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1.
Mutat Res ; 785: 108319, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32800270

RESUMO

Cleft lip and palate (CL/P) is among the most common congenital malformations and affects 1 in 700 newborns. CL/P is caused by genetic and environmental factors (maternal smoking, alcohol or drug use and others). Many genes and loci were associated with cleft lip/palate but the amount of heterogeneity justifies identifying new causal genes and variants. AHRR (Aryl-Hydrocarbon Receptor Repressor) gene has recently been related to CL/P however, few functional studies analyze the genotypephenotype interaction of AHRR with CL/P. Several studies associate the molecular pathway of AHRR to CL/P which indicates this gene as a functional candidate in CL/P etiology. METHODS: Systematic Literature Review was performed using PUBMED database with the keywords cleft lip, cleft palate, orofacial cleft, AHRR and synonyms. SLR resulted in 37 included articles. RESULTS: AHRR is a positional and functional candidate gene for CL/P. In silico analysis detected interactions with other genes previously associated to CL/P like ARNT and CYP1A1. AHRR protein regulates cellular toxicity through TCDD mediated AHR pathway. Exposure to TCDD in animal embryos is AHR mediated and lead to cleft palate due to palate fusion failure and post fusion rupture. AHRR regulates cellular growth and differentiation, fundamental to lip and palatogenesis. AHRR decreases carcinogenesis and recently a higher tumor risk has been described in CL/P patients and families. AHRR is also a smoking biomarker due to changed methylation sites found in smokers DNA although folate intake may partially revert these methylation alterations. This corroborates the role of maternal smoking and lack of folate supplementation as risk factors for CL/P. CONCLUSION: This research identified the importance of AHRR in dioxin response and demonstrated an example of genetic and environmental interaction, indispensable in the development of many complex diseases.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fenda Labial/genética , Fissura Palatina/genética , Proteínas Repressoras/genética , Fumar/efeitos adversos , Motivos de Aminoácidos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Biomarcadores/metabolismo , Metilação de DNA , Suplementos Nutricionais , Feminino , Ácido Fólico/metabolismo , Estudos de Associação Genética , Humanos , Recém-Nascido , Masculino , Modelos Moleculares , Domínios Proteicos , Isoformas de RNA/genética , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Fatores de Risco
2.
Am J Hum Genet ; 107(1): 124-136, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32574564

RESUMO

Although de novo mutations (DNMs) are known to increase an individual's risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 child-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs to an individual's OFC risk. Overall, we identified a significant excess of loss-of-function DNMs in genes highly expressed in craniofacial tissues, as well as genes associated with known autosomal dominant OFC syndromes. This analysis also revealed roles for zinc-finger homeobox domain and SOX2-interacting genes in OFC etiology.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença/genética , Mutação/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento Completo do Genoma/métodos
3.
Hum Genet ; 139(10): 1261-1272, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32318854

RESUMO

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect for which only ~ 20% of the underlying genetic variation has been identified. Variants in noncoding regions have been increasingly suggested to contribute to the missing heritability. In this study, we investigated whether variation in craniofacial enhancers contributes to NSCLP. Candidate enhancers were identified using VISTA Enhancer Browser and previous publications. Prioritization was based on patterning defects in knockout mice, deletion/duplication of craniofacial genes in animal models and results of whole exome/whole genome sequencing studies. This resulted in 20 craniofacial enhancers to be investigated. Custom amplicon-based sequencing probes were designed and used for sequencing 380 NSCLP probands (from multiplex and simplex families of non-Hispanic white (NHW) and Hispanic ethnicities) using Illumina MiSeq. The frequencies of identified variants were compared to ethnically matched European (CEU) and Los Angeles Mexican (MXL) control genomes and used for association analyses. Variants in mm427/MSX1 and hs1582/SPRY1 showed genome-wide significant association with NSCLP (p ≤ 6.4 × 10-11). In silico analysis showed that these enhancer variants may disrupt important transcription factor binding sites. Haplotypes involving these enhancers and also mm435/ABCA4 were significantly associated with NSCLP, especially in NHW (p ≤ 6.3 × 10-7). Importantly, groupwise burden analysis showed several enhancer combinations significantly over-represented in NSCLP individuals, revealing novel NSCLP pathways and supporting a polygenic inheritance model. Our findings support the role of craniofacial enhancer sequence variation in the etiology of NSCLP.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Elementos Facilitadores Genéticos , Predisposição Genética para Doença , Variação Genética , Herança Multifatorial , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Doenças Assintomáticas , Fenda Labial/etnologia , Fenda Labial/patologia , Fissura Palatina/etnologia , Fissura Palatina/patologia , Embrião de Mamíferos , Grupo com Ancestrais do Continente Europeu , Feminino , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Hispano-Americanos , Humanos , Fator de Transcrição MSX1/genética , Masculino , Proteínas de Membrana/genética , Camundongos , Linhagem , Fosfoproteínas/genética , Estados Unidos
4.
PLoS Comput Biol ; 16(4): e1007819, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32287273

RESUMO

Historically, the majority of statistical association methods have been designed assuming availability of SNP-level information. However, modern genetic and sequencing data present new challenges to access and sharing of genotype-phenotype datasets, including cost of management, difficulties in consolidation of records across research groups, etc. These issues make methods based on SNP-level summary statistics particularly appealing. The most common form of combining statistics is a sum of SNP-level squared scores, possibly weighted, as in burden tests for rare variants. The overall significance of the resulting statistic is evaluated using its distribution under the null hypothesis. Here, we demonstrate that this basic approach can be substantially improved by decorrelating scores prior to their addition, resulting in remarkable power gains in situations that are most commonly encountered in practice; namely, under heterogeneity of effect sizes and diversity between pairwise LD. In these situations, the power of the traditional test, based on the added squared scores, quickly reaches a ceiling, as the number of variants increases. Thus, the traditional approach does not benefit from information potentially contained in any additional SNPs, while our decorrelation by orthogonal transformation (DOT) method yields steady gain in power. We present theoretical and computational analyses of both approaches, and reveal causes behind sometimes dramatic difference in their respective powers. We showcase DOT by analyzing breast cancer and cleft lip data, in which our method strengthened levels of previously reported associations and implied the possibility of multiple new alleles that jointly confer disease risk.


Assuntos
Biologia Computacional/métodos , Estudo de Associação Genômica Ampla/métodos , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Mama/genética , Fenda Labial/genética , Feminino , Marcadores Genéticos/genética , Predisposição Genética para Doença/genética , Humanos , Modelos Estatísticos
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(4): 471-474, 2020 Apr 10.
Artigo em Chinês | MEDLINE | ID: mdl-32219840

RESUMO

OBJECTIVE: To explore the genetic basis for a fetus with cleft lip and palate. METHODS: Copy number variations (CNVs) in the fetus and his parents were detected with chromosomal microarray analysis (CMA). RESULTS: As revealed by the CMA assay, the fetus has carried a 228 kb deletion in Xp11.22 region and a 721 kb duplication in 9p21.1. Both CNVs were inherited from the parents. The CNV in Xp11.22 was predicted to be pathogenic by involving the PHF8 gene, whilst the CNV in 9p21.1 was predicted to be benign. CONCLUSION: Deletion of the Xp11.22 region probably underlies the cleft lip and palate in this fetus.


Assuntos
Fenda Labial , Fissura Palatina , Análise em Microsséries , Diagnóstico Pré-Natal , Deleção Cromossômica , Cromossomos Humanos X/genética , Fenda Labial/diagnóstico , Fenda Labial/genética , Fissura Palatina/diagnóstico , Fissura Palatina/genética , Variações do Número de Cópias de DNA , Feminino , Feto , Histona Desmetilases , Humanos , Análise em Microsséries/métodos , Gravidez , Fatores de Transcrição
6.
PLoS One ; 15(3): e0230534, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32196525

RESUMO

Dermatoglyphic patterns on the fingers often differ in syndromes and other conditions with a developmental component, compared to the general population. Previous literature on the relationship between orofacial clefts-the most common craniofacial birth defect in humans-and dermatoglyphics is inconsistent, with some studies reporting altered pattern frequencies and/or increased asymmetry and others failing to find differences. To investigate dermatoglyphics in orofacial clefting, we obtained dermatoglyphic patterns in a large multiethnic cohort of orofacial cleft cases (N = 367), their unaffected family members (N = 836), and controls (N = 299). We categorized fingerprint pattern types from males and females who participated at five sites of the Pittsburgh Orofacial Cleft study (Hungary, United States of America (Pennsylvania, Texas), Spain, and Argentina). We also calculated a pattern dissimilarity score for each individual as a measure of left-right asymmetry. We tested for group differences in the number of arches, ulnar and radial loops, and whorls on each individual's hands, and in the pattern dissimilarity scores using ANOVA. After taking sex and site differences into account, we did not find any significant pattern count differences between cleft and non-cleft individuals. Notably, we did observe increased pattern dissimilarity in individuals with clefts, compared to both their unaffected relatives and controls. Increased dermatoglyphic pattern dissimilarity in individuals with nonsyndromic orofacial clefts may reflect a generalized developmental instability.


Assuntos
Encéfalo/anormalidades , Fenda Labial/diagnóstico , Fissura Palatina/diagnóstico , Dermatoglifia , Análise de Variância , Fenda Labial/genética , Fissura Palatina/genética , Estudos de Coortes , Família , Feminino , Humanos , Masculino , Fenótipo , Fatores Sexuais
7.
BMC Oral Health ; 20(1): 39, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019513

RESUMO

BACKGROUND: Previous genome-wide association studies have identified a link between the rs13041247 single nucleotide polymorphisms (SNPs) in the chromosome 20q12 locus and the development of the congenital malformation known as nonsyndromic cleft lip with or without cleft palate (NSCL/P). The present meta-analysis was therefore designed to formally assess the relationship between rs13041247 and NSCL/P. METHODS: We searched Embase, Web of Science, PubMed, the China National Knowledge Internet (CNKI), and the China Wanfang database in order to identify relevant published through 25 June 2019. This allowed us to identify 13 studies incorporating 4914 patients and 5981 controls for whom rs13041247 genotyping had been conducted, with STATA 12.0 then being used to conduct a meta-analysis of these pooled results. The I2 statistic was used to compare heterogeneity among studies. RESULTS: In total this analysis incorporated 13 case-control studies. No association between the rs13041247 polymorphism and NSCL/P risk was detected in individuals of Asian ethnicity (C vs T: OR = 0.847, 95% CI = 0.702-1.021; CC vs TT: OR = 0.725, 95% CI = 0.494-1.063; CC vs CT: OR = 0.837, 95% CI = 0.657-1.067; CT + TT vs CC: OR = 1.265, 95% CI = 0.951-1.684; CC + CT vs TT: OR = 0.805, 95% CI = 0.630-1.029) or Caucasian ethnicity (C vs T: OR = 0.936, 95% CI = 0.786-1.114; CC vs TT: OR = 0.988, 95% CI = 0.674-1.446; CC vs CT: OR = 1.197, 95% CI = 0.816-1.757; CT + TT vs CC: OR = 0.918, 95% CI = 0.639-1.318; CC + CT vs TT: OR = 0.855, 95% CI = 0.677-1.081). However, an overall analysis of all participants in these studies revealed the rs13041247 C allele, the CT genotype, and the CC + CT model to be linked to a reduced NSCL/P risk (C vs T: OR = 0.897, 95% CI: 0.723-1.114, P = 0.048; CT vs TT: OR = 0.839, 95% CI: 0.734-0.959, P = 0.01; CC + CT vs TT: OR = 0.824, 95% CI: 0.701-0.968, P = 0.019). CONCLUSION: These results suggest that the rs13041247 SNP located at the 20q12 chromosomal locus is associated with NSCL/P risk in an overall pooled study population, although this association was not significant in East Asian or Caucasian populations.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 20/genética , Fenda Labial/genética , Fissura Palatina/genética , Estudos de Casos e Controles , Pré-Escolar , China , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(2): 139-141, 2020 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-32034739

RESUMO

OBJECTIVE: To detect potential variant in a male fetus suspected for Ectrodactyly, Ectodermal dysplasia, Cleft lip/palate (EEC) syndrome. METHODS: Peripheral blood samples of the fetus and his parents were collected for the extraction of DNA. Whole-exome sequencing was carried out to detect potential variants. Suspected variants were verified by Sanger sequencing. RESULTS: The fetus was found to carry a heterozygous c.673C>T missense variant of the Tp63 gene, which was known to underlie split-hand/split-foot malformation. The same variant was not found in either parents. CONCLUSION: The heterozygous c.673C>T missense variant of the Tp63 gene probably underlies the EEC syndrome in the fetus. Above finding also expanded the phenotypic spectrum for this variant.


Assuntos
Fenda Labial , Fissura Palatina , Displasia Ectodérmica , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Fenda Labial/genética , Fissura Palatina/genética , Displasia Ectodérmica/genética , Humanos , Deformidades Congênitas dos Membros , Masculino , Sequenciamento Completo do Exoma
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(1): 75-79, 2020 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-31922603

RESUMO

OBJECTIVE: To assess the association of JAG2 gene single nucleotide polymorphisms with the occurrence of nonsyndromic cleft lip with or without cleft palate (NSCLP) among northwest Chinese population. METHODS: A case-control study was carried out on 301 NSCLP patients and 304 healthy controls. An iMLDR(TM) genotyping technique was used to detect three single nucleotide polymorphisms (SNPs) [rs741859 (T/C), rs11621316 (A/G) and rs1057744(C/T)] of the JAG2 gene. Allelic and genotypic frequencies and haplotypic distribution among the two groups were compared. RESULTS: A significant difference was found in the frequency of C and T alleles for rs741859 between the two groups. The CT genotype of rs741859 could significantly reduce the risk for NSCLP to 65% (P< 0.05) and the risk for cleft lip with or without cleft palate (CL/P) to 62% (P< 0.05). rs11621316 and rs1057744 are in the same linkage disequilibrium (LD) region with a high degree of linkage (γ 2> 0.8), whose distribution difference between the two groups was not statistically significant (P> 0.05). CONCLUSION: The CT genotype of the JAG2 gene rs741859 may confer a protective effect for NSCLP among northwest Chinese population.


Assuntos
Fenda Labial , Fissura Palatina , Proteína Jagged-2 , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , China , Fenda Labial/genética , Fissura Palatina/genética , Frequência do Gene , Genótipo , Humanos , Proteína Jagged-2/genética
10.
Genes (Basel) ; 11(1)2020 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-31940751

RESUMO

Human midfacial clefting is a rare subset of orofacial clefting and in severe cases, the cleft separates the nostrils splitting the nose into two independent structures. To begin to understand the morphological and genetic causes of midfacial clefting we recovered the Unicorn mouse line. Unicorn embryos develop a complete midfacial cleft through the lip, and snout closely modelling human midfacial clefting. The Unicorn mouse line has ethylnitrosourea (ENU)-induced missense mutations in Raldh2 and Leo1. The mutations segregate with the cleft face phenotype. Importantly, the nasal cartilages and surrounding bones are patterned and develop normal morphology, except for the lateral displacement because of the cleft. We conclude that the midfacial cleft arises from the failure of the medial convergence of the paired medial nasal prominences between E10.5 to E11.5 rather than defective cell proliferation and death. Our work uncovers a novel mouse model and mechanism for the etiology of midfacial clefting.


Assuntos
Aldeído Oxirredutases/genética , Fenda Labial/genética , Fissura Palatina/genética , Mutação de Sentido Incorreto , Fatores de Transcrição/genética , Animais , Modelos Animais de Doenças , Etilnitrosoureia/toxicidade , Camundongos , Camundongos Mutantes , Mutagênese/efeitos dos fármacos
11.
J Vet Med Sci ; 82(2): 212-216, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-31902834

RESUMO

A 3.5-year-old, 2.9 kg, multiparous Chihuahua presented with abdominal distension; pregnancy was diagnosed. On Day 7 before parturition, prenatal sonograms showed anechoic bilateral dilated cerebral lateral ventricles, suggesting fluid-filled regions (ventriculomegaly) in one foetus. A Caesarean section was performed and the male newborn had an abnormally enlarged dome-shaped head and a cleft lip, and died 6 days after birth. According to the family pedigree, the X-linked recessive inheritance of an orofacial cleft from the unaffected mother was suggested. This report clearly demonstrates that canine foetal ventriculomegaly (hydrocephalus) can be diagnosed in utero. For dog breeds predisposed to congenital ventriculomegaly, early detection is important for the prediction of perinatal survival and adequate supportive care can be applied at delivery.


Assuntos
Fenda Labial/veterinária , Doenças do Cão/congênito , Hidrocefalia/veterinária , Diagnóstico Pré-Natal/veterinária , Animais , Cesárea/veterinária , Fenda Labial/genética , Doenças do Cão/diagnóstico por imagem , Doenças do Cão/genética , Cães , Feminino , Hidrocefalia/congênito , Hidrocefalia/diagnóstico por imagem , Masculino , Gravidez , Ultrassonografia Pré-Natal/veterinária
12.
J Oral Pathol Med ; 49(3): 201-209, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31479540

RESUMO

Orofacial clefts are facial malformations caused by the improper development of the lips and palate. Many genetic and epigenetic molecules have been involved in the mechanisms of orofacial clefts, one of which are miRNAs. This systematic review aimed to identify miRNAs associated to non-syndromic orofacial clefts in humans. After applying a series of criteria, four studies were selected for analysis. In total, one hundred miRNAs were observed in the literature, of which 57 were reported as upregulated and 43 as downregulated in all orofacial cleft classifications. Moreover, nine miRNAs were differentially expressed only in cleft palate patients, which might suggest distinct regulatory mechanisms for the etiology of cleft lips and palates. We suggest broader population sampling in order to include diverse ethnic groups in the future, as well as analyses toward identifying miRNA target genes and pathways. We highlight the need for experimental validation and of these results to allow further translational approaches and clinical applications.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , MicroRNAs/genética , Biomarcadores , Humanos
13.
Oral Dis ; 26(1): 159-165, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31713293

RESUMO

OBJECTIVE: To assess the association between polymorphic variants from SHMT1 and MTHFS genes, involved in the cytoplasmic futile folate cycle, and the risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P) in the Chilean population. SUBJECTS AND METHODS: In a sample of 139 Chilean NSCL/P cases and 278 controls, we obtained the genotypes for nine variants of SHMT1 and MTHFS and the association between them and the phenotype was evaluated using odds ratios (OR) in additive (allele), dominant, and recessive models. RESULTS: After correction for multiple comparisons, only the variant rs1979277 (G > A; p.Leu474Phe) from SHMT1 showed a significant and protective effect for additive (OR 0.60; 95% CI 0.42-0.86; p = .0054, q = 0.0488) and dominant models (OR 0.48; 95% CI 0.29-0.75; p = .0009; q = 0.0081). Our bioinformatic prediction plus functional evidence from previous reports demonstrate that the A allele for this missense variant decreases the enzymatic activity. CONCLUSIONS: Owing to the rs1979277 A allele, which reduces the cytoplasmic SHMT activity and has a higher frequency in controls than in NSCL/P cases, we hypothesized that a low enzyme activity may increase the cytoplasmic concentration of folates and, therefore, explain the protective role against OFCs.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Glicina Hidroximetiltransferase/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Chile , Feminino , Genótipo , Humanos , Masculino
14.
Oral Dis ; 26(1): 145-151, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31564061

RESUMO

OBJECTIVE: To investigate the association of single-nucleotide polymorphisms (SNP) in grainyhead-like 3 (GRHL3) and to verify its possible interactions with others genes responsible for craniofacial development in the risk of non-syndromic oral cleft (NSOC). METHODS: Applying TaqMan allelic discrimination assays, we evaluated GRHL3 SNPs (rs10903078, rs41268753, and rs4648975) in an ancestry-structured case-control sample composed of 1,127 Brazilian participants [272 non-syndromic cleft palate only (NSCPO), 242 non-syndromic cleft lip only (NSCLO), 319 non-syndromic cleft lip and palate (NSCLP), and 294 healthy controls]. Additionally, SNP-SNP interactions of GRHL3 and previously reported variants in FAM49A, FOXE1, NTN1, and VAX1 were verified in non-syndromic cleft lip with or without cleft palate (NSCL ± P). To eliminate false-positive associations, Bonferroni correction or 1,000 permutation method was applied. RESULTS: The multiple logistic regression analysis showed that the CC genotype of rs10903078 (p = .03) and the haplotype C-C formed by the SNPs rs10903078 and rs41268753 (p = .04) were associated with NSCLO, but the p-values did not withstand Bonferroni correction. However, SNP-SNP test revealed significant interactions between GRHL3 SNPs and FAM49A (rs7552), FOXE1 (rs3758249), VAX1 (rs7078160 and rs751231), and NTN1 (rs9891446). CONCLUSIONS: Our results confirm the importance of GRHL3 and its interactions with previously NSOC-associated genes, including FAM49A, FOXE1, NTN1, and VAX1, in the pathogenesis of NSOC in the Brazilian population.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Proteínas de Ligação a DNA/genética , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Brasil , Estudos de Casos e Controles , Feminino , Fatores de Transcrição Forkhead/genética , Predisposição Genética para Doença , Genótipo , Proteínas de Homeodomínio/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Netrina-1/genética
15.
Arch Oral Biol ; 109: 104556, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31568994

RESUMO

OBJECTIVES: To investigate the association of MSX1 rs12532 polymorphism with the risk of nonsyndromic unilateral complete cleft lip and palate (NSCLP) and tooth agenesis. MATERIALS AND METHODS: The study is comprised of 384 individuals divided into 4 groups: group 1, patients with unilateral complete NSCLP and premolar agenesis (n = 57); group 2, patients with unilateral NSCLP without tooth agenesis (n = 117); group 3, patients with premolar agenesis without oral cleft (n = 53) and group 4 (n = 157), a control group with individuals without tooth agenesis and oral cleft. Genotyping of rs12532 was carried out with Taqman chemistry, and associations were investigated using logistic regression analyses. RESULTS: Overall rs12532 allele and genotype distributions revealed no significant differences between the groups of NSCLP or tooth agenesis. CONCLUSION: Although our results are consistent with a lack of association of MSX1 rs12532 and the risk of unilateral NSCLP and tooth agenesis, further studies with additional SNPs and a more diverse ethnic cohort are warranted.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Fator de Transcrição MSX1/genética , Adolescente , Adulto , Alelos , Anodontia , Estudos de Casos e Controles , Criança , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Adulto Jovem
16.
Clin Dysmorphol ; 29(1): 24-27, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30946036

RESUMO

Microdeletion of the entire interferon regulatory factory 6 (IRF 6) gene is a rare cause of Van der Woude syndrome (VDW) with only few cases reported in medical literature. Its occurrence in multiple affected members of a family is exceptional. The aim of this presentation was to describe a Central African family with typical VDW phenotype carrying an IRF6 gene deletion. Here we reported phenotype features of members of a Central African family with VDW syndrome consisting of labioalveolar cleft, depressions of the lower lip with labial fistulae (lip pits), submucosal clefts and cleft palate. Mutation analysis by means of multiplex ligation-dependent probe amplification and chromosomal microarray revealed a 374.070 kb, deletion encompassing the entire IRF6 gene in four affected family members. Microdeletion of the entire IRF6 gene causes the classical VDW syndrome phenotype.


Assuntos
Anormalidades Múltiplas , Fenda Labial , Fissura Palatina , Cistos , Família , Deleção de Genes , Fatores Reguladores de Interferon/deficiência , Lábio/anormalidades , Linhagem , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Pré-Escolar , Fenda Labial/genética , Fenda Labial/patologia , Fissura Palatina/genética , Fissura Palatina/patologia , Cistos/genética , Cistos/patologia , República Democrática do Congo , Feminino , Humanos , Lábio/patologia , Masculino
17.
Hum Genet ; 139(2): 215-226, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31848685

RESUMO

Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic, and the genetic etiology of non-syndromic OFCs is only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families selected from a multicenter family-based OFC study. This is the first large-scale WGS study of OFC in parent-offspring trios, and a part of the Gabriella Miller Kids First Pediatric Research Program created for the study of childhood cancers and structural birth defects. WGS provides deeper and more specific genetic data than using imputation on present-day single nucleotide polymorphic (SNP) marker panels. Genotypes of case-parent trios at single nucleotide variants (SNV) and short insertions and deletions (indels) spanning the entire genome were called from their sequences using human GRCh38 genome assembly, and analyzed for association using the transmission disequilibrium test. Among genome-wide significant associations, we identified a new locus on chromosome 21 in Colombian families, not previously observed in other larger OFC samples of Latin American ancestry. This locus is situated within a region known to be expressed during craniofacial development. Based on deeper investigation of this locus, we concluded that it contributed risk for OFCs exclusively in the Colombians. This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and underscores the need for larger samples when studying for OFCs and other birth defects in populations with diverse ancestry.


Assuntos
Cromossomos Humanos Par 21/genética , Fenda Labial/genética , Fissura Palatina/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Genoma/métodos , Criança , Colômbia , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino
18.
Int J Mol Sci ; 20(23)2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31795264

RESUMO

Anterior segment dysgenesis (ASD) encompasses a spectrum of ocular disorders affecting the structures of the anterior eye chamber. Mutations in several genes, involved in eye development, are implicated in this disorder. ASD is often accompanied by diverse multisystemic symptoms and another genetic cause, such as variants in genes encoding collagen type IV. Thus, a wide spectrum of phenotypes and underlying genetic diversity make fast and proper diagnosis challenging. Here, we used AMELIE, an automatic text mining tool that enriches data with the most up-to-date information from literature, and wANNOVAR, which is based on well-documented databases and incorporates variant filtering strategy to identify genetic variants responsible for severely-manifested ASD in a newborn child. This strategy, applied to trio sequencing data in compliance with ACMG 2015 guidelines, helped us find two compound heterozygous variants of the B3GLCT gene, of which c.660+1G>A (rs80338851) was previously associated with the phenotype of Peters plus syndrome (PPS), while the second, NM_194318.3:c.755delC (p.T252fs), in exon 9 of the same gene was noted for the first time. PPS, a very rare subtype of ASD, is a glycosylation disorder, where the dysfunctional B3GLCT gene product, O-fucose-specific ß-1,3-glucosyltransferase, is ineffective in providing a noncanonical quality control system for proper protein folding in cells. Our study expands the mutation spectrum of the B3GLCT gene related to PPS. We suggest that the implementation of automatic text mining tools in combination with careful variant filtering could help translate sequencing results into diagnosis, thus, considerably accelerating the diagnostic process and, thereby, improving patient management.


Assuntos
Fenda Labial/genética , Córnea/anormalidades , Galactosiltransferases/genética , Testes Genéticos/métodos , Glucosiltransferases/genética , Transtornos do Crescimento/genética , Deformidades Congênitas dos Membros/genética , Mutação , Segmento Anterior do Olho/patologia , Fenda Labial/diagnóstico , Mineração de Dados/métodos , Transtornos do Crescimento/diagnóstico , Humanos , Recém-Nascido , Deformidades Congênitas dos Membros/diagnóstico , Análise de Sequência de DNA/métodos
19.
Genes (Basel) ; 10(12)2019 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-31817908

RESUMO

Non-syndromic cleft lip with or without cleft palate (nsCL/P) ranks among the most common human congenital malformations, and has a multifactorial background in which both exogenous and genetic risk factors act in concert. The present report describes a genome-wide association study (GWAS) involving a total of 285 nsCL/P patients and 1212 controls from the Netherlands and Belgium. Twenty of the 40 previously reported nsC/LP susceptibility loci were replicated, which underlined the validity of this sample. SNV-based analysis of the data identified an as yet unreported suggestive locus at chromosome 16p12.1 (p-value of the lead SNV: 4.17 × 10-7). This association was replicated in two of three patient/control replication series (Central European and Yemeni). Gene analysis of the GWAS data prioritized SH3PXD2A at chromosome 10q24.33 as a candidate gene for nsCL/P. To date, support for this gene as a cleft gene has been restricted to data from zebrafish and a knockout mouse model. The present GWAS was the first to implicate SH3PXD2A in non-syndromic cleft formation in humans. In summary, although performed in a relatively small sample, the present GWAS generated novel insights into nsCL/P etiology.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Cromossomos Humanos Par 16/genética , Fenda Labial/genética , Fissura Palatina/genética , Animais , Bélgica , Cromossomos Humanos Par 10/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Camundongos Knockout , Países Baixos , Fatores de Risco , Peixe-Zebra
20.
Clín. investig. ginecol. obstet. (Ed. impr.) ; 46(4): 163-166, oct.-dic. 2019. tab, graf, ilus
Artigo em Espanhol | IBECS | ID: ibc-184305

RESUMO

Los trastornos relacionados con mutaciones del gen IRF6, comprenden desde una afectación casi asintomática con la única presencia de hoyuelos labiales que son la manifestación más sutil del síndrome de van der Woude, hasta manifestaciones congénitas graves que incluyen anomalías faciales, musculoesqueléticas y genitourinarias que corresponden al síndrome de pterigium poplíteo. Pese a que existe cierta relación fenotipo-genotipo entre las mutaciones del gen IRF6, estas tienen una penetrancia incompleta y una expresión variable, inter e intrafamiliar


The disorders related to IRF6 encompass a spectrum from an almost asymptomatic affectation, with the only presence of isolated lip pits, which are a mild presentation of van der Woude syndrome, to the presence in the other extreme, of congenital manifestations that include facial anomalies, musculoskeletal and genitourinary malformations, corresponding to popliteal pterygium syndrome. Although there is a certain phenotype-genotype relationship between mutations of the IRF6 gene, such mutations have incomplete penetrance and variable inter-and intra-familial expression


Assuntos
Humanos , Feminino , Gravidez , Adulto , Anormalidades Múltiplas/diagnóstico , Fenda Labial/diagnóstico , Dedos/anormalidades , Sindactilia/diagnóstico , Mutação , Fenda Labial/genética , Deformidades Congênitas das Extremidades Inferiores/diagnóstico , Feto/anormalidades
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