Orofacial clefts embryology, classification, epidemiology, and genetics

Nasreddine, Ghenwa; Hajj, Joëlle El; Ghassibe-Sabbagh, Michella

doi:10.1016/j.mrrev.2021.108373

Cited by 81 publications

(107 citation statements)

References 255 publications

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“…Zebrafish have been successfully used to identify the genes involved in disease development through unbiased forward genetic screening with chemical mutagenesis ( Mullins et al, 1994 ; Kelsh et al, 1996 ; Amsterdam and Hopkins, 2006 ; Swartz et al, 2020 ). The signaling pathways involved in cranial neural crest development are impaired in FAS, leading to various craniofacial anomalies such as cleft palate and holoprosencephaly ( Smith et al, 2014 ; Nasreddine et al, 2021 ). To examine this, an N-ethyl-N-nitrosourea (ENU)-based random mutagenesis was performed to identify novel ethanol-sensitive zebrafish mutants, wherein F3 embryos from 126 inbred F2 families were exposed to 1% ethanol in the medium from 6 h post-fertilization (hpf) until they were screened.…”

Section: Introductionmentioning

confidence: 99%

Analysis of Gene-Environment Interactions Related to Developmental Disorders

Nishimura

Kurosawa

2022

Front. Pharmacol.

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Various genetic and environmental factors are associated with developmental disorders (DDs). It has been suggested that interaction between genetic and environmental factors (G × E) is involved in the etiology of DDs. There are two major approaches to analyze the interaction: genome-wide and candidate gene-based approaches. In this mini-review, we demonstrate how these approaches can be applied to reveal the G × E related to DDs focusing on zebrafish and mouse models. We also discuss novel approaches to analyze the G × E associated with DDs.

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Section: Introductionmentioning

confidence: 99%

Analysis of Gene-Environment Interactions Related to Developmental Disorders

Nishimura

Kurosawa

2022

Front. Pharmacol.

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“…Orofacial clefts (OFCs) are the most common craniofacial birth defects [ 1 ]. OFCs cause health issues and complications early in life such as feeding problems and ear infections, increasing morbidity and mortality risks [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Cleft Palate in Apert Syndrome

Willie

Holmes

Jabs

et al. 2022

JDB

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Apert syndrome is a rare genetic disorder characterized by craniosynostosis, midface retrusion, and limb anomalies. Cleft palate occurs in a subset of Apert syndrome patients. Although the genetic causes underlying Apert syndrome have been identified, the downstream signaling pathways and cellular mechanisms responsible for cleft palate are still elusive. To find clues for the pathogenic mechanisms of palatal defects in Apert syndrome, we review the clinical characteristics of the palate in cases of Apert syndrome, the palatal phenotypes in mouse models, and the potential signaling mechanisms involved in palatal defects. In Apert syndrome patients, cleft of the soft palate is more frequent than of the hard palate. The length of the hard palate is decreased. Cleft palate is associated most commonly with the S252W variant of FGFR2. In addition to cleft palate, high-arched palate, lateral palatal swelling, or bifid uvula are common in Apert syndrome patients. Mouse models of Apert syndrome display palatal defects, providing valuable tools to understand the underlying mechanisms. The mutations in FGFR2 causing Apert syndrome may change a signaling network in epithelial–mesenchymal interactions during palatogenesis. Understanding the pathogenic mechanisms of palatal defects in Apert syndrome may shed light on potential novel therapeutic solutions.

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“…It is characterized by lower lip pits, dental anomalies and a CLP or CPO, and is caused by a mutation in the IRF6 gene on chromosome 1 (Rizos & Spyropoulos, 2004). Kallmann syndrome, EEC syndrome, X-linked clefting and ankyloglossia, Gorlin syndrome, Stickler syndrome, Hardikar syndrome, Treacher-Collins syndrome, siderius X-linked mental retardation, Loeys-Dietz syndrome, and Malpuech facial clefting syndrome are also all monozygotic syndromes associated with CLP (Nasreddine et al, 2021). Other congenital symptoms associated with CLP include: congenital heart anomalies, micrognathia, Congenital hydrocephalus, ectopic kidney among many others (Hadadi et al, 2017).…”

Section: Syndromic Vs Non-syndromic Cleft Lip and Palatementioning

confidence: 99%

“…These include the genes:, TGFα, BCL3, MSX1, IRF6, PVRL1/NECTIN1, TP63, SUMO1, BMP4, DLX4, MTHFR, CRISPLD2 and CLPTM1; and genomic regions such as 6p24-p23, 4q21-q31, 13q33.1-q34, 8q24.3, 1p33 (Saleem et al, 2019). The scientific evidence behind the association of these genes with CLP is one of the following: differentially expressed during facial development, has been shown to lead to a cleft phenotype in transgenic of knock out models, has been associated with a syndromic form of OFC, was previously reported in humans, has a role in nutritional or xenobiotic pathways, or falls within a chromosomal region associated cleft phenotypes (Nasreddine et al, 2021).…”

Section: Syndromic Vs Non-syndromic Cleft Lip and Palatementioning

confidence: 99%

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Dissection of the Genetic and Molecular Pathways of Cleft Lip and Palate. (c2021)

Hatoum¹

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Cleft lip and palate (CLP) is a congenital anomaly affecting the lips and oral cavity and known to have an impact on the quality of life of the individuals who have it. This disease is known to be caused by both environmental and genetic factors and its etiology has been widely studied over the years but is still not close to being fully deciphered. Using whole exome sequencing (WES), we have identified in a Lebanese family two novel CLP variants in two different integrin subtypes coding for ITGA10 and ITGB8 genes. Integrins are cell surface proteins consisting of several subtypes and act as an interface between the extra cellular matrix (ECM) and internal cell signaling pathways involved in many cellular processes such as migration and differentiation (Integrins - an Overview | ScienceDirect Topics, n.d.). In order to further validate our findings, functional tests have been conducted on primary gingival fibroblasts collected from an affected individual of the studied family. Gene and protein expression analysis showed a differential expression of the identified mutated integrins. Cells’ viability, adhesion and motility were studied to be able to identify the process being altered in the affected cells. The cells collected from the proband appeared to have increased adhesion to the ECM and an overall decrease in its motility when compared to wild type gingival fibroblasts used as a control. This deficit in the cells’ migratory ability was attributed to a decrease in the activity of Ras-related C3 botulinum toxin substrate 1 (Rac1), a member of the Rac family of small GTPases known to play role in cytoskeletal reorganization of the cell and ultimately its motility. This study contributes to the process of establishing of a genotype-phenotype correlation in CLP that helps in better understanding the etiology of this complex disease. It does so by emphasizing the role of cell motility in lip and palate formation and establishing one of the mechanisms by which this function can be altered.

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Orofacial clefts embryology, classification, epidemiology, and genetics

Cited by 81 publications

References 255 publications

Analysis of Gene-Environment Interactions Related to Developmental Disorders

Analysis of Gene-Environment Interactions Related to Developmental Disorders

Cleft Palate in Apert Syndrome

Dissection of the Genetic and Molecular Pathways of Cleft Lip and Palate. (c2021)

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