scholarly journals Genetic factors influencing risk to orofacial clefts: today’s challenges and tomorrow’s opportunities

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2800 ◽  
Author(s):  
Terri H. Beaty ◽  
Mary L. Marazita ◽  
Elizabeth J. Leslie
Keyword(s):  
Birth Defects ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Familial Aggregation ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Orofacial Clefts ◽  
Craniofacial Malformations ◽  
Genome Wide ◽  
The Right

Orofacial clefts include cleft lip (CL), cleft palate (CP), and cleft lip and palate (CLP), which combined represent the largest group of craniofacial malformations in humans with an overall prevalence of one per 1,000 live births. Each of these birth defects shows strong familial aggregation, suggesting a major genetic component to their etiology. Genetic studies of orofacial clefts extend back centuries, but it has proven difficult to define any single etiologic mechanism because many genes appear to influence risk. Both linkage and association studies have identified several genes influencing risk, but these differ across families and across populations. Genome-wide association studies have identified almost two dozen different genes achieving genome-wide significance, and there are broad classes of ‘causal genes’ for orofacial clefts: a few genes strongly associated with risk and possibly directly responsible for Mendelian syndromes which include orofacial clefts as a key phenotypic feature of the syndrome, and multiple genes with modest individual effects on risk but capable of disrupting normal craniofacial development under the right circumstances (which may include exposure to environmental risk factors). Genomic sequencing studies are now underway which will no doubt reveal additional genes/regions where variants (sequence and structural) can play a role in controlling risk to orofacial clefts. The real challenge to medicine and public health is twofold: to identify specific genes and other etiologic factors in families with affected members and then to devise effective interventions for these different biological mechanisms controlling risk to complex and heterogeneous birth defects such as orofacial clefts.

scholarly journals FISSURAS LABIAIS E/OU PALATINAS NÃO SINDRÔMICAS: DETERMINANTES AMBIENTAIS E GENÉTICOS.

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Andréa Do Rego Borges ◽  
Jamile De Oliveira Sá ◽  
Lorena Castro Mariano ◽  
Samário Cintra Maranhão ◽  
Alena Peixoto Medrado ◽  
...  
Keyword(s):  
Critical Analysis ◽  
Cleft Lip ◽  
Developmental Disorder ◽  
Association Studies ◽  
Case Control ◽  
Ethnic Composition ◽  
Genome Wide Association Studies ◽  
Orofacial Clefts ◽  
Genome Wide ◽  
Ethnic Factors

The nonsyndromic cleft lip and/or palate (NSCL/P) is a birth anomaly resulting from fusion defects of craniofacial processes. These changes have varied incidence and are more common in nonsyndromic form. The aim of this paper is conduct a literature review about NSCL/P, emphasizing the genetic aspects. In the critical analysis of the selected articles was founded that several genes and chromosomal regions have been associated with orofacial clefts in Genome Wide Association Studies (GWAS), like the genes IRF6, ABCA4, MAFB and region 8q24. It is a developmental disorder of multifactorial origin, involving environmental and genetic agents. The authors also observed strong interference of ethnic factors, particularly in studies of the case-control type. Some polymorphisms were identified in replicated GWAS studies and associated with cleft in the Brazilian population, like the polymorphism rs987525, rs1530300 and rs560426. When the population is stratified, like in Brazil, the ethnic composition has problably a strong effect on the genetic association with NSCL/P. It is recommended the study of genetic ancestry into research’s associating genetic polymorphisms on orofacial clefts.

scholarly journals Identification of Novel Genomic Variations in Susceptibility to Nonsyndromic Cleft Lip and Palate Patients

2021 ◽  
Vol 13 (4) ◽  
pp. 650-657
Author(s):  
Kapil Kumar Avasthi ◽  
Srinivasan Muthuswamy ◽  
Ambreen Asim ◽  
Amit Agarwal ◽  
Sarita Agarwal
Keyword(s):  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Association Studies ◽  
Genetic Variations ◽  
Functional Enrichment ◽  
Genome Wide Association ◽  
Regulatory Sequences ◽  
Genome Wide Association Studies ◽  
Medicine Research ◽  
Genome Wide

Background: Nonsyndromic cleft lip with or without palate (NSCL/P) is a multifactorial and common birth malformation caused by genetic and environmental factors, as well as by teratogens. Genome-wide association studies found genetic variations with modulatory effects of NSCL/P formation in Chinese and Iranian populations. We aimed to identify the susceptibility of single-nucleotide polymorphisms (SNPs) to nonsyndromic cleft lip with or without palate in the Indian population. Material and Methods: The present study was conducted on NSCL/P cases and controls. Genomic DNA was extracted from peripheral blood and Axiom- Precision Medicine Research Array (PMRA) was performed. The Axiom-PMRA covers 902,527 markers and several thousand novel risk variants. Quality control-passed samples were included for candidate genetic variation identification, gene functional enrichment, and pathway and network analysis. Results: The genome-wide association study identified fourteen novel candidate gene SNPs that showed the most significant association with the risk of NSCL/P, and eight were predicted to have regulatory sequences. Conclusion: The GWAS study showed novel candidate genetic variations in NSCL/P formations. These findings contribute to the understanding of genetic predisposition to nonsyndromic cleft lip with or without palate.

scholarly journals A Rare Interstitial Duplication of 8q22.1–8q24.3 Associated with Syndromic Bilateral Cleft Lip/Palate

2014 ◽  
Vol 2014 ◽  
pp. 1-4 ◽  
Author(s):  
Regina Ferreira Rezek ◽  
Ana Angélica Rodrigues Abbas ◽  
Juliana Forte Mazzeu ◽  
Siliana Maria Duarte Miranda ◽  
Cibele Velloso-Rodrigues
Keyword(s):  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Balanced Translocation ◽  
Genome Wide ◽  
Interstitial Duplication ◽  
Bilateral Cleft Lip ◽  
Cleft Lip Palate ◽  
Balanced Translocations

We present a rare case of 8q interstitial duplication derived from maternal balanced translocations in a patient with bilateral cleft lip and palate in syndromic form associated with other congenital malformations. G-banding cytogenetic analysis revealed a chromosomal abnormality in the form of the karyotype 46,XX der(22)t(8;22)(q22.1;p11.1)mat. Chromosome microarray analysis evidenced a 49 Mb duplicated segment of chromosome 8q with no pathogenic imbalances on chromosome 22. Two siblings also carry the balanced translocation. We have compared this case with other “pure” trisomies of 8q patients reported in the literature and with genome wide association studies recently published. This work highlights the involvement of chromosome 8q in orofacial clefts.

scholarly journals Genome-Wide Association Studies in Dogs and Humans Identify ADAMTS20 as a Risk Variant for Cleft Lip and Palate

PLoS Genetics ◽  
2015 ◽  
Vol 11 (3) ◽  
pp. e1005059 ◽  
Author(s):  
Zena T. Wolf ◽  
Harrison A. Brand ◽  
John R. Shaffer ◽  
Elizabeth J. Leslie ◽  
Boaz Arzi ◽  
...  
Keyword(s):  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Association Studies ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Risk Variant ◽  
Genome Wide

scholarly journals Case–Parent Trio Studies in Cleft Lip and Palate

2020 ◽  
Vol 07 (03) ◽  
pp. 075-079
Author(s):  
Mahamad Irfanulla Khan ◽  
Prashanth CS
Keyword(s):  
Genetic Variants ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Association Studies ◽  
Geographical Location ◽  
Genetic Association Studies ◽  
Population Based ◽  
Genome Wide Association Studies ◽  
Family Based ◽  
Study Designs

AbstractCleft lip with or without cleft palate (CL/P) is one of the most common congenital malformations in humans involving various genetic and environmental risk factors. The prevalence of CL/P varies according to geographical location, ethnicity, race, gender, and socioeconomic status, affecting approximately 1 in 800 live births worldwide. Genetic studies aim to understand the mechanisms contributory to a phenotype by measuring the association between genetic variants and also between genetic variants and phenotype population. Genome-wide association studies are standard tools used to discover genetic loci related to a trait of interest. Genetic association studies are generally divided into two main design types: population-based studies and family-based studies. The epidemiological population-based studies comprise unrelated individuals that directly compare the frequency of genetic variants between (usually independent) cases and controls. The alternative to population-based studies (case–control designs) includes various family-based study designs that comprise related individuals. An example of such a study is a case–parent trio design study, which is commonly employed in genetics to identify the variants underlying complex human disease where transmission of alleles from parents to offspring is studied. This article describes the fundamentals of case–parent trio study, trio design and its significances, statistical methods, and limitations of the trio studies.

scholarly journals How Cardiac Embryology Translates into Clinical Arrhythmias

2021 ◽  
Vol 8 (6) ◽  
pp. 70
Author(s):  
Mathilde R. Rivaud ◽  
Michiel Blok ◽  
Monique R. M. Jongbloed ◽  
Bastiaan J. Boukens
Keyword(s):  
Transcription Factors ◽  
Association Studies ◽  
Pulmonary Veins ◽  
Atrioventricular Node ◽  
Right Ventricular Outflow Tract ◽  
Ventricular Outflow Tract ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Congenital Atrioventricular Block ◽  
The Right

The electrophysiological signatures of the myocardium in cardiac structures, such as the atrioventricular node, pulmonary veins or the right ventricular outflow tract, are established during development by the spatial and temporal expression of transcription factors that guide expression of specific ion channels. Genome-wide association studies have shown that small variations in genetic regions are key to the expression of these transcription factors and thereby modulate the electrical function of the heart. Moreover, mutations in these factors are found in arrhythmogenic pathologies such as congenital atrioventricular block, as well as in specific forms of atrial fibrillation and ventricular tachycardia. In this review, we discuss the developmental origin of distinct electrophysiological structures in the heart and their involvement in cardiac arrhythmias.

Morphological Presentation of Orofacial Clefts: An Epidemiological Study of 5004 Patients in a Tertiary Care Hospital of Central India

2021 ◽  
pp. 105566562110577
Author(s):  
Jaideep Singh Chauhan ◽  
Sarwpriya Sharma
Keyword(s):  
Cleft Palate ◽  
Epidemiological Study ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Tertiary Care ◽  
Central India ◽  
Care Hospital ◽  
Orofacial Clefts ◽  
Chi Square ◽  
The Right

Objective: To analyse the morphological presentation of orofacial clefts, gender, syndromes and systemic anomalies associated with them. Design: This was an epidemiological study performed in the patients who were registered for cleft lip and palate surgeries in our centre. The data was evaluated both retrospectively as well as prospectively. Patients/ Participants: The patients registered from November 2006 to April 2021 were studied. Out of 5276 patients, data of 5004 cases were analysed, rest 272 patients were excluded due to lack of information. Statistical analysis and Chi square test were applied. Results: Cleft deformities were more common in males than females. Cleft lip with palate was the commonest phenotype (52.2%). It was followed by isolated cleft lip (22.9%), isolated cleft palate (22.1%), rare clefts (1.62%) and syndromic clefts (1.18%). Unilateral variants were more frequent than bilateral. In unilateral, left side was more common than the right side. Among bilateral, most of the cases had premaxillary protrusion. In the present study, 3.46% of all the patients had associated anomalies affecting their other organs. Less common cleft phenotypes like microform cleft lip and submucous cleft palate ± bifid uvula showed frequency of 0.62% and 0.64% respectively. Conclusion: Thorough examination of cleft deformity should be done as it may appear as an isolated deformity or part of a syndrome and have associated systemic anomalies. This may help us to deliver comprehensive care to the patients and can prevent potential operative complications.

scholarly journals TAGOOS: genome-wide supervised learning of non-coding loci associated to complex phenotypes

2019 ◽  
Vol 47 (14) ◽  
pp. e79-e79
Author(s):  
Aitor González ◽  
Marie Artufel ◽  
Pascal Rihet
Keyword(s):  
Cleft Lip ◽  
Association Studies ◽  
Area Under The Curve ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Functional Snps ◽  
Functional Regions ◽  
Complex Phenotypes ◽  
Genome Wide ◽  
Intergenic Regions

Abstract Genome-wide association studies (GWAS) associate single nucleotide polymorphisms (SNPs) to complex phenotypes. Most human SNPs fall in non-coding regions and are likely regulatory SNPs, but linkage disequilibrium (LD) blocks make it difficult to distinguish functional SNPs. Therefore, putative functional SNPs are usually annotated with molecular markers of gene regulatory regions and prioritized with dedicated prediction tools. We integrated associated SNPs, LD blocks and regulatory features into a supervised model called TAGOOS (TAG SNP bOOSting) and computed scores genome-wide. The TAGOOS scores enriched and prioritized unseen associated SNPs with an odds ratio of 4.3 and 3.5 and an area under the curve (AUC) of 0.65 and 0.6 for intronic and intergenic regions, respectively. The TAGOOS score was correlated with the maximal significance of associated SNPs and expression quantitative trait loci (eQTLs) and with the number of biological samples annotated for key regulatory features. Analysis of loci and regions associated to cleft lip and human adult height phenotypes recovered known functional loci and predicted new functional loci enriched in transcriptions factors related to the phenotypes. In conclusion, we trained a supervised model based on associated SNPs to prioritize putative functional regions. The TAGOOS scores, annotations and UCSC genome tracks are available here: https://tagoos.readthedocs.io.

Searching for new genes and loci involved in cleft lip and palate in the Polish population – genome-wide association study

2016 ◽  
Vol 83 (3) ◽  
pp. 265-268 ◽  
Author(s):  
Adrianna Mostowska ◽  
Kamil K. Hozyasz ◽  
Piotr Wójcicki ◽  
Barbara Biedziak ◽  
Joanna Wesoły ◽  
...  
Keyword(s):  
Association Study ◽  
Cleft Lip ◽  
Genome Wide Association Study ◽  
Cleft Lip And Palate ◽  
Genome Wide Association ◽  
Polish Population ◽  
Orofacial Clefts ◽  
New Genes ◽  
Genome Wide ◽  
History Of

The project “Searching for new genes and loci involved in cleft lip and palate in the Polish population – genome-wide association study” is a case-control study in a group of unrelated subjects with non-syndromic cleft lip with or without cleft palate (NSCL/P) and healthy individuals with no family history of clefting or other congenital disorders. The overall goal of this grant proposal is to identify novel genetic factors, which can play a significant role in the pathogenesis of orofacial clefts in the Polish population. To accomplish the proposed aim, a two stage genome-wide association study will be performed. In the first stage, Illumina's HumanOmni Express BeadChips arrays will be used to genotype over 700,000 polymorphisms in NSCL/P patients and controls. In the second stage, SNPs showing the most compelling association with the risk of orofacial clefts will be tested in an independent sample set using standard genotyping methods. This research project is expected to be completed in July 2015.

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