Non-syndromic Cleft Lip and Palate Polymorphisms Affect Normal Lip Morphology

Wilson-Nagrani, Caryl; Richmond, Stephen; Paternoster, Lavinia

doi:10.3389/fgene.2018.00413

Cited by 12 publications

(10 citation statements)

References 52 publications

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“…5E). Although overt clefts of the lip represent a clinically relevant outcome of impaired lip development in humans, more subtle genetic alterations are increasingly recognized to manifest as milder phenotypes affecting lip and mid-facial morphology in the unaffected population (Boehringer et al, 2011;Liu et al, 2012;Miller et al, 2014;Wilson-Nagrani et al, 2018;Xiong et al, 2019). Our comparison identified a considerable overlap between genes identified in the 'organ morphogenesis' pathway and those associated with facial variations, thus supporting the concept of shared genetic effects on orofacial clefting and variations of facial development.…”

Section: Msx1 Deficiency Induces Pax9-dependent Morphogenetic Regulationsupporting

confidence: 63%

Msx1 deficiency interacts with hypoxia and induces a morphogenetic regulation during lip development

et al. 2020

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Nonsyndromic clefts of the lip and palate are common birth defects resulting from gene-gene and gene-environment interactions. Mutations in human MSX1 have been linked to orofacial clefting and we show here that Msx1 deficiency causes a growth defect of the medial nasal process (Mnp) in mouse embryos. Although this defect alone does not disrupt lip formation, Msx1-deficient embryos develop a cleft lip when the mother is transiently exposed to reduced oxygen levels or to phenytoin, a drug known to cause embryonic hypoxia. In the absence of interacting environmental factors, the Mnp growth defect caused by Msx1 deficiency is modified by a Pax9-dependent 'morphogenetic regulation', which modulates Mnp shape, rescues lip formation and involves a localized abrogation of Bmp4-mediated repression of Pax9. Analyses of GWAS data revealed a genome-wide significant association of a Gene Ontology morphogenesis term (including assigned roles for MSX1, MSX2, PAX9, BMP4 and GREM1) specifically for nonsyndromic cleft lip with cleft palate. Our data indicate that MSX1 mutations could increase the risk for cleft lip formation by interacting with an impaired morphogenetic regulation that adjusts Mnp shape, or through interactions that inhibit Mnp growth.

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Section: Msx1 Deficiency Induces Pax9-dependent Morphogenetic Regulationsupporting

confidence: 63%

Msx1 deficiency interacts with hypoxia and induces a morphogenetic regulation during lip development

et al. 2020

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“…In this study, low heritability was specifically observed in the small segments around the philtrum (segments 48–55) and cheeks (segment 32), whether or not significant. A number of genes associated with lip morphology have previously been identified ( Wilson-Nagrani, 2016 ), yet differing levels of heritability were reported in literature (Tables 1 – 3 ). Moderate heritability of the mouth (segment 38) was found in this study.…”

Section: Discussionmentioning

confidence: 99%

Spatially Dense 3D Facial Heritability and Modules of Co-heritability in a Father-Offspring Design

Hoskens

Indencleef

et al. 2018

Front. Genet.

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Introduction: The human face is a complex trait displaying a strong genetic component as illustrated by various studies on facial heritability. Most of these start from sparse descriptions of facial shape using a limited set of landmarks. Subsequently, facial features are preselected as univariate measurements or principal components and the heritability is estimated for each of these features separately. However, none of these studies investigated multivariate facial features, nor the co-heritability between different facial features. Here we report a spatially dense multivariate analysis of facial heritability and co-heritability starting from data from fathers and their children available within ALSPAC. Additionally, we provide an elaborate overview of related craniofacial heritability studies.Methods: In total, 3D facial images of 762 father-offspring pairs were retained after quality control. An anthropometric mask was applied to these images to establish spatially dense quasi-landmark configurations. Partial least squares regression was performed and the (co-)heritability for all quasi-landmarks (∼7160) was computed as twice the regression coefficient. Subsequently, these were used as input to a hierarchical facial segmentation, resulting in the definition of facial modules that are internally integrated through the biological mechanisms of inheritance. Finally, multivariate heritability estimates were obtained for each of the resulting modules.Results: Nearly all modular estimates reached statistical significance under 1,000,000 permutations and after multiple testing correction (p ≤ 1.3889 × 10-3), displaying low to high heritability scores. Particular facial areas showing the greatest heritability were similar for both sons and daughters. However, higher estimates were obtained in the former. These areas included the global face, upper facial part (encompassing the nasion, zygomas and forehead) and nose, with values reaching 82% in boys and 72% in girls. The lower parts of the face only showed low to moderate levels of heritability.Conclusion: In this work, we refrain from reducing facial variation to a series of individual measurements and analyze the heritability and co-heritability from spatially dense landmark configurations at multiple levels of organization. Finally, a multivariate estimation of heritability for global-to-local facial segments is reported. Knowledge of the genetic determination of facial shape is useful in the identification of genetic variants that underlie normal-range facial variation.

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“…(2) those identified by structural abnormalities of chromosomes, syndromes associated with known teratogens, like Pato Syndrome, Trisomy 18, Turner Syndrome, and Down Syndrome; (3) those with idiopathic etiologies that are ambiguous and, therefore, currently unknown (13). Nonsyndromic clefts are primarily classified as polygenic and multifactorial disorders and have specific characteristics.…”

Section: Classification and Etiology In Syndromic And Nonsyndromic Cleft Lip And Palatementioning

confidence: 99%

Orofacial Closure Defects: Forty-Five Genes Associated Cleft Lip and Palate

Ashouri¹,

Hamidreza

Ebadifar

2021

Precis Med Clin OMICS

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Context: Cleft lip and palate (CLP) is the most common congenital malformations in the face and neck. Given that the inheritance of this disease is multifactorial and both genetic and environmental factors play crucial roles in its creation, studying these factors may be a step toward reducing the prevalence of the disease in future generations. Method: For this study, we looked through several national and international databases, consisting of Scientific Information Database, IranDoc, ScienceDirect, Google Scholar, PubMed, and Scopus. Based on our search method, we found 800 published articles, of which 750 were obtained from the international databases, and the remaining 50 were extracted from the national databases. After data refining, 600 articles with eligible criteria remained for data extraction, and data related to embryological origin, classification and etiology, genes and environmental factors, and complications caused by CLP were collected. Results: The CLP etiology was multifactorial and involved both genetic and environmental risk factors. The primary purpose of this review was to give the reader an overview of studies on multifactorial causes of this congenital disability. The functions of genes are very different, indicating a high level of vulnerability in the cranial and facial growth pathways. Conclusions: These findings have advanced our understanding of genes associated with CLP and genetic polymorphisms involved in orofacial closure defects. The findings can create new clinical and molecular research opportunities.

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Non-syndromic Cleft Lip and Palate Polymorphisms Affect Normal Lip Morphology

Cited by 12 publications

References 52 publications

Msx1 deficiency interacts with hypoxia and induces a morphogenetic regulation during lip development

Msx1 deficiency interacts with hypoxia and induces a morphogenetic regulation during lip development

Spatially Dense 3D Facial Heritability and Modules of Co-heritability in a Father-Offspring Design

Orofacial Closure Defects: Forty-Five Genes Associated Cleft Lip and Palate

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