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Event: 2042

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Ororofacial clefting

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
Cleft palate increased
cleft upper lip increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Anatagonsim SMO leads to OFC AdverseOutcome Jacob Reynolds (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
Vertebrates Vertebrates NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
Embryo High

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Orofacial clefts (OFC) are one of the most common birth defects. Orofacial clefts are commonly divided on the anatomy they affect by clefts of the lip and/or palate (CL/P) and those of the palate only (CPO) (Murray 2002). Clefts can also be classified as either syndromic when they occur with other physical or developmental anomalies or nonsydromic in the absence of other symptoms (Stanier and Moore 2004). Like most births, the etiology of OFCs are complex and include a combination of genetic and chemical factors (Lipinski and Bushman 2010, Heyne, Melberg et al. 2015). Orofacial development is tightly regulated by multiple signaling pathways and genes including: fibroblast growth factors (Fgfs), Sonic Hedgehog (shh), bone morphogenic protein (Bmp), transforming growth factor beta (Tgf- β) and transcription factors including Dlx, Pitx, Hox, Gli and T-box (Stanier and Moore 2004). Orofacial development requires precise cell migration, growth, differentiation and apoptosis to create the needed orofacial structures from the oropharyngeal membrane (Jugessur and Murray 2005).  During the sixth week of human embryogenesis the medial nasal prominences merge to form the primary palate and the upper lip. The mandibular prominences merge across the midline to produce the lower jaw and lip. Development of the secondary palate begins in the sixth week where the palatal shelves extend internally to the maxillary processes. The shelves then elevate above the tongue and grow towards each other until contact occurs. During weeks 7-8 the medial edges of the palatal shelves fuse through as series of epithelial-mesenchyme transition (EMT) and apoptosis(Jugessur and Murray 2005, Zhang, Tian et al. 2016). Disruption to the complex processes required for proper orofacial development can occur both through genetic factors and environmental (i.e. chemical) exposure by causing disruption to one or multiple steps of orofacial development resulting in OFC.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help
  • OFC can be visually observed both in humans and in animals. It can be classified by which tissues (e.g.cleft lip and palate) are effected and its’ severity (complete/incomplete, unilateral/bilateral). Techniques such as the revised Smith-modified Kernahan ‘Y’ classification can be used describe the type, location, and extent of OFC deformities (Khan, Ullah et al. 2013).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help
  • Sex- OFC can occur for all sexes. Differences in incidence between males and females have been found however a clear understanding of what causes this difference is not understood. Cleft lip with or without cleft palate is more common in males while cleft palate only is more common for females (Barbosa Martelli, Machado et al. 2012).
  • Life stages- Orofacial development and any disruption leading to clefting occurs early in embryonic development. This begins between the 6th and 12th week of pregnancy in humans and between day 10.0 and 15 in mice (Okuhara and Iseki 2012).
  • Taxonomic- Orofacial development occurs in all vertebrates.  

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

OFC is one of the most common birth defects occurring in approximately 1 in 700 live births. The etiology of OFC is poorly understood and is believed to be a combination of genetic and environmental factors. Understanding the genetic and environmental factors that can lead to OFC is the first step in preventing this birth defect.


List of the literature that was cited for this KE description. More help

Barbosa Martelli, D. R., R. A. Machado, M. S. Oliveira Swerts, L. A. Mendes Rodrigues, S. N. de Aquino and H. M. Júnior (2012). "Non sindromic cleft lip and palate: relationship between sex and clinical extension." Brazilian Journal of Otorhinolaryngology 78(5): 116-120.

Heyne, G. W., C. G. Melberg, P. Doroodchi, K. F. Parins, H. W. Kietzman, J. L. Everson, L. J. Ansen-Wilson and R. J. Lipinski (2015). "Definition of critical periods for Hedgehog pathway antagonist-induced holoprosencephaly, cleft lip, and cleft palate." PLoS One 10(3): e0120517.

Jugessur, A. and J. C. Murray (2005). "Orofacial clefting: recent insights into a complex trait." Curr Opin Genet Dev 15(3): 270-278.

Khan, M., H. Ullah, S. Naz, T. Iqbal, T. Ullah, M. Tahir and O. Ullah (2013). "A revised classification of the cleft lip and palate." Can J Plast Surg 21(1): 48-50.

Lipinski, R. J. and W. Bushman (2010). "Identification of Hedgehog signaling inhibitors with relevant human exposure by small molecule screening." Toxicol In Vitro 24(5): 1404-1409.

Murray, J. C. (2002). "Gene/environment causes of cleft lip and/or palate." Clin Genet 61(4): 248-256.

Okuhara, S. and S. Iseki (2012). "Epithelial integrity in palatal shelf elevation." Japanese Dental Science Review 48(1): 18-22.

Stanier, P. and G. E. Moore (2004). "Genetics of cleft lip and palate: syndromic genes contribute to the incidence of non-syndromic clefts." Hum Mol Genet 13 Spec No 1: R73-81.

Zhang, J., X.-J. Tian and J. Xing (2016). "Signal Transduction Pathways of EMT Induced by TGF-β, SHH, and WNT and Their Crosstalks." Journal of clinical medicine 5(4): 41.