UNASSIGNED: This study aims to identify fracture patterns on the lingual aspect of the mandible following Bilateral Sagittal Osteotomy of the Mandibular Ramus and correlate these patterns with mandibular anatomical characteristics in patients with cleft lip and palate.
UNASSIGNED: Two hundred cone beam CT scans were analyzed, with 100 scans in the preoperative period to assess mandibular anatomy and 100 in the postoperative period to evaluate the course of fractures on the lingual surface after surgery.
UNASSIGNED: Statistical analysis revealed no correlation between the depth of the mandibular fossa and the type of fracture after bilateral sagittal osteotomy. Similarly, there was no association between the height and angle of the mandibular body and the type of fracture. The most common fracture type observed was the type 3 pattern, characterized by a line running through the mandibular canal. Furthermore, no relationship was identified between the studied anatomical aspects and the occurrence of undesired fractures.
UNASSIGNED: The anatomical data presented in this study can assist surgeons in selecting the safest surgical techniques and optimal osteotomy sites, particularly in patients with cleft lip and palate.
UNASSIGNED: Este estudio tiene como objetivo identificar los patrones de fractura en la superfície lingual de la mandíbula después de la osteotomía sagital bilateral de la rama mandibular y correlacionar estos patrones con las características anatómicas mandibulares en pacientes com fisura labiopalatina.
UNASSIGNED: Se analizaron doscientas tomografías computarizadas de haz cónico, con cien tomografías en el período preoperatorio para evaluar la anatomía mandibular y cien en el período postoperatorio para evaluar el curso de las fracturas en la superficie lingual después de la cirugía.
UNASSIGNED: El análisis estadístico no reveló correlación entre la profundidad de la fosa mandibular y el tipo de fractura después de la osteotomía sagital bilateral. Del mismo modo, no hubo asociación entre la altura y el ángulo del cuerpo mandibular y el tipo de fractura. El tipo de fractura más común observado fue el patrón tipo 3, caracterizado por una línea que atraviesa el canal mandibular. Además, no se identificó relación entre los aspectos anatómicos estudiados y la ocurrencia de fracturas no deseadas.
UNASSIGNED: Los datos anatómicos presentados en este estudio pueden ayudar a los cirujanos a seleccionar las técnicas quirúrgicas más seguras y los sitios de osteotomía óptimos, especialmente en pacientes con fisura labiopalatina.

BACKGROUND: Orofacial clefts (OFCs) are among the most common birth defects (BD). In 2008, a series of improvements began in the Costa Rican Birth Defect Register Center (CREC). We aim to explore trends between 1996 and 2021.
METHODS: A trend analysis of OFCs from 1996 to 2021 and a descriptive analysis of OFCs from 2010 to 2021 were performed based on data from the CREC, the national BD surveillance system. Prevalence at birth was calculated according to the type: cleft palate (CP), cleft lip with or without CP (CL ± P), and presentation (isolated, multiple non-syndromic, or syndromes). We used joinpoint regression to identify if a significant change in trend occurred; the average annual percent change (AAPC) was determined. Marginal means and prevalence ratios by subperiod (1996-2009 as referent and 2010-2021) were estimated using Poisson regression and compared using Wald\'s chi-square tests (α ≤.05).
RESULTS: We found a significant AAPC for OFCs prevalence of +1.4: +0.6 for isolated, +2.9 for multiple non-syndromic, and +7.7 for syndromes (p < .05). When comparing the OFC\'s prevalence of the subperiod 2010-2021 (11.86 per 10,000) with 1996-2009 (9.36 per 10,000) the prevalence ratio was 1.3 (p < .01): 1.1 (p < .05) for isolated, 1.6 (p < .01) for multiple non-syndromic, and 3.3 (p < .01) for syndromes. The prevalence of OFCs from 2010 to 2021 was 9.1 for CL ± P and 2.8 for CP. Seventy-one percent of the OFCs were isolated, 22% multiple non-syndromic, and 7% syndromes.
CONCLUSIONS: The trend in OFCs\' prevalence is toward increasing, mainly due to improvements in the surveillance system.

OBJECTIVE: Orofacial clefts (OFCs) are some of the most common congenital anomalies worldwide. The aim of this case-control study was to evaluate the association of OFCs with selected maternal characteristics.
METHODS: Data on isolated non-syndromic cases of OFCs were extracted from the population-based registry of congenital anomalies of Tuscany. A sample of live-born infants without any congenital anomaly was used as the control group. We investigated the association with sex and some maternal characteristics: age, body mass index, smoking, and education. Adjusted odds ratios (OR) were calculated using a logistic regression model. Analyses were performed for the total OFCs and separately for cleft lip (CL) and cleft palate (CP).
RESULTS: Data on 219 cases and 37,988 controls were analyzed. A higher proportion of males (57.9%) was observed, particularly for CL. A decreasing trend among the maternal age classes was observed (OR:0.81 (95%CI 0.70-0.94)). Underweight mothers had a higher prevalence of OFCs, in particular for CL (OR:1.88 (95%CI 1.08-3.26)).
CONCLUSIONS: We found an association of OFCs with lower maternal age. The association with maternal age remains controversial and further epidemiological evidence is needed through multicenter studies. We observed that CL was more common in underweight mothers, suggesting actions of primary prevention.

OBJECTIVE: This case-control study investigated the associations between maternal plasma vitamin B12, homocysteine, and red blood cell (RBC) folate levels and the risk of cleft lip with or without cleft palate (CL/P) in offspring.
METHODS: The study compared 94 mothers and children with non-syndromic CL/P from a teaching hospital in Thailand to 94 mother-infant controls from local well-baby clinics, frequency-matched by birth date and mother\'s education. Data included anthropometric measurements, blood sample analyses, and a questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the associations through multiple logistic regression, adjusting for confounders.
RESULTS: Mothers with higher plasma vitamin B12 levels had a lower risk of having a child with CL/P compared to those in the lowest quartile. This association was more pronounced among mothers without a family history of orofacial clefts and those who were not underweight. Conversely, elevated homocysteine levels, a marker of impaired B vitamin metabolism, increased the risk of CL/P. No association was found between RBC folate and CL/P.
CONCLUSIONS: Higher maternal vitamin B12 levels are associated with a reduced risk of CL/P, while elevated homocysteine levels may increase the risk.

Several mutations in the IRF6 gene have been identified as a causative link to VWS. In this investigation, whole-exome sequencing (WES) and Sanger sequencing of a three-generation pedigree with an autosomal-dominant inheritance pattern affected by VWS identified a unique stop-gain mutation-c.748C>T:p.R250X-in the IRF6 gene that co-segregated exclusively with the disease phenotype. Immunofluorescence analysis revealed that the IRF6-p.R250X mutation predominantly shifted its localization from the nucleus to the cytoplasm. WES and protein interaction analyses were conducted to understand this mutation\'s role in the pathogenesis of VWS. Using LC-MS/MS, we found that this mutation led to a reduction in the binding of IRF6 to histone modification-associated proteins (NAA10, SNRPN, NAP1L1). Furthermore, RNA-seq results show that the mutation resulted in a downregulation of TGFβ2-AS1 expression. The findings highlight the mutation\'s influence on TGFβ2-AS1 and its subsequent effects on the phosphorylation of SMAD2/3, which are critical in maxillofacial development, particularly the palate. These insights contribute to a deeper understanding of VWS\'s molecular underpinnings and might inform future therapeutic strategies.

Non-syndromic orofacial clefts (NSOFCs) are common birth defects with a complex etiology. While over 60 common risk loci have been identified, they explain only a small proportion of the heritability for NSOFCs. Rare variants have been implicated in the missing heritability. Thus, our study aimed to identify genes enriched with nonsynonymous rare coding variants associated with NSOFCs. Our sample included 814 non-syndromic cleft lip with or without palate (NSCL/P), 205 non-syndromic cleft palate only (NSCPO), and 2150 unrelated control children from Nigeria, Ghana, and Ethiopia. We conducted a gene-based analysis separately for each phenotype using three rare-variants collapsing models: (1) protein-altering (PA), (2) missense variants only (MO); and (3) loss of function variants only (LOFO). Subsequently, we utilized relevant transcriptomics data to evaluate associated gene expression and examined their mutation constraint using the gnomeAD database. In total, 13 genes showed suggestive associations (p = E-04). Among them, eight genes (ABCB1, ALKBH8, CENPF, CSAD, EXPH5, PDZD8, SLC16A9, and TTC28) were consistently expressed in relevant mouse and human craniofacial tissues during the formation of the face, and three genes (ABCB1, TTC28, and PDZD8) showed statistically significant mutation constraint. These findings underscore the role of rare variants in identifying candidate genes for NSOFCs.

Orofacial clefts (OFCs) are among the most common human congenital birth defects. Previous multiethnic studies have identified dozens of associated loci for both cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP). Although several nearby genes have been highlighted, the \"casual\" variants are largely unknown. Here, we developed DeepFace, a convolutional neural network model, to assess the functional impact of variants by SNP activity difference (SAD) scores. The DeepFace model is trained with 204 epigenomic assays from crucial human embryonic craniofacial developmental stages of post-conception week (pcw) 4 to pcw 10. The Pearson correlation coefficient between the predicted and actual values for 12 epigenetic features achieved a median range of 0.50-0.83. Specifically, our model revealed that SNPs significantly associated with OFCs tended to exhibit higher SAD scores across various variant categories compared to less related groups, indicating a context-specific impact of OFC-related SNPs. Notably, we identified six SNPs with a significant linear relationship to SAD scores throughout developmental progression, suggesting that these SNPs could play a temporal regulatory role. Furthermore, our cell-type specificity analysis pinpointed the trophoblast cell as having the highest enrichment of risk signals associated with OFCs. Overall, DeepFace can harness distal regulatory signals from extensive epigenomic assays, offering new perspectives for prioritizing OFC variants using contextualized functional genomic features. We expect DeepFace to be instrumental in accessing and predicting the regulatory roles of variants associated with OFCs, and the model can be extended to study other complex diseases or traits.

Nonsyndromic orofacial clefts (NSOFCs) represent a large proportion (70%-80%) of all OFCs. They can be broadly categorized into nonsyndromic cleft lip with or without cleft palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO). Although NSCL/P and NSCPO are considered etiologically distinct, recent evidence suggests the presence of shared genetic risks. Thus, we investigated the genetic overlap between NSCL/P and NSCPO using African genome-wide association study (GWAS) data on NSOFCs. These data consist of 814 NSCL/P, 205 NSCPO cases, and 2159 unrelated controls. We generated common single-nucleotide variants (SNVs) association summary statistics separately for each phenotype (NSCL/P and NSCPO) under an additive genetic model. Subsequently, we employed the pleiotropic analysis under the composite null (PLACO) method to test for genetic overlap. Our analysis identified two loci with genome-wide significance (rs181737795 [p = 2.58E-08] and rs2221169 [p = 4.5E-08]) and one locus with marginal significance (rs187523265 [p = 5.22E-08]). Using mouse transcriptomics data and information from genetic phenotype databases, we identified MDN1, MAP3k7, KMT2A, ARCN1, and VADC2 as top candidate genes for the associated SNVs. These findings enhance our understanding of genetic variants associated with NSOFCs and identify potential candidate genes for further exploration.

OBJECTIVE: Metabolic syndrome (MetS) has been suggested to play a role in congenital defects. This study investigated the association of MetS and its components with orofacial clefts (OFCs).
METHODS: We conducted a case-control study in Northeast Thailand. Ninety-four cases with cleft lip, with or without cleft palate, were frequency matched with 94 controls on the infant\'s age and mother\'s education. We administered a mother\'s health questionnaire and collected anthropometric measurements and blood samples. Multiple logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses were performed among infants without a family history of OFCs, mothers who were not currently breastfeeding, and mothers who were >6 months postpartum.
RESULTS: When compared to mothers of normal weight, the OR associated with OFCs were 2.44 (95% CI, 1.04-5.76, P = .04) in overweight mothers, and 3.30 (95% CI, 1.14-9.57, P = .03) in obese mothers. Low HDL-C raised the risk of OFCs 2.95 times (95% CI, 1.41-6.14, P = .004) compared to normal HDL-C levels. Mothers with 4 or 5 features of MetS were 2.77 times as likely to have the affected child than those who did not (95% CI, 0.43-17.76), but this difference was not statistically significant (P = .28). Subgroup analyses showed similar results, uncovering an additional significant association between underweight mothers and OFCs.
CONCLUSIONS: The results indicate a robust association between underweight and overweight/obese maternal body mass index and increased OFC risk. Additionally, low HDL-C in mothers is linked to an elevated risk of OFCs. Further research is needed to evaluate if promoting strategies to maintain optimal body weight and enhance HDL-C levels in reproductive-age and pregnant women icould contribute to a reduction of the risk of OFCs in their progeny.

CDK13-related disorder, also known as congenital heart defects, dysmorphic facial features and intellectual developmental disorder (CHDFIDD) is associated with mutations in the CDK13 gene encoding transcription-regulating cyclin-dependent kinase 13 (CDK13). Here, we focused on the development of craniofacial structures and analyzed early embryonic stages in CHDFIDD mouse models, with one model comprising a hypomorphic mutation in Cdk13 and exhibiting cleft lip/palate, and another model comprising knockout of Cdk13, featuring a stronger phenotype including midfacial cleft. Cdk13 was found to be physiologically expressed at high levels in the mouse embryonic craniofacial structures, namely in the forebrain, nasal epithelium and maxillary mesenchyme. We also uncovered that Cdk13 deficiency leads to development of hypoplastic branches of the trigeminal nerve including the maxillary branch. Additionally, we detected significant changes in the expression levels of genes involved in neurogenesis (Ache, Dcx, Mef2c, Neurog1, Ntn1, Pou4f1) within the developing palatal shelves. These results, together with changes in the expression pattern of other key face-specific genes (Fgf8, Foxd1, Msx1, Meis2 and Shh) at early stages in Cdk13 mutant embryos, demonstrate a key role of CDK13 in the regulation of craniofacial morphogenesis.