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1.
J Biol Regul Homeost Agents ; 33(3 Suppl. 1): 145-151, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31538461

RESUMO

Nonsyndromic cleft lip with or without cleft palate is the most common craniofacial anomaly affecting around 1 in 700 live births worldwide. Clefts of the human face can be classified anatomically as cleft palate only (CPO), cleft lip only (CLO), cleft lip and palate (CLP) or a combined group of cleft lip with or without cleft palate (CL/P), based on different in embryologic development. These malformations have some genetic origin, in fact several association studies have been performed to obtain important information about the candidate genes; but more important are gene-environment interactions that play an increasing role in its etiology. Epidemiological studies have shown how environmental factors (alcohol, smoking, drugs), as well as possible gene-environment interactions, play an important role in the onset of the malformation. On the contrary, folic acid intake seems to have a protective effect. In this review, we analyze the role of environmental factors related to onset of cleft.


Assuntos
Fenda Labial/etiologia , Fissura Palatina/etiologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Fenda Labial/genética , Fissura Palatina/genética , Ácido Fólico/administração & dosagem , Interação Gene-Ambiente , Humanos , Fumar/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/complicações
2.
Medicine (Baltimore) ; 98(26): e16170, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261547

RESUMO

OBJECTIVE: Non-syndromic cleft of the lip and/or palate (NSCL/P) is one of the most common polygenic diseases. In this study, both case-control and family-based association study were used to confirm whether the Single Nucleotide Polymorphisms (SNPs) were associated with NSCL/P. METHODS: A total of 37 nuclear families and 189 controls were recruited, whose blood DNA was extracted and subjected to genotyping of SNPs of 27 candidate genes by polymerase chain reaction-improved multiple ligase detection reaction technology (PCR-iMLDR). Case-control statistical analysis was performed using the SPSS 19.0. Haplotype Relative Risk (HRR), transmission disequilibrium test (TDT), and Family-Based Association Test (FBAT) were used to test for over-transmission of the target alleles in case-parent trios. The gene-gene interactions on NSCL/P were analyzed by Unphased-3.1.4. RESULTS: In case-control statistical analysis, only C14orf49 chr14_95932477 had statistically significant on genotype model (P = .03) and allele model (P = .03). Seven SNPs had statistically significant on TDT. None of 26 alleles has association with NSCL/P on FBAT. Some SNPs had haplotype-haplotype interactions and genotype-genotype interactions. CONCLUSION: C14orf49 chr14_95932477 was significantly different between cases and controls on genotype model and allele model by case-control design. Seven SNPs were significantly different on HRR. Four SNPs were significantly different on TDT.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Fenda Labial/complicações , Fissura Palatina/complicações , Família , Feminino , Estudos de Associação Genética , Humanos , Masculino , Modelos Genéticos , Fosfatases de Fosfoinositídeos/genética , Proteínas de Transporte Vesicular/genética
3.
Zhonghua Liu Xing Bing Xue Za Zhi ; 40(6): 670-675, 2019 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-31238617

RESUMO

Objective: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect with its genetic evidence widely explored. This study explored the potential the parent-of-origin (PoO) effect of WNT pathway on the risks of NSCL/P, using a case-parent trio design. Methods: Data on the single nucleotide polymorphism (SNP) of WNT genes were selected from a genome-wide association study (GWAS). A total of 806 Chinese non-syndromic cleft lip patients, with or without cleft palate (NSCL/P) case-parent trios, were gathered from an international consortium. PoO effect of WNT pathway genes and its haplotypes were explored by log-linear models. Additional Wald tests were performed to assess: a) the heterogeneity of PoO effect between different maternal exposures, b) the interaction between PoO effect, c) maternal exposure to environmental tobacco smoke (ETS), and d) multivitamin supplementation during pregnancy. The threshold for statistical significance was adjusted as 3.47×10(-4), according to Bonferroni correction. Results: After quality control, a total of 144 SNPs within seven genes were included for analyses, among which 8 SNPs were of potential PoO effect (P<0.05). However, none of them achieved the statistical significance after Bonferroni correction. The haplotype rs4074668-rs12725747 (T-A) on WNT9A showed significant PoO effect, based on the haplotype test for PoO (P=2.74×10(-4)). In addition, no statistically significant interaction was found in further exploration of this haplotype under environmental exposures as ETS or multivitamin supplementation. Conclusions: Genes in the WNT pathway may influence the NSCL/P risks through the potential PoO effect. Particularly, the haplotype rs4074668-rs12725747 (T-A) on WNT9A presented significant PoO effect on NSCL/P, statistically. From this current study, findings on WNT pathway related risks among the NSCL/P, need to be further validated by independent samples in the future.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença , Via de Sinalização Wnt/genética , Fenda Labial/fisiopatologia , Fissura Palatina/fisiopatologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Gravidez
5.
Shanghai Kou Qiang Yi Xue ; 28(1): 57-62, 2019 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-31081001

RESUMO

PURPOSE: To study DNA methylation patterns of non-syndromic cleft lip/palate(NSCL/P) using bioinformatic methods, including methylated positions and regions. METHODS: Whole blood DNA methylation data of NSCL/P samples was download from Gene Expression Omnibus(GEO) database, including 67 NSCL/P cases and 59 controls without birth defects. Data analysis included ①data cleaning, such as probes filtering, quality control and normalization; ②differential methylation analysis, including methylated positions and regions; ③Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis on differential methylated genes. R 3.4.3 software was used for data cleaning, differential methylated positions and regions analysis. DAVID6.8 tool was used for GO and KEGG analysis. RESULTS: 814 differential methylated positions were detected (adjusted P<0.001,|Δß|>0.125), of which 178 were hypermethylated in NSCL/P patients, and 636 were hypomethylated. In addition, 386 differential methylated regions were identified (P<0.05), of which 204 were hypermethylation regions and 182 were hypomethylation regions. GO analysis showed that 38 differential methylated genes were involved in 7 kinds of biological processes, 163 differential methylated genes were involved in 3 kinds of molecular functions, and 114 differential methylated genes were involved in 3 kinds of cellular components (P<0.01). KEGG analysis showed that 59 differential methylated genes were involved in 9 kinds of signal pathways. CONCLUSIONS: Abnormal DNA methylation patterns of NSCL/P might be an important epigenetic mechanism affecting the development of NSCL/P. This study might contribute to the identification of identification of biomarkers and targeted interventions of NSCL/P.


Assuntos
Fenda Labial , Fissura Palatina , Metilação de DNA , Fenda Labial/genética , Fissura Palatina/genética , Biologia Computacional , Humanos , Palato , Software
6.
J Clin Pediatr Dent ; 43(4): 288-291, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31094634

RESUMO

The 13q deletion syndrome is a rare genetic disorder caused by structural and functional monosomy of chromosome 13. On 13q34, which is the terminal of the long arm, causative genes of coagulation factors VII and X (FVII and FX) are mapped. Patients with a combination of FVII and FX deficiencies are extremely rare and there have been few articles about perioperative coagulation support for such patients. Herein, we report on a case of bilateral cleft lip and palate accompanied by 13q deletion syndrome with deficiencies of FVII and FX. The chromosomal investigation indicated 46, XX, del(13)(q33) by G-banding. Prothrombin time and activated partial thromboplastin time were found to be 21.0 seconds (sec) (prothrombin time-international normalized ratio 1.76) and 41.6 sec (normal range; 23.9 - 39.7 sec), respectively. The activities of coagulation FVII and FX were 22% and 36%, respectively. A two-stage cheiloplasty was performed at 4 and 7 months of age followed by a palatoplasty at 1 year and 6 months. Tranexamic acid was given intravenously three times a day for three days after each surgery. There were no adverse events such as bleeding from the oral or nasal cavities and healing of the surgical wound was good without dehiscence.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos , Cromossomos Humanos Par 13 , Fenda Labial , Fissura Palatina , Deficiência do Fator VII , Transtornos Cromossômicos/complicações , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 13/genética , Fenda Labial/genética , Fissura Palatina/genética , Fator VII , Deficiência do Fator VII/genética , Humanos , Palato
7.
Zhonghua Kou Qiang Yi Xue Za Zhi ; 54(3): 205-208, 2019 Mar 09.
Artigo em Chinês | MEDLINE | ID: mdl-30856701

RESUMO

With the continuous development of bioinformatics technology and precision medicine, genetic mechanism investigations of genetic diseases including cleft lip and palate (CLP) have been getting more and more attention. Researchers have focused on the coding sequence of the genome and successfully found many CLP causative mutations, but there still remain some unsolved questions. In recent years, researchers' vision has gradually shifted to non-protein coding region of the genome. This article reviews several coding sequence mutations, non-protein coding variants and their genetic mechanisms discovered in CLP researches.


Assuntos
Fenda Labial , Fissura Palatina , Fenda Labial/genética , Fissura Palatina/genética , Humanos , Mutação , RNA não Traduzido
8.
Clin Epigenetics ; 11(1): 40, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30832715

RESUMO

BACKGROUND: Isolated orofacial clefts are among the most common congenital birth defects. Although the underlying biological mechanisms remain largely unknown, clefts are thought to be complex disorders influenced by genetic, environmental, and potentially epigenetic factors. METHODS: In blood samples from 2- to 3-day-old infants (n = 747) collected in a nationwide population-based study of orofacial clefts in Norway, we measured DNA methylation profiles for more than 450,000 CpGs and then conducted epigenome-wide association analyses (EWAS). We tested methylation profile difference at each CpG between controls (n = 436) and each of the cleft subtypes (92 cleft lip only, CLO; 84 cleft palate only, CPO; 132 cleft lip and palate, CLP). We also compared controls to various combinations of case groups and compared case subtypes to each other. Finally, using the EWAS results, we searched for larger differentially methylated regions (DMRs) associated with orofacial clefts. RESULTS: In EWAS comparing controls to individual cleft subtypes, we found no significant associations at a Bonferroni P value threshold of 10-7. After pooling case groups, we found two significantly differentially methylated CpGs: cg09696939 near gene BICC1 is associated with CLO+CLP (P = 9.58 × 10-8); cg26985354 in gene CLASRP is associated with CPO+CLP (P = 7.38 × 10-8). In DMR analysis, we identified a total of 56 significant regions when comparing controls to individual cleft subtypes (10 for CLO, 6 for CPO, 41 for CLP). Only one DMR is shared among the three cleft groups. In combined case group analysis, we found 26 DMRs for CLP+CLO, 31 for CLP+CPO, and 37 when all subtypes are combined. Finally, in case-case comparisons of subtypes, we identified 10 DMRs when comparing CLP to CPO, 9 in CLP compared to CLO, and 13 in CLP compared to CPO. CONCLUSIONS: We identified two individual CpGs and multiple DMRs that differ between controls and cleft case subtypes. Although we find some evidence for the possible role of DNA methylation in etiology of orofacial clefts, our study does not support previous reports of widespread differences in blood DNA methylation between babies with and without facial clefts.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Metilação de DNA , Estudo de Associação Genômica Ampla/métodos , Proteínas de Ligação a RNA/genética , Fatores de Processamento de Serina-Arginina/genética , Estudos de Casos e Controles , Ilhas de CpG , Epigênese Genética , Feminino , Humanos , Recém-Nascido , Masculino , Noruega
9.
Mol Med Rep ; 19(5): 3831-3840, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896870

RESUMO

Congenital heart disease (CHD), and cleft lip and palate (CLP) are currently the most common types of structural malformation in infants. Various methods have been used to identify the disease­associated genes. However, targeted next­generation sequencing (NGS) is not yet considered an option for routine use. Thus, the present study aimed to assess the safety and feasibility of using targeted NGS in patients with CHD concomitant with CLP. Between November 2015 and May 2017, a total of 17 patients with CHD concomitant with CLP, who were excluded from a diagnosis of trisomy syndrome, were selected at The Second Xiangya Hospital of Central South University (Changsha, China). Genomic DNA was extracted from peripheral blood samples of the patients. The copy number variants (CNVs) were determined by conducting a single nucleotide polymorphism (SNP) array with Illumina HumanOmni1­Quad Beadchip, while information on other gene mutations was obtained from targeted sequencing. The functions of gene mutations were then predicted using the PolyPhen­2, SIFT and Mutation Taster tools. Finally, Sanger sequencing was used to verify the mutations. The results identified no pathogenic mutations in CNVs analyzed by high­throughput SNP sequencing. Targeted NGS results demonstrated that 10 patients (58.8%) carried gene mutations, including 4 (23.5%) genetically diagnosed cases and 6 (35.3%) cases with unknown etiology. The 4 known diseases were Opitz G/BBB syndrome caused by MID1 gene mutation, Loeys­Dietz syndrome caused by TGFBR1 gene mutation, Ritscher­Schinzel/3C syndrome caused by KIAA0196 gene mutation and CHARGE syndrome caused by CHD7 gene mutation. The remaining 6 cases were not genetically diagnosed, although they carried candidate genes. In conclusion, the present study demonstrated that targeted NGS was an effective and accurate candidate gene detection method in patients with CHD concomitant with CLP.


Assuntos
Biomarcadores/sangue , Fenda Labial/diagnóstico , Fissura Palatina/diagnóstico , Cardiopatias Congênitas/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Polimorfismo de Nucleotídeo Único , Criança , Pré-Escolar , Fenda Labial/sangue , Fenda Labial/complicações , Fenda Labial/genética , Fissura Palatina/sangue , Fissura Palatina/complicações , Fissura Palatina/genética , Feminino , Cardiopatias Congênitas/sangue , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/genética , Humanos , Lactente , Masculino
10.
Mol Genet Genomic Med ; 7(5): e635, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30924295

RESUMO

BACKGROUND: Nonsyndromic cleft lip and/or palate is one of the most common human birth defects worldwide that affects the lip and/or palate. The incidence of clefts varies among populations through ethnic, race, or geographical differences. The focus on Malay nonsyndromic cleft lip and/or palate (NSCL/P) is because of a scarce report on genetic study in relation to this deformity in Malaysia. We are interested to discuss about the genes that are susceptible to cause orofacial cleft formation in the family. METHODS: Genome-wide linkage analysis was carried out on eight large extended families of NSCL/P with the total of 91 individuals among Malay population using microarray platform. Based on linkage analyses findings, copy number variation (CNV) of LPHN2, SATB2, PVRL3, COL21A1, and TOX3 were identified in four large extended families that showed linkage evidence using quantitative polymerase chain reaction (qPCR) as for a validation purpose. Copy number calculated (CNC) for each genes were determined with Applied Biosystems CopyCallerTM Software v2.0. Normal CNC of the target sequence expected was set at two. RESULTS: Genome-wide linkage analysis had discovered several genes including TOX3 and COL21A1 in four different loci 4p15.2-p16.1, 6p11.2-p12.3, 14q13-q21, and 16q12.1. There was significant decreased, p < 0.05 of SATB2, COL21A1, and TOX3 copy number in extended families compared to the normal controls. CONCLUSION: Novel linkage evidence and significant low copy number of COL21A1 and TOX3 in NSCLP family was confirmed. These genes increased the risks toward NSCLP formation in that family traits.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Colágenos Fibrilares/genética , Receptores de Progesterona/genética , Fenda Labial/patologia , Fissura Palatina/patologia , Variações do Número de Cópias de DNA , Feminino , Humanos , Malásia , Masculino , Proteínas de Ligação à Região de Interação com a Matriz/genética , Linhagem , Fatores de Transcrição/genética
11.
J Dermatol ; 46(5): 422-425, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30809829

RESUMO

A Chinese female infant presented with ectodermal dysplasia, cleft palate and severe skin erosions at birth. Although all the typical clinical features of ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome were present, the ankyloblepharon was not very marked. We misdiagnosed epidermolysis bullosa and congenital ichthyosiform erythroderma at first and confirmed the diagnosis of AEC syndrome only when she presented with the typical clinical manifestation of recurrent infected scalp erosions at 1 year of age. Mutation analysis of exon 13 of the p63 gene revealed a missense mutation Ile482Thr (c.1445T>C) in the sterile alpha motive domain. In this work we review the clinical features, differential diagnosis and prognosis in AEC syndrome.


Assuntos
Fenda Labial/diagnóstico , Fissura Palatina/diagnóstico , Erros de Diagnóstico , Displasia Ectodérmica/diagnóstico , Epidermólise Bolhosa/diagnóstico , Anormalidades do Olho/diagnóstico , Pálpebras/anormalidades , Eritrodermia Ictiosiforme Congênita/diagnóstico , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Biópsia , Fenda Labial/genética , Fenda Labial/patologia , Fenda Labial/terapia , Fissura Palatina/genética , Fissura Palatina/patologia , Fissura Palatina/terapia , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Displasia Ectodérmica/terapia , Epidermólise Bolhosa/patologia , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Anormalidades do Olho/terapia , Pálpebras/patologia , Feminino , Testes Genéticos , Heterozigoto , Humanos , Eritrodermia Ictiosiforme Congênita/patologia , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Prematuro , Mutação de Sentido Incorreto , Pele/patologia
12.
Artigo em Inglês | MEDLINE | ID: mdl-30769929

RESUMO

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of common birth defects in China, with genetic and environmental components contributing to the etiology. Genome wide association studies (GWASs) have identified SPRY1 and SPRY2 to be associated with NSCL/P among Chinese populations. This study aimed to further explore potential genetic effect and gene-environment interaction among SPRY genes based on haplotype analysis, using 806 Chinese case-parent NSCL/P trios drawn from an international consortium which conducted a genome-wide association study. After the process of quality control, 190 single nucleotide polymorphisms (SNPs) of SPRY genes were included for analyses. Haplotype and haplotype-environment interaction analyses were conducted in Population-Based Association Test (PBAT) software. A 2-SNP haplotype and three 3-SNP haplotypes showed a significant association with the risk of NSCL/P after Bonferroni correction (corrected significance level = 2.6 × 10-4). Moreover, haplotype-environment interaction analysis identified these haplotypes respectively showing statistically significant interactions with maternal multivitamin supplementation or maternal environmental tobacco smoke. This study showed SPRY2 to be associated with NSCL/P among the Chinese population through not only gene effects, but also a gene-environment interaction, highlighting the importance of considering environmental exposures in the genetic etiological study of NSCL/P.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Grupo com Ancestrais do Continente Asiático/genética , China , Suplementos Nutricionais , Feminino , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Masculino , Mães , Polimorfismo de Nucleotídeo Único , Poluição por Fumaça de Tabaco , Vitaminas/administração & dosagem
13.
Genet Test Mol Biomarkers ; 23(1): 45-50, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30633559

RESUMO

OBJECTIVE: Nonsyndromic orofacial cleft (NSOFC) including cleft lip with or without cleft palate (CL±P) and cleft palate (CP) are multifactorial developmental disorders with both genetic and environmental etiological factors. In this study we investigated the association between CL±P and CP, and two polymorphisms previously determined using genome-wide association studies, as well as the association between consanguinity and CL±P and CP. METHODS: DNA was extracted from saliva specimens from 171 triads consisting of affected individuals and their parents, as well as 189 control triads (matched for age, gender, and location) that were recruited from 11 referral hospitals in Saudi Arabia. Two polymorphisms, rs4752028 and rs7078160, located in the VAX1 gene were genotyped using real-time polymerase chain reaction. A transmission disequilibrium test was carried out using the Family-Based Association Test and PLINK (genetic tool-set) to measure the parent-of-origin effect. RESULTS: Significant differences were found between affected individuals and the control group. In the case of the rs4752028 risk allele in cleft, the phenotypes were: CL±P (fathers: odds ratio [OR] 2.16 [95% CI 1.38-3.4]; mothers: OR 2.39 [95% CI 1.53-3.71]; and infants: OR 2.77 [95% CI 1.77-4.34]) and CP (fathers: OR 2.24 [95% CI 1.15-4.36] and infants: OR 2.43 [95% CI 1.25-4.7]). For CL±P and the rs7078160 risk allele, the phenotypes were: (fathers: OR 1.7 [95% CI 1.05-2.86]; mothers: OR 2.43 [95% CI 1.49-3.97]; and infants: OR 2.34 [95% CI 1.44-3.81]). In terms of consanguinity, we found significant association between consanguinity and the rs4752028 polymorphism minor allele among CL±P compared with controls (p = 0.001). CONCLUSION: This is the first study to find a relationship between these two loci on 10q25 (rs4752028 and rs7078160) and NSOFC in a population with high levels of consanguinity.


Assuntos
Encéfalo/anormalidades , Fenda Labial/genética , Fissura Palatina/genética , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Adulto , Alelos , Estudos de Casos e Controles , Consanguinidade , Família , Feminino , Heterogeneidade Genética , Predisposição Genética para Doença/genética , Testes Genéticos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Arábia Saudita
14.
Arch Oral Biol ; 98: 273-279, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30579244

RESUMO

OBJECTIVE: To evaluate the association between polymorphism of reduced folate carrier 1 (RFC1) A80 G in infants and the risk of non-syndromic cleft lip/palate (NSCL/P), in a meta-analysis of case-control studies. DESIGN: We searched databases of PubMed, Scopus, Web of Science, and Cochrane Library for studies on the association of mentioned polymorphism and NSCL/P risk published until August 2018. RESULTS: Seven articles were selected based on the criteria and were analyzed in this meta-analysis (1486 NSCL/P patients and 1596 controls). Overall, it was not obtained a significant association between the polymorphism and NSCL/P risk, with the exception of the recessive model (odds ratio = 1.45; 95% confidence interval = 1.03, 2.05; P = 0.03). A subgroup analysis showed that the frequency of GG genotype in the homozygote and recessive models in the Caucasian ethnicity was significantly higher in NSCL/P patients than in controls. Sensitivity analysis showed that the frequency of G allele and GG genotype in NSCL/P cases was significantly higher than that in controls. CONCLUSIONS: The results identified an association between the GG genotype and NSCL/P risk and just confirmed this association in the Caucasian ethnicity. Therefore, the GG genotype of RFC1 (A80 G) polymorphism can be related to NSCL/P risk in some ethnicities more than others.


Assuntos
Fenda Labial/genética , Palato , Polimorfismo Genético , Proteína Carregadora de Folato Reduzido/genética , Alelos , Bases de Dados Factuais , Frequência do Gene , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Lactente
15.
Oral Dis ; 25(3): 803-811, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30578605

RESUMO

OBJECTIVE: Non-syndromic tooth agenesis (NSTA) may share common genetic factors with non-syndromic cleft lip with or without cleft palate (NSCL/P). Single-nucleotide polymorphisms (SNPs) were associated with individual's susceptibility to these anomalies. We selected five NSCL/P-associated SNPs from our previous genome-wide association study (GWAS) to test for the associations with NSTA. MATERIALS AND METHODS: A total of 677 NSTA cases and 1,144 healthy controls were recruited in this case-control study. Five genome-wide NSCL/P-associated SNPs (rs2235371, rs7078160, rs8049367, rs4791774, and rs13041247) were genotyped by TaqMan platform and evaluated for the associations with NSTA using plink software. RESULTS: No significant associations between these SNPs and risk of NSTA were observed in the overall analysis and subgroup analysis with the number of missing teeth. However, in the subgroup analysis by tooth position, rs8049367 was nominally associated with mandibular premolar agenesis (Dominant model: ORdom  = 0.66, 95% CIdom  = 0.47-0.93, pdom  = 0.016; Heterozygote model: ORhet  = 0.60, 95% CIhet  = 0.41-0.88, Phet  = 0.008). Rs4791774 showed a nominal association with congenitally missing maxillary canine (Dominant model: ORdom  = 0.53, 95% CIdom  = 0.28-0.98, pdom  = 0.041; Heterozygote model: ORhet  = 0.50, 95% CIhet  = 0.26-0.97, Phet  = 0.041) and premolar (Additive model: OR = 0.59, 95% CI = 0.36-0.96, p = 0.035). CONCLUSION: This study showed that NSCL/P susceptible loci rs8049367 and rs4791774 were probably associated with the risk of NSTA.


Assuntos
Anodontia/genética , Fenda Labial/genética , Fissura Palatina/genética , Adolescente , Adulto , Anodontia/complicações , Dente Pré-Molar , Estudos de Casos e Controles , Criança , Fenda Labial/complicações , Fissura Palatina/complicações , Dente Canino , Feminino , Loci Gênicos , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Netrina-1/genética , Polimorfismo de Nucleotídeo Único , Adulto Jovem
16.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 36(6): 623-627, 2018 12 01.
Artigo em Chinês | MEDLINE | ID: mdl-30593107

RESUMO

OBJECTIVE: This study aimed to investigate the clinical phenotype and genetic characteristics of Chinese families with Van der Woude syndrome (VWS). METHODS: Clinical manifestations between 14 families and within each family were recorded. Possible inheritance modes and pathogenic genes were analyzed. Phenotypic distribution and gene frequencies were calculated. RESULTS: Of the pedigrees investigated, an autosomal dominant inheritance pattern was suggested. All patients had typical symptoms. The pathogenic gene was interferon regulatory factor 6 (IRF6). Phenotypic distribution frequencies were as follows: lip pits (91.9%), cleft lip and/or palate (73.0%), and hyperdontia (8.1%). There were significant differences in clinical phenotypes among individuals of different families and individuals of the same family. CONCLUSIONS: VWS in a Chinese population was dominantly inherited with high penetrance and variable expressivity. The pathogenic gene was IRF6. VWS in a Chinese population was genotyped as VWS1.


Assuntos
Anormalidades Múltiplas , Fenda Labial , Fissura Palatina , Cistos , Fatores Reguladores de Interferon , Lábio/anormalidades , Anormalidades Múltiplas/genética , Fenda Labial/genética , Fissura Palatina/genética , Cistos/genética , Humanos , Fatores Reguladores de Interferon/genética , Mutação , Linhagem , Síndrome
17.
Genomics Proteomics Bioinformatics ; 16(5): 354-364, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30578914

RESUMO

The isolated type of orofacial cleft, termed non-syndromic cleft lip with or without cleft palate (NSCL/P), is the second most common birth defect in China, with Asians having the highest incidence in the world. NSCL/P involves multiple genes and complex interactions between genetic and environmental factors, imposing difficulty for the genetic assessment of the unborn fetus carrying multiple NSCL/P-susceptible variants. Although genome-wide association studies (GWAS) have uncovered dozens of single nucleotide polymorphism (SNP) loci in different ethnic populations, the genetic diagnostic effectiveness of these SNPs requires further experimental validation in Chinese populations before a diagnostic panel or a predictive model covering multiple SNPs can be built. In this study, we collected blood samples from control and NSCL/P infants in Han and Uyghur Chinese populations to validate the diagnostic effectiveness of 43 candidate SNPs previously detected using GWAS. We then built predictive models with the validated SNPs using different machine learning algorithms and evaluated their prediction performance. Our results showed that logistic regression had the best performance for risk assessment according to the area under curve. Notably, defective variants in MTHFR and RBP4, two genes involved in folic acid and vitamin A biosynthesis, were found to have high contributions to NSCL/P incidence based on feature importance evaluation with logistic regression. This is consistent with the notion that folic acid and vitamin A are both essential nutritional supplements for pregnant women to reduce the risk of conceiving an NSCL/P baby. Moreover, we observed a lower predictive power in Uyghur than in Han cases, likely due to differences in genetic background between these two ethnic populations. Thus, our study highlights the urgency to generate the HapMap for Uyghur population and perform resequencing-based screening of Uyghur-specific NSCL/P markers.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Aprendizado de Máquina , Polimorfismo de Nucleotídeo Único , Grupo com Ancestrais do Continente Asiático/genética , China/etnologia , Estudo de Associação Genômica Ampla , Humanos , Lactente , Modelos Logísticos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Proteínas Plasmáticas de Ligação ao Retinol/genética , Medição de Risco
18.
Genet Epidemiol ; 42(7): 664-672, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30277614

RESUMO

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans and is notable for its apparent sexual dimorphism where approximately twice as many males are affected as females. The sources of this disparity are largely unknown, but interactions between genetic and sex effects are likely contributors. We examined gene-by-sex (G × S) interactions in a worldwide sample of 2,142 NSCL/P cases and 1,700 controls recruited from 13 countries. First, we performed genome-wide joint tests of the genetic (G) and G × S effects genome-wide using logistic regression assuming an additive genetic model and adjusting for 18 principal components of ancestry. We further interrogated loci with suggestive results from the joint test ( p < 1.00 × 10 -5 ) by examining the G × S effects from the same model. Out of the 133 loci with suggestive results ( p < 1.00 × 10 -5 ) for the joint test, we observed one genome-wide significant G × S effect in the 10q21 locus (rs72804706; p = 6.69 × 10 -9 ; OR = 2.62 CI [1.89, 3.62]) and 16 suggestive G × S effects. At the intergenic 10q21 locus, the risk of NSCL/P is estimated to increase with additional copies of the minor allele for females, but the opposite effect for males. Our observation that the impact of genetic variants on NSCL/P risk differs for males and females may further our understanding of the genetic architecture of NSCL/P and the sex differences underlying clefts and other birth defects.


Assuntos
Alelos , Encéfalo/anormalidades , Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Caracteres Sexuais , Estudos de Casos e Controles , Epistasia Genética , Feminino , Frequência do Gene/genética , Loci Gênicos , Humanos , Masculino , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Fatores de Risco
19.
Medicine (Baltimore) ; 97(34): e12057, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30142861

RESUMO

The aim of this study was to investigate the value of chromosomal microarray analysis (CMA) for the prenatal diagnosis of orofacial clefts.A total of 143 fetuses with oral clefts were detected by ultrasound during prenatal exam between 2012 and 2017 in our center. We categorized the cases into 4 groups: isolated cleft lip (CL) (CL only), isolated cleft palate (CP only), isolated cleft lip and palate (CLP) (CLP only), and syndromic CLP (combined with other malformations). The CMA was performed in all cases, while 139 fetuses were referred for G-banded chromosome analysis.There were 42 male and 10 female fetuses were born, with a sex ratio of 4.2:1. The isolated CLP group accounted for 74.1% (106/143) of cases, while the isolated CL, isolated CP, and syndromic CP groups accounted for 13.9% (20/143), 2% (3/143), and 10% (14/143), respectively. A total of 11 fetuses had pathogenic copy number variants (CNVs, 7.7%), including isolated CP (1/143, 0.7%), isolated CLP (5/143, 3.5%), and syndromic CLP (5/143, 3.5%). Compared with the CMA results, 5 fetuses were found to have an abnormal karyotype (5/139, 3.6%). However, no abnormalities were found in either karyotype analysis or CMA in the isolated CL group.CMA is a valuable tool for identifying submicroscopic chromosomal abnormalities in the prenatal diagnosis of oral clefts. An excellent outcome can be expected for fetuses with isolated CL that are negative for chromosomal abnormalities.


Assuntos
Transtornos Cromossômicos/diagnóstico , Fenda Labial/diagnóstico , Fissura Palatina/diagnóstico , Análise em Microsséries/métodos , China , Aberrações Cromossômicas , Transtornos Cromossômicos/genética , Fenda Labial/genética , Fissura Palatina/genética , Variações do Número de Cópias de DNA , Feminino , Feto , Humanos , Recém-Nascido , Cariotipagem , Masculino , Gravidez , Diagnóstico Pré-Natal
20.
Eur J Pediatr ; 177(11): 1727-1731, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30088137

RESUMO

Sweating deficiency has been reported to represent a cardinal symptom of ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome and ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome, two rare p63-associated disorders. According to online resources, hypohidrosis may lead to most life-threatening complications in affected patients. Thus, counseling on the prevention of hyperthermia would be indispensable in case of such syndromes, although detailed information on this issue is missing in the literature. We investigated 14 individuals with ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome (age range 2-48 years) and 9 individuals with ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome (0.5-60 years of age) by confocal laser scanning microscopy to determine their palmar sweat duct density and by quantification of pilocarpine-induced sweating. Genotype-phenotype correlations were assessed. In 12 of 23 patients (52%), a normal amount of sweat ducts was detected. These individuals (9 with ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome, 3 with ankyloblepharon-ectodermal dysplasia-cleft lip/palate syndrome) produced sufficient sweat volumes (≥ 20 µl) in response to pilocarpine. All other patients had clearly reduced sweating ability and fewer sweat glands, but no anhidrosis. Alteration of a specific proline residue (Pro590) of p63 was consistently linked to impaired perspiration.Conclusion: Hypohidrosis in p63-associated syndromes is less common and potentially less severe than previously thought and may be attributable to certain genotypes. What is Known: • Hypohidrosis which has been listed as a cardinal symptom of AEC and EEC syndromes may lead to life-threatening hyperthermia. What is New: • Patients with EEC and AEC syndromes often can sweat normally. • Hypohidrosis seems to be attributed to certain TP63 genotypes.


Assuntos
Fenda Labial/complicações , Fissura Palatina/complicações , Displasia Ectodérmica/complicações , Anormalidades do Olho/complicações , Pálpebras/anormalidades , Hipo-Hidrose/etiologia , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Criança , Pré-Escolar , Fenda Labial/genética , Fissura Palatina/genética , Displasia Ectodérmica/genética , Anormalidades do Olho/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Pilocarpina/administração & dosagem , Glândulas Sudoríparas/anormalidades , Sudorese/fisiologia , Adulto Jovem
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