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1.
Sci Adv ; 5(5): eaaw0946, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31049400

RESUMO

The transcription factor p63 is a key mediator of epidermal development. Point mutations in p63 in patients lead to developmental defects, including orofacial clefting. To date, knowledge on how pivotal the role of p63 is in human craniofacial development is limited. Using an inducible transdifferentiation model, combined with epigenomic sequencing and multicohort meta-analysis of genome-wide association studies data, we show that p63 establishes enhancers at craniofacial development genes to modulate their transcription. Disease-specific substitution mutation in the DNA binding domain or sterile alpha motif protein interaction domain of p63, respectively, eliminates or reduces establishment of these enhancers. We show that enhancers established by p63 are highly enriched for single-nucleotide polymorphisms associated with nonsyndromic cleft lip ± cleft palate (CL/P). These orthogonal approaches indicate a strong molecular link between p63 enhancer function and CL/P, illuminating molecular mechanisms underlying this developmental defect and revealing vital regulatory elements and new candidate causative genes.

2.
Eur J Hum Genet ; 27(7): 1101-1112, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30850703

RESUMO

We aimed to identify novel deletions and variants of TP63 associated with orofacial clefting (OFC). Copy number variants were assessed in three OFC families using microarray analysis. Subsequently, we analyzed TP63 in a cohort of 1072 individuals affected with OFC and 706 population-based controls using molecular inversion probes (MIPs). We identified partial deletions of TP63 in individuals from three families affected with OFC. In the OFC cohort, we identified several TP63 variants predicting to cause loss-of-function alleles, including a frameshift variant c.569_576del (p.(Ala190Aspfs*5)) and a nonsense variant c.997C>T (p.(Gln333*)) that introduces a premature stop codon in the DNA-binding domain. In addition, we identified the first missense variants in the oligomerization domain c.1213G>A (p.(Val405Met)), which occurred in individuals with OFC. This variant was shown to abrogate oligomerization of mutant p63 protein into oligomeric complexes, and therefore likely represents a loss-of-function allele rather than a dominant-negative. All of these variants were inherited from an unaffected parent, suggesting reduced penetrance of such loss-of-function alleles. Our data indicate that loss-of-function alleles in TP63 can also give rise to OFC as the main phenotype. We have uncovered the dosage-dependent functions of p63, which were previously rejected.

3.
Transl Psychiatry ; 9(1): 77, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30741946

RESUMO

Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562-3468). We observed a genome-wide significant effect (p < 1 × 10-8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10-9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10-8). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10-8) and with all the cognitive traits tested (p = 3.07 × 10-8), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10-5-10-7]) and negatively associated with ADHD PRS (p ~ [10-8-10-17]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.


Assuntos
Cognição , Dislexia/genética , Dislexia/psicologia , Adolescente , Adulto , Criança , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Adulto Jovem
4.
Epigenomics ; 11(2): 133-145, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30638414

RESUMO

AIM: To determine if nonsyndromic cleft lip with or without cleft palate (nsCL/P) genetic risk variants influence liability to nsCL/P through gene regulation pathways, such as those involving DNA methylation. MATERIALS & METHODS: nsCL/P genetic summary data and methylation data from four studies were used in conjunction with Mendelian randomization and joint likelihood mapping to investigate potential mediation of nsCL/P genetic variants. RESULTS & CONCLUSION: Evidence was found at VAX1 (10q25.3), LOC146880 (17q23.3) and NTN1 (17p13.1), that liability to nsCL/P and variation in DNA methylation might be driven by the same genetic variant, suggesting that genetic variation at these loci may increase liability to nsCL/P by influencing DNA methylation. Follow-up analyses using different tissues and gene expression data provided further insight into possible biological mechanisms.

5.
PLoS One ; 13(10): e0205895, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30379966

RESUMO

Bipolar disorder (BD) is a major psychiatric illness affecting around 1% of the global population. BD is characterized by recurrent manic and depressive episodes, and has an estimated heritability of around 70%. Research has identified the first BD susceptibility genes. However, the underlying pathways and regulatory networks remain largely unknown. Research suggests that the cumulative impact of common alleles with small effects explains only around 25-38% of the phenotypic variance for BD. A plausible hypothesis therefore is that rare, high penetrance variants may contribute to BD risk. The present study investigated the role of rare, nonsynonymous, and potentially functional variants via whole exome sequencing in 15 BD cases from two large, multiply affected families from Cuba. The high prevalence of BD in these pedigrees renders them promising in terms of the identification of genetic risk variants with large effect sizes. In addition, SNP array data were used to calculate polygenic risk scores for affected and unaffected family members. After correction for multiple testing, no significant increase in polygenic risk scores for common, BD-associated genetic variants was found in BD cases compared to healthy relatives. Exome sequencing identified a total of 17 rare and potentially damaging variants in 17 genes. The identified variants were shared by all investigated BD cases in the respective pedigree. The most promising variant was located in the gene SERPING1 (p.L349F), which has been reported previously as a genome-wide significant risk gene for schizophrenia. The present data suggest novel candidate genes for BD susceptibility, and may facilitate the discovery of disease-relevant pathways and regulatory networks.

6.
PLoS Genet ; 14(8): e1007501, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30067744

RESUMO

There is increasing evidence that genetic risk variants for non-syndromic cleft lip/palate (nsCL/P) are also associated with normal-range variation in facial morphology. However, previous analyses are mostly limited to candidate SNPs and findings have not been consistently replicated. Here, we used polygenic risk scores (PRS) to test for genetic overlap between nsCL/P and seven biologically relevant facial phenotypes. Where evidence was found of genetic overlap, we used bidirectional Mendelian randomization (MR) to test the hypothesis that genetic liability to nsCL/P is causally related to implicated facial phenotypes. Across 5,804 individuals of European ancestry from two studies, we found strong evidence, using PRS, of genetic overlap between nsCL/P and philtrum width; a 1 S.D. increase in nsCL/P PRS was associated with a 0.10 mm decrease in philtrum width (95% C.I. 0.054, 0.146; P = 2x10-5). Follow-up MR analyses supported a causal relationship; genetic variants for nsCL/P homogeneously cause decreased philtrum width. In addition to the primary analysis, we also identified two novel risk loci for philtrum width at 5q22.2 and 7p15.2 in our Genome-wide Association Study (GWAS) of 6,136 individuals. Our results support a liability threshold model of inheritance for nsCL/P, related to abnormalities in development of the philtrum.

7.
Birth Defects Res ; 110(10): 871-882, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29498243

RESUMO

BACKGROUND: Nonsyndromic cleft palate only (nsCPO) is a common and multifactorial form of orofacial clefting. In contrast to successes achieved for the other common form of orofacial clefting, that is, nonsyndromic cleft lip with/without cleft palate (nsCL/P), genome wide association studies (GWAS) of nsCPO have identified only one genome wide significant locus. Aim of the present study was to investigate whether common variants contribute to nsCPO and, if so, to identify novel risk loci. METHODS: We genotyped 33 SNPs at 27 candidate loci from 2 previously published nsCPO GWAS in an independent multiethnic sample. It included: (i) a family-based sample of European ancestry (n = 212); and (ii) two case/control samples of Central European (n = 94/339) and Arabian ancestry (n = 38/231), respectively. A separate association analysis was performed for each genotyped dataset, and meta-analyses were performed. RESULTS: After association analysis and meta-analyses, none of the 33 SNPs showed genome-wide significance. Two variants showed nominally significant association in the imputed GWAS dataset and exhibited a further decrease in p-value in a European and an overall meta-analysis including imputed GWAS data, respectively (rs395572: PMetaEU = 3.16 × 10-4 ; rs6809420: PMetaAll = 2.80 × 10-4 ). CONCLUSION: Our findings suggest that there is a limited contribution of common variants to nsCPO. However, the individual effect sizes might be too small for detection of further associations in the present sample sizes. Rare variants may play a more substantial role in nsCPO than in nsCL/P, for which GWAS of smaller sample sizes have identified genome-wide significant loci. Whole-exome/genome sequencing studies of nsCPO are now warranted.

8.
Birth Defects Res ; 110(4): 336-341, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29134786

RESUMO

Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is one of the most common congenital malformation worldwide, and its etiology involves both genetic and environmental factors. Recent genome-wide and targeted genetic studies of nsCL/P have identified numerous genetic risk loci, under the hypothesis of a multiplicative mode of inheritance. The present study investigated whether novel nsCL/P risk loci could be identified by analyzing dominant/recessive genetic effects in single nucleotide polymorphism (SNP) data from genome-wide association studies. For this purpose, a genome-wide investigation of dominant/recessive common SNP effects was performed in our previously published meta-analysis data set. Twenty-four loci were identified as candidate regions. In a subsequent association analysis in an independent study cohort of 224 nsCL/P patients and 986 controls of European descent, none of the loci could be replicated. Therefore, our strategy of identifying novel loci by applying different genetic models did not yield any novel findings, suggesting that recessive/dominant common variation only make a limited contribution to nsCL/P in Europeans. However, we cannot rule out that such effects are present at some of the loci that have previously been identified, or are present in different populations.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Genes Dominantes , Genes Recessivos , Estudo de Associação Genômica Ampla , Modelos Genéticos , Feminino , Humanos , Masculino
9.
Immunity ; 47(4): 789-802.e9, 2017 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-29045907

RESUMO

Inhibitors of the receptor tyrosine kinase c-MET are currently used in the clinic to target oncogenic signaling in tumor cells. We found that concomitant c-MET inhibition promoted adoptive T cell transfer and checkpoint immunotherapies in murine cancer models by increasing effector T cell infiltration in tumors. This therapeutic effect was independent of tumor cell-intrinsic c-MET dependence. Mechanistically, c-MET inhibition impaired the reactive mobilization and recruitment of neutrophils into tumors and draining lymph nodes in response to cytotoxic immunotherapies. In the absence of c-MET inhibition, neutrophils recruited to T cell-inflamed microenvironments rapidly acquired immunosuppressive properties, restraining T cell expansion and effector functions. In cancer patients, high serum levels of the c-MET ligand HGF correlated with increasing neutrophil counts and poor responses to checkpoint blockade therapies. Our findings reveal a role for the HGF/c-MET pathway in neutrophil recruitment and function and suggest that c-MET inhibitor co-treatment may improve responses to cancer immunotherapy in settings beyond c-MET-dependent tumors.


Assuntos
Imunoterapia/métodos , Neoplasias Experimentais/terapia , Neutrófilos/imunologia , Proteínas Proto-Oncogênicas c-met/imunologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/imunologia , Interferon gama/imunologia , Interferon gama/metabolismo , Estimativa de Kaplan-Meier , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Neutrófilos/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
10.
Mol Genet Genomic Med ; 5(5): 570-579, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28944239

RESUMO

BACKGROUND: Nonsyndromic oral clefts are craniofacial malformations, which include cleft lip with or without cleft palate. The etiology for oral clefts is complex with both genetic and environmental factors contributing to risk. Previous genome-wide association (GWAS) studies have identified multiple loci with small effects; however, many causal variants remain elusive. METHODS: In this study, we address this by specifically looking for rare, potentially damaging variants in family-based data. We analyzed both whole exome sequence (WES) data and whole genome sequence (WGS) data in multiplex cleft families to identify variants shared by affected individuals. RESULTS: Here we present the results from these analyses. Our most interesting finding was from a single Syrian family, which showed enrichment of nonsynonymous and potentially damaging rare variants in two genes: CASP9 and FAT4. CONCLUSION: Neither of these candidate genes has previously been associated with oral clefts and, if confirmed as contributing to disease risk, may indicate novel biological pathways in the genetic etiology for oral clefts.

11.
Psychiatr Genet ; 27(3): 96-102, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28272115

RESUMO

OBJECTIVES: Social anxiety disorder (SAD) is a common and heritable psychiatric disorder. However, genetic studies in SAD are rare and only a few candidate genes have been implicated so far. In the present study, we investigated whether single-nucleotide polymorphisms (SNPs) associated with other psychiatric disorders also contribute toward the development of SAD and followed up variants associated with SAD on the phenotypic level. PATIENTS AND METHODS: We genotyped a total of 24 SNPs in a German sample of 321 SAD patients and 804 controls. We carried out single-marker analyses as well as quantitative association analyses of SAD severity and harm avoidance. RESULTS: None of the variants investigated showed an association with SAD in our case-control sample after Bonferroni correction. Two SNPs reached nominal significance (rs818702, P=0.032; rs140701, P=0.048). Of these, only rs140701 showed an association in the same allelic direction as reported previously. This SNP is located within the serotonin transporter gene SLC6A4, which is the primary target of selective-serotonin reuptake inhibitors used for the treatment of depressive and anxiety disorders. The quantitative association analysis of all cases with available data on symptom severity showed four SNPs with a nominal significant association. Among these SNPs, rs10994359 showed the strongest association (P=0.001) and was located near the ANK3 gene. In addition, rs10994359 was nominally associated with harm avoidance scores (P=0.001). CONCLUSION: Our results provide further evidence for an involvement of the serotonin transporter gene SLC6A4 in the etiology of anxiety-related traits. Furthermore, our study implicates that genetic variation at the genome-wide associated bipolar disorder locus ANK3 might influence anxiety-related personality traits.


Assuntos
Transtornos de Ansiedade/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adulto , Ansiedade/genética , Ansiedade/metabolismo , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença/genética , Variação Genética , Genótipo , Alemanha , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
12.
Nat Commun ; 8: 14364, 2017 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-28232668

RESUMO

Non-syndromic cleft lip with palate (NSCLP) is the most serious sub-phenotype of non-syndromic orofacial clefts (NSOFC), which are the most common craniofacial birth defects in humans. Here we conduct a GWAS of NSCLP with multiple independent replications, totalling 7,404 NSOFC cases and 16,059 controls from several ethnicities, to identify new NSCLP risk loci, and explore the genetic heterogeneity between sub-phenotypes of NSOFC. We identify 41 SNPs within 26 loci that achieve genome-wide significance, 14 of which are novel (RAD54B, TMEM19, KRT18, WNT9B, GSC/DICER1, PTCH1, RPS26, OFCC1/TFAP2A, TAF1B, FGF10, MSX1, LINC00640, FGFR1 and SPRY1). These 26 loci collectively account for 10.94% of the heritability for NSCLP in Chinese population. We find evidence of genetic heterogeneity between the sub-phenotypes of NSOFC and among different populations. This study substantially increases the number of genetic susceptibility loci for NSCLP and provides important insights into the genetic aetiology of this common craniofacial malformation.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Loci Gênicos/genética , Predisposição Genética para Doença , Adulto , Fatores Etários , Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Fenda Labial/etnologia , Fissura Palatina/etnologia , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores Sexuais
13.
Hum Mol Genet ; 26(4): 829-842, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28087736

RESUMO

Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is among the most common human birth defects with multifactorial etiology. Here, we present results from a genome-wide imputation study of nsCL/P in which, after adding replication cohort data, four novel risk loci for nsCL/P are identified (at chromosomal regions 2p21, 14q22, 15q24 and 19p13). On a systematic level, we show that the association signals within this high-density dataset are enriched in functionally-relevant genomic regions that are active in both human neural crest cells (hNCC) and mouse embryonic craniofacial tissue. This enrichment is also detectable in hNCC regions primed for later activity. Using GCTA analyses, we suggest that 30% of the estimated variance in risk for nsCL/P in the European population can be attributed to common variants, with 25.5% contributed to by the 24 risk loci known to date. For each of these, we identify credible SNPs using a Bayesian refinement approach, with two loci harbouring only one probable causal variant. Finally, we demonstrate that there is no polygenic component of nsCL/P detectable that is shared with nonsyndromic cleft palate only (nsCPO). Our data suggest that, while common variants are strongly contributing to risk for nsCL/P, they do not seem to be involved in nsCPO which might be more often caused by rare deleterious variants. Our study generates novel insights into both nsCL/P and nsCPO etiology and provides a systematic framework for research into craniofacial development and malformation.

14.
Genom Data ; 10: 22-9, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27630819

RESUMO

Previous research suggests a genetic overlap between nonsyndromic cleft lip with or without cleft palate (NSCL/P) and cancer. The aim of the present study was to identify common genetic risk loci for NSCL/P and cancer entities that have been reported to co-occur with orofacial clefting. This was achieved through the investigation of large genome-wide association study datasets. Investigations of 12 NSCL/P single nucleotide polymorphisms (SNPs) in 32 cancer datasets, and 204 cancer SNPs in two NSCL/P datasets, were performed. The SNPs rs13041247 (20q12) and rs6457327 (6p21.33) showed suggestive evidence for an association with both NSCL/P and a specific cancer entity. These loci harbor genes of biological relevance to oncogenesis (MAFB and OCT4, respectively). This study is the first to characterize possible pleiotropic risk loci for NSCL/P and cancer in a systematic manner. The data represent a starting point for future research by identifying a genetic link between NSCL/P and cancer.

15.
Psychiatr Genet ; 26(6): 293-296, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27668412

RESUMO

Duplications in 16p11.2 are a risk factor for schizophrenia (SCZ). Using genetically modified zebrafish, Golzio and colleagues identified KCTD13 within 16p11.2 as a major driver of the neuropsychiatric phenotype observed in humans. The aims of the present study were to explore the role of KCTD13 in the development of SCZ and to provide a more complete picture of the allelic architecture at this risk locus. The exons of KCTD13 were sequenced in 576 patients. The mutations c.6G>T and c.598G>A were identified in one patient each. Both mutations were predicted to be functionally relevant and were absent from the 1000 Genomes Project data and the Exome Variant Server. The mutation c.6G>T was predicted to abolish a potential transcription factor-binding site for specifity protein 1. Altered specifity protein 1 expression has been reported in SCZ patients compared with controls. Further studies in large cohorts are warranted to determine the relevance of the two identified mutations.


Assuntos
Cromossomos Humanos Par 16 , Proteínas Nucleares/genética , Esquizofrenia/genética , Adulto , Alelos , Variações do Número de Cópias de DNA , Exoma , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença , Variação Genética , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Nucleares/metabolismo
16.
Birth Defects Res A Clin Mol Teratol ; 106(9): 767-72, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27384521

RESUMO

BACKGROUND: Nonsyndromic cleft with or without cleft palate (nsCL/P) is a common birth defect. Although genome-wide association studies (GWAS) have identified numerous risk variants, a considerable fraction of the genetic heritability remains unknown. The aim of the present study was to replicate a previous finding that de novo deletions in a 62 kb region of chromosome 7p14 are a risk factor for nsCL/P, using an independent cohort. METHODS: Data from a published case-control GWAS cohort of 399 patients and 1318 controls were used. Copy number variant (CNV) detection in the 62 kb candidate region of 7p14 was performed using QuantiSNP. Putative CNVs in probands were verified and validated by quantitative polymerase chain reaction. Segregation analyses were performed in family members for whom DNA was available. RESULTS: Within the 62 kb candidate region, a deletion of 7.4 kb showed association with nsCL/P (13/387 cases, 20/1300 controls, plowest = 0.024, odds ratio = 2.22). In all families with a sporadic case (n = 3), the deletion occurred de novo. In multiplex families, both incomplete segregation and incomplete penetrance were observed. CONCLUSION: The present data support the hypothesis that deletions at 7p14 are a common risk factor for nsCL/P. Genome-wide CNV analyses in nsCL/P cohorts are warranted to explore the functional relevance of these deletions and their contribution to nsCL/P, and to determine exact breakpoints. Birth Defects Research (Part A) 106:767-772, 2016. © 2016 Wiley Periodicals, Inc.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 7/genética , Fenda Labial/genética , Bases de Dados de Ácidos Nucleicos , Estudo de Associação Genômica Ampla , Fissura Palatina/genética , Feminino , Humanos , Masculino , Fatores de Risco
17.
Genet Med ; 18(11): 1158-1162, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26963285

RESUMO

PURPOSE: We aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole-exome sequencing (WES) and targeted resequencing in a large cohort of TA and OFC patients. METHODS: WES was performed in two unrelated patients: one with severe TA and OFC and another with severe TA only. After deleterious mutations were identified in a gene encoding low-density lipoprotein receptor-related protein 6 (LRP6), all its exons were resequenced with molecular inversion probes in 67 patients with TA, 1,072 patients with OFC, and 706 controls. RESULTS: We identified a frameshift (c.4594delG, p.Cys1532fs) and a canonical splice-site mutation (c.3398-2A>C, p.?) in LRP6, respectively, in the patient with TA and OFC and in the patient with severe TA only. The targeted resequencing showed significant enrichment of unique LRP6 variants in TA patients but not in nonsyndromic OFC patients. Of the five variants in patients with TA, two affected the canonical splice site and three were missense variants; all variants segregated with the dominant phenotype, and in one case the missense mutation occurred de novo. CONCLUSION: Mutations in LRP6 cause TA in humans.Genet Med 18 11, 1158-1162.


Assuntos
Anodontia/genética , Exoma/genética , Predisposição Genética para Doença , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Adolescente , Anodontia/patologia , Criança , Feminino , Mutação da Fase de Leitura/genética , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Linhagem , Análise de Sequência de DNA , Via de Sinalização Wnt/genética
18.
Am J Hum Genet ; 98(4): 755-62, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27018475

RESUMO

Nonsyndromic cleft lip with/without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO) are the most frequent subphenotypes of orofacial clefts. A common syndromic form of orofacial clefting is Van der Woude syndrome (VWS) where individuals have CL/P or CPO, often but not always associated with lower lip pits. Recently, ∼5% of VWS-affected individuals were identified with mutations in the grainy head-like 3 gene (GRHL3). To investigate GRHL3 in nonsyndromic clefting, we sequenced its coding region in 576 Europeans with nsCL/P and 96 with nsCPO. Most strikingly, nsCPO-affected individuals had a higher minor allele frequency for rs41268753 (0.099) than control subjects (0.049; p = 1.24 × 10(-2)). This association was replicated in nsCPO/control cohorts from Latvia, Yemen, and the UK (pcombined = 2.63 × 10(-5); ORallelic = 2.46 [95% CI 1.6-3.7]) and reached genome-wide significance in combination with imputed data from a GWAS in nsCPO triads (p = 2.73 × 10(-9)). Notably, rs41268753 is not associated with nsCL/P (p = 0.45). rs41268753 encodes the highly conserved p.Thr454Met (c.1361C>T) (GERP = 5.3), which prediction programs denote as deleterious, has a CADD score of 29.6, and increases protein binding capacity in silico. Sequencing also revealed four novel truncating GRHL3 mutations including two that were de novo in four families, where all nine individuals harboring mutations had nsCPO. This is important for genetic counseling: given that VWS is rare compared to nsCPO, our data suggest that dominant GRHL3 mutations are more likely to cause nonsyndromic than syndromic CPO. Thus, with rare dominant mutations and a common risk variant in the coding region, we have identified an important contribution for GRHL3 in nsCPO.


Assuntos
Fissura Palatina/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Fases de Leitura Aberta , Fatores de Transcrição/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Alelos , Estudos de Casos e Controles , Fenda Labial/diagnóstico , Fenda Labial/genética , Fissura Palatina/diagnóstico , Grupos de Populações Continentais/genética , Cistos/diagnóstico , Cistos/genética , Humanos , Lábio/anormalidades , Mutação , Polimorfismo de Nucleotídeo Único
19.
PLoS Genet ; 12(3): e1005914, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26968009

RESUMO

Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively). Although genetic components play an important role in nsCLP, the genetic factors that predispose to palate involvement are largely unknown. In this study, we carried out a meta-analysis on genetic and clinical data from three large cohorts and identified strong association between a region on chromosome 15q13 and nsCLP (P = 8.13 × 10(-14) for rs1258763; relative risk (RR): 1.46, 95% confidence interval (CI): 1.32-1.61)) but not nsCLO (P = 0.27; RR: 1.09 (0.94-1.27)). The 5 kb region of strongest association maps downstream of Gremlin-1 (GREM1), which encodes a secreted antagonist of the BMP4 pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold increase in risk was observed in patients displaying clefts of both the lip and soft palate but who had an intact hard palate (RR: 3.76, CI: 1.47-9.61, Pdiff<0.05). While we did not find lip or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014). The present study identified a non-coding region at 15q13 as the second, genome-wide significant locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically involves abnormalities of the lip and soft palate, which develop at different time-points and in separate anatomical regions.


Assuntos
Encéfalo/anormalidades , Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Peptídeos e Proteínas de Sinalização Intercelular/genética , Alelos , Animais , Encéfalo/patologia , Cromossomos Humanos Par 15 , Fenda Labial/patologia , Fissura Palatina/patologia , Grupo com Ancestrais do Continente Europeu , Genótipo , Humanos , Camundongos
20.
Birth Defects Res A Clin Mol Teratol ; 106(2): 81-7, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26648166

RESUMO

BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is one of the most common congenital malformations in humans. Its average global incidence is 1.7 per 1000 live births, with wide variation according to geographical location and ethnicity. Its etiology involves both genetic and environmental factors. The aim of the present study was to confirm genetic association of a selection of 15 candidate nsCL/P loci using an independent sample of the Italian population. METHODS: At least one single-nucleotide polymorphism (SNP) for each locus was genotyped in 380 nuclear trios. RESULTS: Transmission disequilibrium analysis revealed significant associations for three variants at two loci (8q24 and 1p22). Two SNPs at 8q24 showed the strongest level of association, the rs987525 (PTDT = 6.81 × 10(-6) ; homozygous relative risk = 3.60 [95% confidence interval, 2.12-6.13]), and the rs17241253 (PTDT = 1.03 × 10(-5) ; homozygous relative risk = 3.75 [95% confidence interval, 2.10-6.67]). Four additional loci (at 1q32, 3q12, 8q21, and 10q25) achieved nominally significant p-values. Two SNPs at 1p36 achieved p-values of < 0.1. The present data suggest that 6 of the 15 analyzed nsCL/P risk loci contribute significantly to nsCL/P risk in the Italian population. These include the 1p22 locus, which previous research has implicated predominantly in Asian populations. CONCLUSION: Different loci, including 8q24 and 1p22 have been found associated with nsCL/P in multiple populations. Further efforts are needed to identify causative variants and transfer knowledge to clinical application, such as personal genetic risk assessment.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Fenda Labial/epidemiologia , Fissura Palatina/epidemiologia , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Itália/epidemiologia , Desequilíbrio de Ligação/genética
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