It is possible that facial clefts are caused by a disorder in the migration of neural crest cells. Another theory is that facial clefts are caused by failure of the fusion process and failure of inwards growth of the mesoderm. Other theories are that genetics play a part in the development of facial clefts or that they are caused by amniotic bands. Genetics Overview Around one in 700 individuals are born with<unk> s. There are multiple genetic and environmental factors which contribute to<unk>  development. Within<unk>  disorders and abnormalities, orofacial clefts, and specifically cleft lip (CL) and cleft palate (CP) are the most common in humans. Occurrences of CL/P are most often (around seventy percent of cases) isolated and nonsyndromic, meaning they are not associated with a syndrome or inherited genetic conditions. Around thirty percent occur with other structural variances, and over 500 syndromes have been identified in which clefting is a principal feature. Clefting can result from teratogens, an agent that disrupts embryo development such as, radiation, maternal infection, chemicals, or drugs. Chromosomal abnormalities or mutations at single gene loci have also contributed to clefting development. Genetic causes are linked with most<unk>  syndromes, and CL/P and other orofacial clefts are recognized as heterogeneous disorders, meaning there are multiple recognized causes. Orofacial clefts have great phenotypic diversity, and their associated genetic environments have called for vast research and investigation. Environmental Interaction<unk>  disorders have high variance in phenotypic expression, and researchers have suggested this variance could be due to interactions between the mutated/deviated genes and other genes, along with interactions with environmental factors. Environmental causes have been found to contribute to<unk> ing, however, these are still influenced by and supported by genetic factors. Many studies, for example, have linked maternal smoking to increased CLP risk; however, the increased risk suggests that genes in metabolic pathways could still contribute to susceptibility or formation of CL/P. Development and Inheritance The<unk>  complex begins its progress in the fourth week of development, and results from neural crest cells migrating to form and fuse the facial primordia. Failures or deviations in this process result in<unk> s, either CL or CP. The range of variation in phenotype aligns with ancestry. Studies have found increased amounts of clefting in the relatives of patients with clefts, suggesting genetic factors are the underlying cause for CL/P. Inheritance has a known and significant role in human<unk>  morphology. This is supported through cephalometric and anthropometric comparisons of family members including between triplets, twins, siblings, and parents and children. Genetic Experimentation Genetic factors of<unk> ing can be investigated and tracked through several methods including sequencing in humans, Genome-wide association studies (GWAs), fate mapping, expression analysis, and animal studies (knockout experiments or models with clefting from chemical mutagenesis). Twin studies and familial clustering have also revealed that facial structure and formation are genetically linked. Several genes have been associated with<unk>  disorders through experimentation, including sequencing Mendelian clefting syndromes. Over 25 loci have been identified as potential influencers of<unk> s across populations. Linked Genes The transforming growth factor (TGF) family has provided multiple candidate genes linked with<unk>  development and malformation. TGF is involved in cell migration, differentiation, and proliferation, as well as regulating the extracellular matrix. Another gene that has been flagged as causal for<unk>  disorders, including CL/P, is interferon regulatory factor 6 or, IRF6. Mutations in IRF6 cause Van der Woude syndrome, the most common clefting syndrome. Ventral anterior homeobox 1, VAX1, and noggin, NOG, were identified with genome-wide significance for contributing to CL/P. Additionally, mutations in SPECC1L have recently been identified as influential to facial structure formation, and as causal for syndromic facial clefting. Nonsyndromic CL/P has been associated with the transcription factor forkhead box protein E1 (FOXE1), as mutations have resulted in cases of CL/P in mice. Other genes which have been found to interact with or contribute to<unk> ing include FGFRs, TWIST, MSXs, GREM1, TCOF1, PAXs, MAFB, ABCA4, and WNT allowing great cause for more research into the genetic basis for<unk>  disorders.
Craniofacial cleft
Hemifacial microsomia
Oxycephaly
Scaphocephaly
Trigonocephaly
Cranioschisis
Otocephaly
Cleft Lip and Palate Association