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Oral and craniofacial disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Before genetic counselling is given, a careful examination must be made to exclude the numerous syndromal associations with clefting. In some of these (e.g. chromosomal trisomies), the other defects are obvious, while in others, e.g. the Van der Woude (lip pits) syndrome (IRF6 at chromosome 1q), they may be inconspicuous and even absent in some family members. Maternal teratogens (notably anticonvulsants) must also be considered. The most important syndromes to recognise are those that follow Mendelian inheritance; Box 17.1 lists some of the major ones. Cleft lip and palate also occur with other malformations in a non-specific manner and are more common than one might expect. If a careful search for a specific syndrome proves negative, one is forced to use the empirical risks for the abnormalities in isolation. Intriguing associations and interactions of oral clefts have been found with numerous gene loci, including genes in the folate and TGF-β pathways, but there has been a dearth of consistency in these results.
Cleft Lip and Palate
Published in John C Watkinson, Raymond W Clarke, Christopher P Aldren, Doris-Eva Bamiou, Raymond W Clarke, Richard M Irving, Haytham Kubba, Shakeel R Saeed, Paediatrics, The Ear, Skull Base, 2018
David M. Wynne, Louisa Ferguson
Non-syndromic clefting is multifactorial and is influenced by both genetic and environmental factors. Non-syndromic clefting may have a known or unknown cause. Variants of the IRF6 gene (interferon regulatory factor 6) can cause a Mendelian type inheritance, notably Van der Woude syndrome, but variants of IRF6 have also been implicated in non-syndromic orofacial clefts.7 Genome-wide association studies have provided insights into the genetic background of non-syndromic CL±P and contributing genes include aberrations in TGF-b3, NAT 1TBX22, MSX1 and FGFR.9–12
Cleft Lip and Palate
Published in Crystal D. Karakochuk, Kyly C. Whitfield, Tim J. Green, Klaus Kraemer, The Biology of the First 1,000 Days, 2017
Eman Allam, Ahmed Ghoneima, Katherine Kula
CLP is etiologically heterogeneous, with complex genetic and environmental interactions. It is essential to distinguish between isolated nonsyndromic cases and those clefts associated with particular syndromes, as both are considered etiologically distinct. More than 350 specific genetic syndromes are identified as being associated with CLP [12,13]. Advances in segregation analysis, genetic linkage, and association studies, as well as twin studies, have made it possible to identify major genetic factors related to clefts [12–14]. Three classes of genes are suggested to play a role in the susceptibility to clefting: (1) genes involved in the process of palate development, specifically the transforming growth factors alpha and beta (TGFα, TGFβ 2, TGFβ 3); (2) genes identified in transgenic animal models with clefts, such as the Msx1, Msx2, Gabrb3, and Ap-2 genes; and (3) genes involved in certain biological activities that are linked to CLP pathogenesis, such as xenobiotic metabolism (CYP1A1, glutathione S-transferase μ1 [GSTM1], N-acetyltransferase [NAT2]), and nutrient metabolism (methylene tetrahydrofolate reductase [MTHFR], retinoic acid receptor [RAR-α], and folate receptor [FOLR1]). Candidate gene studies on CLP cases associated with Van der Woude (VWS) syndrome have also provided strong evidence for the involvement of the interferon regulatory factor 6 (IRF6) gene in cleft development. VWS is an autosomal dominant disorder that is considered to be the most important model for isolated CLP [15–17].
Identification of potential prognostic biomarkers in vulval squamous cell carcinoma based on human papillomavirus infection Status-Analysis of GSE183454
Published in Journal of Obstetrics and Gynaecology, 2023
Ruxing Xi, Donghong Li, Shuanque Yang, Hui Zhang, Lijuan Hu, Xiaowei Wang, Guoqing Wang, Yan Wang
It has been reported that HPV-associated carcinoma accounts for 40% of all VSCC and is considered to be the cause of the recent increase worldwide. Both Low-Grade Squamous Intraepithelial Lesion (LSIL) and High-Grade Squamous Intraepithelial Lesion (HSIL) are precancerous lesions of VSCC and could be caused by high-risk HPV, which is also called oncogenic HPV based on its extreme carcinogenic capability. Among this, HPV16 is related with more than 77% cases of HSIL, whereas HPV 33 and 18 are related with 11% and 2.6% cases of cases, respectively (Leonard et al.2014). As previously mentioned, the preneoplastic of another HPV independent type of VSCC is differentiated vulval intraepithelial neoplasia (VIN) which occurs frequently in elderly females with inflammatory dermatosis, mostly lichen scleroses. Furthermore, it is also reported that the aberrant of Interferon regulatory factor-6 (IRF6) promoter methylation promote the occurrence of lesions from vulva normal skin to vulvar lichen sclerosus, VIN and VSCC (Rotondo et al.2016). Meanwhile, smoking, multiple sexual partners, young age of first intercourse and immunosuppression are additional risk factors for VSCC in general (Reyes and Cooper 2014, American Cancer Society 2022).
Role of N6-methyladenosine modification in pathogenesis of ischemic stroke
Published in Expert Review of Molecular Diagnostics, 2022
Hongtao Chang, Jun Yang, Qianwen Wang, Jingjing Zhao, Ruixia Zhu
Mo et al [45]. first integrated the m6A-SNP database, GEO database, and IS-associated GWAS and found 310 m6A-SNP associated with IS. Their results indicated that the m6A-SNP rs2013162 was associated with large artery AS-related stroke risk by affecting IRF6 expression. A significant relationship between m6A-SNP rs2273235 within the NDST1 gene and cardioembolic stroke risk was also found. Subsequently, their study also identified significant associations among m6A-SNPs rs9847953, rs197922, and blood pressure [46]. The two m6A-SNPs might influence ZNF589 and GOSR2 gene expression by regulating m6A methylation, which affects susceptibility to developing hypertension. The study also showed that the rs7398833 C allele not only decreased the risk of hypertension, but it also reduced the risk of IS by inducing the acquisition of an m6A site. Hyperlipidemia and hypertension are major risk factors for IS. Moreover, the effect of m6A modification on lipid metabolism was investigated by excavating the GWAS database of 188,578 individuals and 304 m6A-SNPs affected m6A methylation and m6A-SNP rs6859 was found to be associated with lipid metabolism [44].
Long-term drug treatment in multiple sclerosis: safety success and concerns
Published in Expert Opinion on Drug Safety, 2020
Dejan Jakimovski, Caila B Vaughn, Svetlana Eckert, Robert Zivadinov, Bianca Weinstock-Guttman
An indirect but important modulator of the risk-benefit analysis should include proper management of lifestyle-based modifiable risk factors and age stratification [218]. Both smoking and greater body mass index have been shown to significantly lower drug effectiveness, even affecting potent anti-inflammatory effects from drugs such as natalizumab [219,220]. Furthermore, presence of comorbidities (cardiovascular, neurological, or psychiatric) accelerate the disease progression and may lower the drug potency [221]. Identifying new genetic factors that increase the risk for SAEs or predict ‘super responders’ may further improve the safety of MS treatment. For example, recent study has uncovered a trait locus (rs2205986) which alters the expression of interferon regulatory factor-6 gene (IRF6) and increases the risk for IFN-β-induced liver injury [222]. As previously mentioned with some medications, demographic factors such as sex and age can significantly modulate the MS disease course and play an important role in DMT selection. Males may exhibit early and greater neurodegenerative changes when compared to the late, menopause-induced atrophy in females [223]. Furthermore, a meta-analysis incorporating most pivotal DMTs trials suggests that aging MS patients may not derive therapeutic benefit of immunomodulatory treatment after the age of 53 [224]. Greater effort in understanding the risk-benefit of DMT use in elderly MS patients is highly warranted.