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1.
Development ; 147(18)2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958507

RESUMO

The FaceBase Consortium was established by the National Institute of Dental and Craniofacial Research in 2009 as a 'big data' resource for the craniofacial research community. Over the past decade, researchers have deposited hundreds of annotated and curated datasets on both normal and disordered craniofacial development in FaceBase, all freely available to the research community on the FaceBase Hub website. The Hub has developed numerous visualization and analysis tools designed to promote integration of multidisciplinary data while remaining dedicated to the FAIR principles of data management (findability, accessibility, interoperability and reusability) and providing a faceted search infrastructure for locating desired data efficiently. Summaries of the datasets generated by the FaceBase projects from 2014 to 2019 are provided here. FaceBase 3 now welcomes contributions of data on craniofacial and dental development in humans, model organisms and cell lines. Collectively, the FaceBase Consortium, along with other NIH-supported data resources, provide a continuously growing, dynamic and current resource for the scientific community while improving data reproducibility and fulfilling data sharing requirements.

2.
Development ; 147(21)2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32616565

RESUMO

Understanding the etiology of congenital disorders requires interdisciplinary research and close collaborations between clinicians, geneticists and developmental biologists. The pace of gene discovery has quickened due to advances in sequencing technology, resulting in a wealth of publicly available sequence data but also a gap between gene discovery and crucial mechanistic insights provided by studies in model systems. In this Spotlight, I highlight the opportunities for developmental biologists to engage with human geneticists and genetic resources to advance the study of congenital disorders.

3.
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
4.
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
5.
Genetics ; 214(2): 295-303, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31843756

RESUMO

Standard methods for case-control association studies of rare variation often treat disease outcome as a dichotomous phenotype. However, both theoretical and experimental studies have demonstrated that subjects with a family history of disease can be enriched for risk variation relative to subjects without such history. Assuming family history information is available, this observation motivates the idea of replacing the standard dichotomous outcome variable used in case-control studies with a more informative ordinal outcome variable that distinguishes controls (0), sporadic cases (1), and cases with a family history (2), with the expectation that we should observe increasing number of risk variants with increasing category of the ordinal variable. To leverage this expectation, we propose a novel rare-variant association test that incorporates family history information based on our previous GAMuT framework for rare-variant association testing of multivariate phenotypes. We use simulated data to show that, when family history information is available, our new method outperforms standard rare-variant association methods, like burden and SKAT tests, that ignore family history. We further illustrate our method using a rare-variant study of cleft lip and palate.

6.
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
7.
Genet Epidemiol ; 43(6): 704-716, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31172578

RESUMO

Phenotypic heterogeneity is a hallmark of complex traits, and genetic studies of such traits may focus on them as a single diagnostic entity or by analyzing specific components. For example, in orofacial clefting (OFC), three subtypes-cleft lip (CL), cleft lip and palate (CLP), and cleft palate (CP) have been studied separately and in combination. To further dissect the genetic architecture of OFCs and how a given associated locus may be contributing to distinct subtypes of a trait we developed a framework for quantifying and interpreting evidence of subtype-specific or shared genetic effects in complex traits. We applied this technique to create a "cleft map" of the association of 30 genetic loci with three OFC subtypes. In addition to new associations, we found loci with subtype-specific effects (e.g., GRHL3 [CP], WNT5A [CLP]), as well as loci associated with two or all three subtypes. We cross-referenced these results with mouse craniofacial gene expression datasets, which identified additional promising candidate genes. However, we found no strong correlation between OFC subtypes and expression patterns. In aggregate, the cleft map revealed that neither subtype-specific nor shared genetic effects operate in isolation in OFC architecture. Our approach can be easily applied to any complex trait with distinct phenotypic subgroups.


Assuntos
Encéfalo/anormalidades , Fenda Labial/classificação , Fenda Labial/genética , Fissura Palatina/classificação , Fissura Palatina/genética , Loci Gênicos , Marcadores Genéticos , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla/métodos , Fenótipo , Encéfalo/patologia , Fenda Labial/patologia , Fissura Palatina/patologia , Humanos , Transcriptoma
8.
Biol Res Nurs ; 21(2): 157-165, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30700110

RESUMO

OBJECTIVE: We examined genomic variation potentially associated with the cortisol stress response in children having a painful medical procedure. DESIGN: Children 4-10 years old having a peripheral intravenous line inserted provided saliva samples for evaluation of the cortisol response as a biological measure of distress: two on the day of the procedure and two at home on a nonstressful day for comparison values. Children and biological parents also provided samples for genotyping of variants with known or suspected association with the cortisol stress response. Analysis included child-only association and family-based transmission disequilibrium tests (TDTs). RESULTS: Genotype and phenotype data on the cortisol stress response were available from 326 children for child-only association analyses and 376 complete family trios for TDTs. Children were 50% female, an average of 7.5 years old, and mostly (83%) White/non-Hispanic. We identified four single-nucleotide polymorphisms (SNPs) potentially associated with the cortisol stress response: rs1176744 ( HTR3B), rs10062367 ( CRHBP), rs634479 ( OPRM1), and rs8030107 ( NTRK3). Family-based analysis identified a two-SNP haplotype in HTR1B suggestive for association with the cortisol response (rs6296, rs11568817). Allelic TDTs identified rs7897947 ( NFKB2) as potentially related to cortisol response. CONCLUSIONS: Findings provide preliminary evidence for genes potentially important in cortisol response to an acute stressor in children in the serotonin, dopamine, and brain-derived neurotrophic factor pathways, the hypothalamic-pituitary-adrenal axis, and the inflammatory response. Combined with analyses of related phenotypes and clinical data, these results could help identify patients at increased risk of adverse responses to painful medical procedures who might benefit from tailored interventions.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Variação Genética , Hidrocortisona/genética , Hidrocortisona/metabolismo , Estresse Psicológico/genética , Estresse Psicológico/fisiopatologia , Adulto , Alelos , Criança , Pré-Escolar , Feminino , Genótipo , Haplótipos , Humanos , Sistema Hipotálamo-Hipofisário/fisiologia , Masculino , Pais , Fenótipo , Sistema Hipófise-Suprarrenal/fisiologia , Polimorfismo de Nucleotídeo Único
9.
Hum Mol Genet ; 28(10): 1726-1737, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30689861

RESUMO

Mutations in IRF6, TFAP2A and GRHL3 cause orofacial clefting syndromes in humans. However, Tfap2a and Grhl3 are also required for neurulation in mice. Here, we found that homeostasis of Irf6 is also required for development of the neural tube and associated structures. Over-expression of Irf6 caused exencephaly, a rostral neural tube defect, through suppression of Tfap2a and Grhl3 expression. Conversely, loss of Irf6 function caused a curly tail and coincided with a reduction of Tfap2a and Grhl3 expression in tail tissues. To test whether Irf6 function in neurulation was conserved, we sequenced samples obtained from human cases of spina bifida and anencephaly. We found two likely disease-causing variants in two samples from patients with spina bifida. Overall, these data suggest that the Tfap2a-Irf6-Grhl3 genetic pathway is shared by two embryologically distinct morphogenetic events that previously were considered independent during mammalian development. In addition, these data suggest new candidates to delineate the genetic architecture of neural tube defects and new therapeutic targets to prevent this common birth defect.


Assuntos
Proteínas de Ligação a DNA/genética , Fatores Reguladores de Interferon/genética , Neurulação/genética , Fator de Transcrição AP-2/genética , Fatores de Transcrição/genética , Animais , Sequência Conservada/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Camundongos , Mutação , Tubo Neural/crescimento & desenvolvimento , Tubo Neural/patologia , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/patologia , Transdução de Sinais/genética , Disrafismo Espinal/genética , Disrafismo Espinal/patologia
10.
Bioinformatics ; 35(4): 571-578, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30084993

RESUMO

MOTIVATION: De novo copy number deletions have been implicated in many diseases, but there is no formal method to date that identifies de novo deletions in parent-offspring trios from capture-based sequencing platforms. RESULTS: We developed Minimum Distance for Targeted Sequencing (MDTS) to fill this void. MDTS has similar sensitivity (recall), but a much lower false positive rate compared to less specific CNV callers, resulting in a much higher positive predictive value (precision). MDTS also exhibited much better scalability. AVAILABILITY AND IMPLEMENTATION: MDTS is freely available as open source software from the Bioconductor repository. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Algoritmos , Variações do Número de Cópias de DNA , Deleção de Sequência , Software , Biologia Computacional
11.
Am J Med Genet A ; 179(3): 467-474, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30582786

RESUMO

Genome-wide scans have shown that common risk alleles for orofacial clefts (OFC) tend to be located in noncoding regulatory elements and cumulatively explain only part of the heritability of OFCs. Low-frequency variants may account for some of the "missing" heritability. Therefore, we scanned low-frequency variants located within putative craniofacial enhancers to identify novel OFC risk variants and implicate new regulatory elements in OFC pathogenesis. Analyses were performed in a multiethnic sample of 1,995 cases of cleft lip with or without cleft palate (CL/P), 221 cases with cleft palate (CP) only, and 1,576 unaffected controls. One hundred and nineteen putative craniofacial enhancers identified from ChIP-Seq studies in craniofacial tissues or cell lines contained multiple low-frequency (0.01-1%) variants, which we genotyped in participants using a custom Illumina panel. Two complementary statistical approaches, sequence kernel association test and combined multivariate and collapsing, were used to test association of the aggregated low-frequency variants across each enhancer region with CL/P and CP. We discovered a significant association between CP and a branchial arch enhancer near FOXP1 (mm60; p-value = .0002). Additionally, we observed a suggestive association between CL/P and a forebrain enhancer near FOXE1 (hs1717; p-value = .001). These findings suggest that low-frequency variants in craniofacial enhancer regions contribute to the complex etiology of nonsyndromic OFCs.


Assuntos
Encéfalo/anormalidades , Fenda Labial/diagnóstico , Fenda Labial/genética , Fissura Palatina/diagnóstico , Fissura Palatina/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Sequências Reguladoras de Ácido Nucleico , Alelos , Elementos Facilitadores Genéticos , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único
12.
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
13.
Sci Rep ; 8(1): 8470, 2018 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-29855589

RESUMO

Velopharyngeal dysfunction (VPD) occurs when the muscular soft palate (velum) and lateral pharyngeal walls are physically unable to separate the oral and nasal cavities during speech production leading to hypernasality and abnormal speech reduction. Because VPD is often associated with overt or submucous cleft palate, it could be present as a subclinical phenotype in families with a history of orofacial clefting. A key assumption to this model is that the overt and subclinical manifestations of the orofacial cleft phenotype exist on a continuum and therefore share common etiological factors. We performed a genome-wide association study in 976 unaffected relatives of isolated CP probands, 54 of whom had VPD. Five loci were significantly (p < 5 × 10-8) associated with VPD: 3q29, 9p21.1, 12q21.31, 16p12.3 and 16p13.3. An additional 15 loci showing suggestive evidence of association with VPD were observed. Several genes known to be involved in orofacial clefting and craniofacial development are located in these regions, such as TFRC, PCYT1A, BNC2 and FREM1. Although further research is necessary, this could be an indication for a potential shared genetic architecture between VPD and cleft palate, and supporting the hypothesis that VPD is a subclinical phenotype of orofacial clefting.


Assuntos
Estudo de Associação Genômica Ampla , Insuficiência Velofaríngea/patologia , Adolescente , Adulto , Antígenos CD/genética , Criança , Colina-Fosfato Citidililtransferase/genética , Fissura Palatina/genética , Fissura Palatina/patologia , Proteínas de Ligação a DNA/genética , Feminino , Loci Gênicos , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores da Transferrina/genética , Insuficiência Velofaríngea/genética , Adulto Jovem
15.
Nat Genet ; 50(3): 414-423, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29459680

RESUMO

Genome-wide association scans of complex multipartite traits like the human face typically use preselected phenotypic measures. Here we report a data-driven approach to phenotyping facial shape at multiple levels of organization, allowing for an open-ended description of facial variation while preserving statistical power. In a sample of 2,329 persons of European ancestry, we identified 38 loci, 15 of which replicated in an independent European sample (n = 1,719). Four loci were completely new. For the others, additional support (n = 9) or pleiotropic effects (n = 2) were found in the literature, but the results reported here were further refined. All 15 replicated loci highlighted distinctive patterns of global-to-local genetic effects on facial shape and showed enrichment for active chromatin elements in human cranial neural crest cells, suggesting an early developmental origin of the facial variation captured. These results have implications for studies of facial genetics and other complex morphological traits.


Assuntos
Mapeamento Cromossômico , Face/anatomia & histologia , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Adulto , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Estudos de Associação Genética , Genótipo , Humanos , Desenvolvimento Maxilofacial/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Estados Unidos , Adulto Jovem
16.
Am J Hum Genet ; 101(6): 913-924, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29198719

RESUMO

The genetic basis of earlobe attachment has been a matter of debate since the early 20th century, such that geneticists argue both for and against polygenic inheritance. Recent genetic studies have identified a few loci associated with the trait, but large-scale analyses are still lacking. Here, we performed a genome-wide association study of lobe attachment in a multiethnic sample of 74,660 individuals from four cohorts (three with the trait scored by an expert rater and one with the trait self-reported). Meta-analysis of the three expert-rater-scored cohorts revealed six associated loci harboring numerous candidate genes, including EDAR, SP5, MRPS22, ADGRG6 (GPR126), KIAA1217, and PAX9. The large self-reported 23andMe cohort recapitulated each of these six loci. Moreover, meta-analysis across all four cohorts revealed a total of 49 significant (p < 5 × 10-8) loci. Annotation and enrichment analyses of these 49 loci showed strong evidence of genes involved in ear development and syndromes with auricular phenotypes. RNA sequencing data from both human fetal ear and mouse second branchial arch tissue confirmed that genes located among associated loci showed evidence of expression. These results provide strong evidence for the polygenic nature of earlobe attachment and offer insights into the biological basis of normal and abnormal ear development.


Assuntos
Orelha/anatomia & histologia , Herança Multifatorial/genética , Locos de Características Quantitativas/genética , Adolescente , Adulto , Animais , Região Branquial/anatomia & histologia , Criança , Pré-Escolar , Proteínas de Ligação a DNA/genética , Receptor Edar/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Camundongos , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Fator de Transcrição PAX9/genética , Proteínas/genética , Receptores Acoplados a Proteínas-G/genética , Proteínas Ribossômicas/genética , Fatores de Transcrição/genética , Adulto Jovem
17.
Genet Epidemiol ; 41(8): 887-897, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29124805

RESUMO

Orofacial clefts (OFCs) are common, complex birth defects with extremely heterogeneous phenotypic presentations. Two common subtypes-cleft lip alone (CL) and CL plus cleft palate (CLP)-are typically grouped into a single phenotype for genetic analysis (i.e., CL with or without cleft palate, CL/P). However, mounting evidence suggests there may be unique underlying pathophysiology and/or genetic modifiers influencing expression of these two phenotypes. To this end, we performed a genome-wide scan for genetic modifiers by directly comparing 450 CL cases with 1,692 CLP cases from 18 recruitment sites across 13 countries from North America, Central or South America, Asia, Europe, and Africa. We identified a region on 16q21 that is strongly associated with different cleft type (P = 5.611 × 10-8 ). We also identified significant evidence of gene-gene interactions between this modifier locus and two recognized CL/P risk loci: 8q21 and 9q22 (FOXE1) (P = 0.012 and 0.023, respectively). Single nucleotide polymorphism (SNPs) in the 16q21 modifier locus demonstrated significant association with CL over CLP. The marker alleles on 16q21 that increased risk for CL were found at highest frequencies among individuals with a family history of CL (P = 0.003). Our results demonstrate the existence of modifiers for which type of OFC develops and suggest plausible elements responsible for phenotypic heterogeneity, further elucidating the complex genetic architecture of OFCs.


Assuntos
Encéfalo/anormalidades , Cromossomos Humanos Par 16 , Fenda Labial/genética , Fissura Palatina/genética , Alelos , Encéfalo/patologia , Fenda Labial/patologia , Fissura Palatina/patologia , Grupos de Populações Continentais/genética , Feminino , Fatores de Transcrição Forkhead/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de Risco
18.
Am J Med Genet A ; 173(11): 2886-2892, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28884971

RESUMO

Nonsyndromic orofacial clefts (OFCs) are complex traits characterized by multifactorial inheritance and wide phenotypic variability. Numerous studies have shown subtle differences in the faces of unaffected relatives from cleft families compared to controls, the implication being that such outward differences are an incomplete expression reflecting an underlying genetic predisposition. Twins discordant for OFCs provide a unique opportunity to further test this idea, as the unaffected co-twin shares on average 50% (for dizygotic twins) and 100% (for monozygotic twins) of the genetic risk factors as the affected twin. We used 3D surface imaging and spatially-dense morphometry to compare facial shape in a sample of 44 unaffected co-twins and age- and sex-matched unaffected controls (n = 241). Unaffected co-twins showed statistically significant differences in the midface, lateral upper face, and forehead regions, compared to controls. Furthermore, co-twins were characterized by a distinct pattern of midfacial retrusion, broader upper faces, and greater protrusion of the mandible and brow ridges. This same general facial pattern was shown in both unaffected monozygotic and dizygotic co-twin subsets. These results provide additional support that altered facial shape is a phenotypic marker for OFC susceptibility.


Assuntos
Encéfalo/anormalidades , Fenda Labial/fisiopatologia , Fissura Palatina/fisiopatologia , Face/fisiopatologia , Mandíbula/anormalidades , Nariz/anormalidades , Adolescente , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Cefalometria , Criança , Pré-Escolar , Fenda Labial/diagnóstico por imagem , Fissura Palatina/diagnóstico por imagem , Face/anormalidades , Face/diagnóstico por imagem , Feminino , Humanos , Imageamento Tridimensional , Masculino , Mandíbula/diagnóstico por imagem , Pessoa de Meia-Idade , Nariz/diagnóstico por imagem , Fenótipo , Fatores de Risco , Gêmeos Dizigóticos , Gêmeos Monozigóticos , Adulto Jovem
19.
Birth Defects Res ; 109(13): 1030-1038, 2017 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-28762674

RESUMO

BACKGROUND: Orofacial clefts (OFCs), including nonsyndromic cleft lip with or without cleft palate (NSCL/P), are common birth defects. NSCL/P is highly heterogeneous with multiple phenotypic presentations. Two common subtypes of NSCL/P are cleft lip (CL) and cleft lip with cleft palate (CLP) which have different population prevalence. Similarly, NSCL/P can be divided into bilateral and unilateral clefts, with unilateral being the most common. Individuals with unilateral NSCL/P are more likely to be affected on the left side of the upper lip, but right side affection also occurs. Moreover, NSCL/P is twice as common in males as in females. The goal of this study is to discover genetic variants that have different effects in case subgroups. METHODS: We conducted both common variant and rare variant analyses in 1034 individuals of Asian ancestry with NSCL/P, examining four sources of heterogeneity within CL/P: cleft type, sex, laterality, and side. RESULTS: We identified several regions associated with subtype differentiation: cleft type differences in 8q24 (p = 1.00 × 10-4 ), laterality differences in IRF6, a gene previously implicated with wound healing (p = 2.166 × 10-4 ), sex differences and side of unilateral CL differences in FGFR2 (p = 3.00 × 10-4 ; p = 6.00 × 10-4 ), and sex differences in VAX1 (p < 1.00 × 10-4 ) among others. CONCLUSION: Many of the regions associated with phenotypic modification were either adjacent to or overlapping functional elements based on ENCODE chromatin marks and published craniofacial enhancers. We have identified multiple common and rare variants as potential phenotypic modifiers of NSCL/P, and suggest plausible elements responsible for phenotypic heterogeneity, further elucidating the complex genetic architecture of OFCs. Birth Defects Research 109:1030-1038, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Fenda Labial/epidemiologia , Fissura Palatina/epidemiologia , Feminino , Heterogeneidade Genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Anormalidades da Boca/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA/métodos
20.
Development ; 144(11): 2082-2091, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28506991

RESUMO

Cleft lip is one of the most common human birth defects, yet our understanding of the mechanisms that regulate lip morphogenesis is limited. Here, we show in mice that sonic hedgehog (Shh)-induced proliferation of cranial neural crest cell (cNCC) mesenchyme is required for upper lip closure. Gene expression profiling revealed a subset of Forkhead box (Fox) genes that are regulated by Shh signaling during lip morphogenesis. During cleft pathogenesis, reduced proliferation in the medial nasal process mesenchyme paralleled the domain of reduced Foxf2 and Gli1 expression. SHH ligand induction of Foxf2 expression was dependent upon Shh pathway effectors in cNCCs, while a functional GLI-binding site was identified downstream of Foxf2 Consistent with the cellular mechanism demonstrated for cleft lip pathogenesis, we found that either SHH ligand addition or FOXF2 overexpression is sufficient to induce cNCC proliferation. Finally, analysis of a large multi-ethnic human population with cleft lip identified clusters of single-nucleotide polymorphisms in FOXF2 These data suggest that direct targeting of Foxf2 by Shh signaling drives cNCC mesenchyme proliferation during upper lip morphogenesis, and that disruption of this sequence results in cleft lip.


Assuntos
Fenda Labial/genética , Fatores de Transcrição Forkhead/genética , Proteínas Hedgehog/metabolismo , Mesoderma/patologia , Morfogênese/genética , Crista Neural/patologia , Crânio/patologia , Animais , Sítios de Ligação , Proliferação de Células , Fenda Labial/patologia , Regulação para Baixo/genética , Grupos Étnicos/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Estudos de Associação Genética , Loci Gênicos , Humanos , Lábio/embriologia , Lábio/metabolismo , Mesoderma/metabolismo , Camundongos Endogâmicos C57BL , Polimorfismo de Nucleotídeo Único/genética , Transdução de Sinais/genética
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