Cleft Candidate Genes and Their Products in Human Unilateral Cleft Lip Tissue.
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ABSTRACT:
SUBMITTER: Vaivads M
PROVIDER: S-EPMC8167758 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Nonsyndromic or isolated cleft lip with or without cleft palate (CL/P) occurs in wide geographic distribution with an average birth prevalence of 1/700. We used direct sequencing as an approach to study candidate genes for CL/P. We report here the results of sequencing on 20 candidate genes for clefts in 184 cases with CL/P selected with an emphasis on severity and positive family history. Genes were selected based on expression patterns, animal models, and/or role in known human clefting syndromes. For seven genes with identified coding mutations that are potentially etiologic, we performed linkage disequilibrium studies as well in 501 family triads (affected child/mother/father). The recently reported MSX1 P147Q mutation was also studied in an additional 1,098 cleft cases. Selected missense mutations were screened in 1,064 controls from unrelated individuals on the Centre d'Etude du Polymorphisme Humain (CEPH) diversity cell line panel. Our aggregate data suggest that point mutations in these candidate genes are likely to contribute to 6% of isolated clefts, particularly those with more severe phenotypes (bilateral cleft of the lip with cleft palate). Additional cases, possibly due to microdeletions or isodisomy, were also detected and may contribute to clefts as well. Sequence analysis alone suggests that point mutations in FOXE1, GLI2, JAG2, LHX8, MSX1, MSX2, SATB2, SKI, SPRY2, and TBX10 may be rare causes of isolated cleft lip with or without cleft palate, and the linkage disequilibrium data support a larger, as yet unspecified, role for variants in or near MSX2, JAG2, and SKI. This study also illustrates the need to test large numbers of controls to distinguish rare polymorphic variants and prioritize functional studies for rare point mutations.
| S-EPMC1298935 | biostudies-literature
Project description:Objective evaluation of operative performance is increasingly important in surgical training. Evaluation tools include global rating scales of performance and procedure-specific skills checklists. For unilateral cleft lip repair, the numerous techniques make universal evaluation challenging. Thus, we sought to create a unilateral cleft lip evaluation tool agnostic to specific repair technique.MethodsFour surgeons with expertise in 3 common cleft lip repair techniques participated in a 3-round Delphi process to generate consensus evaluation points spanning all techniques. Items were categorized as marking the repair, performing the repair, and final result. Two blinded raters then scored videos of simulated cleft lip repairs using both the 21-item novel checklist and the modified Objective Structured Assessment of Technical Skills. Kappa and T values were calculated for both scales to determine level of agreement.ResultsTen videos of repairs performed by novice residents through experienced craniofacial fellows were scored. Moderate (κ = 0.41-0.60) to substantial (κ = 0.61-0.80) interrater reliability was seen for the majority of questions in both the novel tool and the Objective Structured Assessment of Technical Skills. A single question in the novel tool had almost perfect agreement (κ = 0.81-1.00), 8 had moderate agreement, and 6 had substantial agreement. Poorly scoring questions were discarded from the final 18-item tool.ConclusionsDespite variations in unilateral cleft lip repair technique, common themes exist that can be used to assess performance and outcome. A universal evaluation tool has potential implications for trainee assessment, surgeon credentialing, and screening for surgical missions.
| S-EPMC7413813 | biostudies-literature
Project description:BACKGROUND:Genome-wide association studies are now used routinely to identify genes implicated in complex traits. The panels used for such analyses can detect single nucleotide polymorphisms and copy number variants, both of which may help to identify small deleted regions of the genome that may contribute to a particular disease. METHODS:We performed a candidate gene analysis involving 1,221 SNPs in 333 candidate genes for orofacial clefting, using 2,823 samples from 725 two- and three-generation families with a proband having cleft lip with or without cleft palate. We used SNP genotyping, DNA sequencing, high-resolution DNA microarray analysis, and long-range PCR to confirm and characterize the deletion events. RESULTS:This dataset had a high duplicate reproducibility rate (99.98%), high Mendelian consistency rate (99.93%), and low missing data rate (0.55%), which provided a powerful opportunity for deletion detection. Apparent Mendelian inconsistencies between parents and children suggested deletion events in 15 individuals in 11 genomic regions. We confirmed deletions involving CYP1B1, FGF10, SP8, SUMO1, TBX1, TFAP2A, and UGT7A1, including both de novo and familial cases. Deletions of SUMO1, TBX1, and TFAP2A are likely to be etiologic. CONCLUSIONS:These deletions suggest the potential roles of genes or regulatory elements contained within deleted regions in the etiology of clefting. Our analysis took advantage of genotypes from a candidate-gene-based SNP survey and proved to be an efficient analytical approach to interrogate genes potentially involved in clefting. This can serve as a model to find genes playing a role in complex traits in general.
| S-EPMC3682790 | biostudies-literature
Project description:Management of cleft lip and palate requires a unique understanding of the various dimensions of care to optimize outcomes of surgery. The breadth of treatment spans multiple disciplines and the length of treatment spans infancy to adulthood. Although the focus of reconstruction is on form and function, changes occur with growth and development. This review focuses on the surgical management of the primary cleft lip and nasal deformity. In addition to surgical treatment, the anatomy, clinical spectrum, preoperative care, and postoperative care are discussed. Principles of surgery are emphasized and controversies are highlighted.
| S-EPMC3706039 | biostudies-other
Project description:ObjectiveTo evaluate final posttreatment occlusion in patients with complete unilateral cleft lip and palate (cUCLP) by comparing (1) 3 treatment centers, (2) males and females, (3) cleft and noncleft sides, (4) right- and left-sided clefts, and (5) orthodontic treatment with/without orthognathic surgery (OS).DesignRetrospective cohort study.PatientsBlinded posttreatment dental casts of 56 patients (19.4 ± 1.4 years) with cUCLP from 3 centers in Switzerland.Main outcome measureOcclusal assessment using the modified Huddart/Bodenham (MHB) index.ResultsOur sample comprised 35 males and 21 females, 46 with left- and 10 with right-sided clefts, of which 32 had undergone OS. The final posttreatment occlusion showed a median MHB score of 0 (interquartile range: -1.0 to 2.0) in the total sample and did not seem to depend on treatment center, sex, or OS. The MHB scores for the anterior buccal and the buccal segments were more negative on the cleft than on the noncleft side (P = .002 and P = .006, respectively). When the cleft was on the left side, the MHB score tended to be more positive in the labial (P = .046) and anterior buccal segments (P = .034).ConclusionsThis study shows a very satisfactory final posttreatment occlusion in patients with cUCLP. The more constricted buccal occlusion on the cleft side emphasizes the attention that should be given in correcting the more medially positioned lesser maxillary segment. The influence of cleft-sidedness should be analyzed further on a sample including more patients with right-sided clefts.
| S-EPMC9260490 | biostudies-literature
Project description:The objective of this research was to identify potential biological pathways associated with non-syndromic cleft lip with or without cleft palate (NSCL/P), and to explore the potential biological mechanisms underlying these associated pathways on risk of NSCL/P. This project was based on the dataset of a previously published genome-wide association (GWA) study on NSCL/P (Beaty et al. 2010). Case-parent trios used here originated from an international consortium (The Gene, Environment Association Studies consortium, GENEVA) formed in 2007. A total of 5,742 individuals from 1,908 CL/P case-parents trios (1,591 complete trios and 317 incomplete trios where one parent was missing) were collected and genotyped using the Illumina Human610-Quad array. Candidate pathways were selected using a list of 356 genes that may be related to oral clefts. In total, 42 candidate pathways, which included 1,564 genes and 40,208 SNPs were tested. Using a pathway-based analysis approach proposed by Wang et al (2007), we conducted a permutation-based test to assess the statistical significance of the nominal p-values of 42 candidate pathways. The analysis revealed several pathways yielding nominally significant p-values. However, controlling for the family wise error rate, none of these pathways could retain statistical significance. Nominal p-values of these pathways were concentrated at the lower tail of the distribution, with more than expected low p-values. A permutation based test for examining this type of distribution pattern yielded an overall p-value of 0.029. Thus, while this pathway-based analysis did not yield a clear significant result for any particular pathway, we conclude that one or more of the genes and pathways considered here likely do play a role in oral clefting.
| S-EPMC3404742 | biostudies-literature
Project description:BackgroundTo improve the rotation of Cupid's bow and achieve sufficient vertical lip height, several variations of the Millard rotation-advancement have incorporated a small laterally based triangular flap above the cutaneous roll. This study uses three-dimensional photogrammetry to evaluate the outcomes of unilateral cleft lip repairs performed with and without pennant flaps.MethodsThree-dimensional photographs were analyzed to assess postoperative lip height asymmetry in 90 unilateral cleft lip patients (58 complete and 32 incomplete) treated between 2001 and 2012. Cleft lip repairs were performed by three pediatric cleft surgeons using different techniques. Thirty-nine of 90 procedures (43 percent) used an inferiorly placed triangular flap. All patients were photographed at least 9 months postoperatively (mean, 4.2 years). Lip height asymmetry was based on the vertical distances from the subnasale to the peaks of Cupid's bow.ResultsRegression analysis revealed that the use of a pennant flap was a significant predictor of postoperative lip height asymmetry (β = 4.2 percent, p = 0.015). The surgeon performing the repair was also a significant factor in patients with complete cleft lips (β = 3.6 percent, p = 0.005). All three surgeons achieved greater lip height symmetry when a pennant flap was performed.ConclusionsThe results of unilateral cleft lip repairs are affected by both the surgeon and the surgical technique. Procedures that used a pennant flap showed better philtral height symmetry than nonpennant repairs.Clinical question/level of evidenceTherapeutic, III.
| S-EPMC4708256 | biostudies-literature
Project description:Orofacial development is a multifaceted process involving tightly regulated genetic signaling networks, that when perturbed, lead to orofacial abnormalities including cleft lip and/or cleft palate. We and others have shown an association between the cysteine-rich secretory protein LCCL domain containing 2 (CRISPLD2) gene and nonsyndromic cleft lip with or without cleft palate (NSCLP). Further, we demonstrated that knockdown of Crispld2 in zebrafish alters neural crest cell migration patterns resulting in abnormal jaw and palate development. In this study, we performed RNA profiling in zebrafish embryos and identified 249 differentially expressed genes following knockdown of Crispld2. In silico pathway analysis identified a network of seven genes previously implicated in orofacial development for which differential expression was validated in three of the seven genes (CASP8, FOS, and MMP2). Single nucleotide variant (SNV) genotyping of these three genes revealed significant associations between NSCLP and FOS/rs1046117 (GRCh38 chr14:g.75746690?T?>?C, p?=?0.0005) in our nonHispanic white (NHW) families and MMP2/rs243836 (GRCh38 chr16:g.55534236?G?>?A; p?=?0.002) in our Hispanic families. Nominal association was found between NSCLP and CASP8/rs3769825 (GRCh38 chr2:g.202111380?C?>?A; p?<?0.007). Overtransmission of MMP2 haplotypes were identified in the Hispanic families (p?<?0.002). Significant gene-gene interactions were identified for FOS-MMP2 in the NHW families and for CASP8-FOS in the NHW simplex family subgroup (p?<?0.004). Additional in silico analysis revealed a novel gene regulatory network including five of these newly identified and 23 previously reported NSCLP genes. Our results demonstrate that animal models of orofacial clefting can be powerful tools to identify novel candidate genes and gene regulatory networks underlying NSCLP.
| S-EPMC6138754 | biostudies-literature
Project description:Aim and methodWe analysed DNA samples isolated from individuals born with cleft lip and cleft palate to identify deletions and duplications of candidate gene loci using array comparative genomic hybridisation (array-CGH).ResultsOf 83 syndromic cases analysed we identified one subject with a previously unknown 2.7 Mb deletion at 22q11.21 coinciding with the DiGeorge syndrome region. Eighteen of the syndromic cases had clinical features of Van der Woude syndrome and deletions were identified in five of these, all of which encompassed the interferon regulatory factor 6 (IRF6) gene. In a series of 104 non-syndromic cases we found one subject with a 3.2 Mb deletion at chromosome 6q25.1-25.2 and another with a 2.2 Mb deletion at 10q26.11-26.13. Analyses of parental DNA demonstrated that the two deletion cases at 22q11.21 and 6q25.1-25.2 were de novo, while the deletion of 10q26.11-26.13 was inherited from the mother, who also has a cleft lip. These deletions appear likely to be causally associated with the phenotypes of the subjects. Estrogen receptor 1 (ESR1) and fibroblast growth factor receptor 2 (FGFR2) genes from the 6q25.1-25.2 and 10q26.11-26.13, respectively, were identified as likely causative genes using a gene prioritization software.ConclusionWe have shown that array-CGH analysis of DNA samples derived from cleft lip and palate subjects is an efficient and productive method for identifying candidate chromosomal loci and genes, complementing traditional genetic mapping strategies.
| S-EPMC3732463 | biostudies-literature
Project description:In an effort to comprehensively interrogate genetic variation in the folate pathway for risk of cleft lip with or without cleft palate (CLP), we evaluated 504 common and rare variants in 35 folate-related genes in a panel of 330 infants with CLP and 367 non-malformed controls. Odds ratios (OR) with 95% confidence intervals were computed for common genotypes. A Case-Control Difference metric was calculated for rare variants to highlight differentially occurring alleles. Interactions between variants and a maternal folate intake variable were also evaluated. In gene-only results, significant odds ratios were observed for multiple variants in the BHMT/BHMT2/DMGDH gene cluster, particularly in Hispanic infants. Also in this cluster, rare variant analysis highlighted a substantial case-control difference in BHMT rs60340837 (synonymous Y284Y). In Hispanics, the ALDH1L1 I812V variant (rs4646750) was the most significant risk allele: OR?=?3.8 (95%CI?=?1.6-9.2) when heterozygous. In non-Hispanic white infants, we observed significant risk for AHCYL2 rs1095423 (homozygous OR?=?3.0, 95%CI 1.1-7.8) and the 68?bp CBS insertion (c.844ins68; heterozygous OR?=?2.4, 95%CI?=?1.1-5.3). Rare variant analysis in this group revealed case-control differences in MTRR and several other methionine cycle genes, a process implicated previously in clefting risk. In women with low folate intake specifically, increased risks were observed for CBS rs2851391 (OR?=?3.6, 95%CI?=?1.3-9.6) and the R259P nonsynonymous variant of TCN2 (rs1801198; OR?=?2.8, 95%CI?=?1.2-6.3). This comprehensive study provides further direction on candidate loci to help disentangle the folate-related developmental phenomena in human clefting risk. © 2016 Wiley Periodicals, Inc.
| S-EPMC5634616 | biostudies-literature