODS@#For the 15 MMA patients detected by tandem mass spectrometry, genetic analysis was carried out in twelve pedigrees. Clinical characteristics, genetic finding, treatment and outcomes were retrospectively analyzed.@*RESULTS@#The main features of the patients included poor feeding, recurrent vomiting, lethargy, seizure and development retardation. Blood propionylcarnitine (except for 3 patients), its ratio with acetylcarnitine, and urine methylmalonic acid were increased in all patients. Twelve patients were diagnosed genetically, which included 7 with MUT variants, 4 with MMACHC variants, and 1 with MMAB variant. Nine MUT variants were detected, among which c.1159A>C, 753+1delGinsTGGTTATTA and c.504del were novel. Six known pathogenic MMACHC variants and two novel MMAB variants (c.289_290delGG, c.566G>A) were also detected. Seven patients died of metabolic crises within a year, others had improved effectively following the treatment, but had mild to severe growth delay and/or developmental retardation.@*CONCLUSION@#The clinical manifestation of MMA are complex. Most patients have variants of the MUT and MMACHC genes. High mortality may occur before one year of age.
Subject(s)
Humans , Alkyl and Aryl Transferases , Genetics , Amino Acid Metabolism, Inborn Errors , Genetics , China , Methylmalonyl-CoA Mutase , Genetics , Oxidoreductases , Genetics , Pedigree , Retrospective StudiesABSTRACT
Objective:To investigate the changes of expressions of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in the peripheral blood mononuclear cells and downstream factors interleukin-1β (IL-1β) and interleukin-18 (IL-18) in serum in the children with asthma, and to explore their significances on assessing the condition of the children.Methods:A total of 176cases of children with asthma were divided into acute exacerbation group (n=91) , chronic persistent group (n=49) and clinical remission group (n=36) according to the clinical manifestation.During the same period, 60healthy children were selected from the outpatient physical examination center as control group.The pulmonary function of children was checked with lung function instrument.The expression levels of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC) and cysteinyl aspartate-specific proteinase-1 (Caspase-1) mRNA in peripheral blood mononuclear cells of the subjects in various groups were detected by using real-time quantitative PCR.The serum levels of IL-1βand IL-18of the subjects in various groups were detected by using enzyme-linked immunosorbent assay (ELISA) .Results:Compared with control group, the forced expiratory volume in 1second percentage of predicted value (FEV1％) and fixed ratio of forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) of the children in acute exacerbation, chronic persistent and clinical remission groups were decreased (P＜0.05) ;acute exacerbation group＜chronic persistent group＜clinical remission group, and there were significant differences between various groups (P＜0.05) .The levels of NLRP3, ASC and Caspase-1mRNA in the peripheral blood mononuclear cells and serum levels of IL-1βand IL-18in the children with asthma were higher than those in control group (P＜0.01) .The expression levels of NLRP3, ASC and Caspase-1mRNA in the peripheral blood mononuclear cells of the children in acute exacerbation group were higher than those in chronic persistent and clinical remission groups (P＜0.05) , and the expression levels of NLRP3, ASC and Caspase-1mRNA in chronic persistent group were higher than those in clinical remission group (P＜0.05) .Pearson correlation analysis showed that the expression level of NLRP3mRNA in the peripheral blood mononuclear cells of asthmatic children was positively correlated with the expression levels of ASC, Caspase-1 mRNA and the serum levels of IL-1βand IL-18 (P＜0.05) , while it was negatively correlated with FEV1％and FEV1/FVC;the expression level of ASC mRNA was positively correlated with the expression level of Caspase-1mRNA and the serum levels of IL-1βand IL-18 (P＜0.05) , while it was negatively correlated with FEV1％and FEV1/FVC (P＜0.05) ;the expression level of Caspase-1 mRNA was positively correlated with the expression level of Caspase-1mRNA and the serum levels of IL-1βand IL-18 (P＜0.05) , while it was negatively correlated with FEV1％and FEV1/FVC (P＜0.05) ;the serum level of IL-1βwas negatively correlated with FEV1％and FEV1/FVC (P＜0.05) , and the serum level of IL-18was negatively correlated with FEV1％and FEV1/FVC (P＜0.05) .Conclusion:The expression levels of NLRP3inflammasome and the downstream factor IL-1βand IL-18in peripheral blood of the children with asthma are increased, and they are related to the clinical stage of the children with asthma.NLRP3inflammasome pathway might promote the pathogenesis of asthma in the children.
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Objective To investigate the role of TNSALP gene detection in prenatal diagnosis of HPP. Method The clinical data and the results of complete exon sequencing of TNSALP gene in one neonate with low alkaline phosphatase (HPP) were analyzed retrospectively. Peripheral bloods from his family members were collected. The amniotic fluid cell in fetuses at 17 weeks was tested for candidate gene mutations by Sanger sequencing. Results Mainly manifestations in 6-day-old baby were multiple fractures, limb shortening and bending and dyspnea. He died of respiratory failure 9 days after birth. The serum alkaline phosphatase was decreased and serum calcium was decreased slightly; serum phosphorus, serum 25 hydroxyvitamin-D and parathyroid hormone were normal. X-ray showed that the whole body bone was very poorly mineralized, and the long diaphysis was enlarged with shape of a cup at the end and multiple fractures existed. Gene sequencing revealed a complex heterozygous missense mutation in the TNSALP gene, including the heterozygous missense mutation c.542C>T in exon sixth causing 181st amino acids changed from serine to leucine (p.S181L), and tenth exon heterozygous missense mutation in c.1016G>A causing 339th amino acid changed from glycine to glutamic acid (p.G339E). The parental phenotypes were normal. The c.542C>T mutation is inherited from his father and the c.1016G>A mutation is inherited from his mother. These two mutations were not detected in the fetus. Conclusion TNSALP gene analysis can be applied to the diagnosis and prenatal diagnosis of HPP.
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Objective@#To investigate the urinary metabolic spectrum and pathways in very low birth weight (VLBW) premature infants.@*Method@#A prospective case-control study was conducted to collect and compare the data of VLBW premature infants and full term infants from the Sixth Affiliated Hospital of Sun Yet-Sen University in 2014. Within 24 hours after birth, urine specimens in each group were collected. Metabolites of urine samples including amino acid, fatty acid and organic acid were detected using the urease pre-processing and gas chromatography mass spectrometry (GC-MS) technology. Using the orthogonal partial least squares discriminant analysis (OPLS-DA), the biomarkers and differences between the two groups were found. The online metabolic pathway website was explored and multivariable analysis was conducted to investigate the valuable pathways and biomarkers related to the prematurity.@*Result@#A total of 20 VLBW premature infants were enrolled, among whom 11 were male, 9 were female; and 20 full term infants were enrolled, among whom 9 were male, 11 were female. The urinary metabolites were established and compared between the VLBW premature and term infants. The investigation showed that the following nine pathways were enriched: amino-acyl-tRNA biosynthesis(P=0.000), lysine degradation(P=0.007), fatty acid biosynthesis(P=0.008), pyrimidine metabolism(P=0.014), pantothenate and CoA biosynthesis(P=0.022), valine, leucine and isoleucine biosynthesis(P=0.022), lysine biosynthesis(P=0.031), glycerolipid metabolism(P=0.046), and valine, leucine and isoleucine degradation(P=0.031). Almost all the metabolites decreased except for the glyceric acid exhibiting a higher content in the VLBW premature infant. 12 potential biomarkers were explored with the most significant covariance and correlation, within which stearic acid, palmiticacid, myristic acid, β-amino-isobutyric acid, and uric acid were lower, while myo-inositol, mannitol, glycine, glucose1, glucose2, glyceric acid and N-acetyl-tyrosine were higher in the VLBW premature group compared with the control group.@*Conclusion@#There is a significant difference between the VLBW premature infants and full-term infants in the metabolic state and pathways. The urease pre-processing and GC-MS technology followed by the OPLS-DA and multivariable analysis to investigate VLBW premature infants′ urinary metabolites is a valuable method to evaluate the patients′ metabolism.
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Objective To detect the incidence of inherited metabolic diseases(IMD)and disorders of metabo-lism in 4 710 high - risk infants,as well as providing basis of clinical diagnosis and treatment by using urease pretreat-ment - gas chromatography - mass spectrometry(UP - GC - MS). Methods Samples were collected from high - risk infants with IMD,after removing urea,putting in internal standard,removing protein,vacuum drying and bis (trimethyl - silyl)trifluoroacetamide / trimethyl - chlorosilane derivativing,UP - GC - MS was used to analyze compo-sitions such as organic acids,amino acids,carbohydrates,pyridoxines,purines and pyrimidines,then metabolic analysis was proceeded to refer to the normal detection value of the healthy children,finally a metabolic diagnosis was made ba-sing on the clinical data such as the high - risk clinical manifestations and general biochemical tests and other special examinations. Results In the 4 710 cases,there were 98 cases of IMD(2. 1% ),326 cases of suspected IMD(6. 9% ), 2 610 cases of metabolic disorders(55. 4% ). There were 98 cases of IMD,including 57 cases of methylmalonic aciduria,12 cases of propionic acidemia,7 cases of glutaric aciduria,5 cases of hyperphenylalaninemia,maple syrup u-rine disease and multiple carboxylase defects each,4 cases of isovaleric acidemia and 3 cases of 4 - hydroxy butyric acid urine disease. Conclusions UP - GC - MS is a effective way to diagnose IMD and metabolic disorders of infants. Common IMD in Guangdong Province include methylmalonic aciduria,propionic academia,glutaric aciduria,hyperphe-nylalaninemia,maple syrup urine disease and multiple carboxylase defects. The results of the tests can provide effective guidance for diagnosis and treatment of suspected infants.
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Objective To explore the interaction between polymorphisms of rs17222919 which located in the 5-1ipoxygenase-activating protein(ALOX5AP) gene promoter and environmental risk factors in ischemic stroke(IS).Methods We conducted a case-control study involving a total of 622 cases and 631 unrelated healthy controls which were selected from Henan Han populations,and the environment risk factors were recorded.Genotyping aimed at detecting both genetic and environmental factors in relation to IS was performed by TaqMan-polymerase chain reaction technology while interaction indexes (Υ) were calculated to determine interactions and their role models.Results The rs17222919 TG (189/622,30.4％),GG (18/622,2.9％)genotype frequencies and G (225/1244,18.1％)allele frequencies in IS subjects were significantly lower than those in controls (221/631,35.0％ ; 31/631,4.9％ ; 283/1262,22.4％ ; x2 =4.117,P =0.042 ; x2 =4.457,P =0.035 ; x2 =7.294,P =0.007).Negative interactions between TG + GG genotype and hypertension,diabetes or cigarette smoking in the occurrence of IS (Υ =0.943,0.922,0.830) were observed,whose role models were all super-multiplicative models.Conclusions According to our study,ischemic stroke is the result of the interaction of genetic and environmental factors and G allele of rs17222919 may have weakened the role of environmental factors for hypertension,diabetes and cigarette smoking in IS incidence.
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Objective To explore associations between SG13S114A/T and SG13S32A/C polymorphisms of ALOX5AP gene and the genetic susceptibility of ischemic cerebrovascular diseases (ICVD) in Henan Han population.Methods Two hundred and forty-six ICVD patients and 245 healthy controls were recruited from Han population in Henan province. Polymorphisms of SG13S114A/T and SG13S32A/C in ALOX5AP gene were genotyped in these samples by SnaPshot minisequencing method.Each genotype frequency and allele frequency were statistically analyzed and compared between ICVD group and control group using SPSS16.0 software.Haplotype and linkage disequilibrium were analyzed by SHEsis software.Results The SG13S114 AA genotype frequency ( 18.7％ ) and A allele frequency (41.3％) in ICVD group were significantly higher than those in control group (9.0％ and 32.7％,respectively; P =0.002 and P =0.005 ).It was also found that in male ICVD group and in younger ICVD group ( ＜50 years old),the SG13S114 AA genotype frequencies (22.1％ and 22.0％,respectively) and A allele frequencies (42.1％ and 42.7％,respectively) were significantly higher than those in male control group and younger control group (SG13S114 AA genotype:9.0％ and 8.9％ ; P =0.010 and P =0.006,respectively) ;A allele frequencies,34.0％ and 32.0％ ; P =0.048 and P =0.020,respectively.Finally,the prevalence of A-A haplotype in ICVD group was significantly higher than that in control group(30.4％ vs 23.5％,OR =1.419,95％ CI 1.068-1.885,P =0.015).T-C haplotype frequency of ICVD group was significantly lower than that in control group (22.0％ vs 28.8％,OR =0.698,95％ CI 0.523-0.932,P =0.014 ).Conclusions The A allele in SG13S114 loci of ALOX5AP may be a genetic risk factor for ICVD in Han population in Henan province.The association is predominant in ICVD patients of male and younger than 50 years old.Maybe A-A haplotype increases the risk of ICVD and T-C haplotype and has a protective effect against ICVD in Henan Han population.