Risk Of Clefts Research Articles

Genetic Variants in METTL16 Affect the Risk of Non-Syndromic Orofacial Clefts.

N6-methyladenosine (m6A) is the most prevalent modification of RNA in eukaryotes which is associated with many cellular processes and diseases. Here, our objective is to explore whether genetic variants in m6A modification genes are associated with the risk of non-syndrome orofacial clefts (NSOCs). The transmission disequilibrium test (TDT) was performed to calculate the association between single nucleotide polymorphisms (SNPs) in m6A modification genes and NSOCs risk in 944 case-parent trios. The function of SNP was predicted by HaploReg, RegulomeDB and histone enrichment data. The expression quantitative trait locus (eQTL) analysis was examined using Genotype-Tissue Expression (GTEx) and eQTLGen. The role of gene in the development of NSOCs was assessed with correlation and enrichment analysis based on gene expression data in mice craniofacial tissue and zebrafish embryo. We identified that rs8078195 (A > C) in METTL16 was suggestively associated with the increased risk of NSOCs (OR = 1.32, p = 1.80E - 03). The region surrounding rs8078195 was subjected to deoxyribonuclease hypersensitivity and enriched with multiple histone modifications. In addition, it had a significant eQTL effect with METTL16 in skin tissue and human peripheral blood, which played an important role in NSOCs development. Bioinformatic analysis indicated that METTL16 contributed to the development of NSOCs probably by regulating cell cycle process. Rs8078195 in METTL16 was associated with the occurrence of NSOCs.

Elementomics of 32 elements in cord serum depicts the risk of orofacial clefts: a case-control study in Shanxi, China

Maternal exposure to various metallic and non-metallic elements has been linked to the occurrence of orofacial clefts (OFCs), yet there remains a dearth of comprehensive research on the potential ramifications of simultaneous exposure to multiple elements. In this study, we investigated the individual and combined effects of element exposure on OFCs in a cohort of 168 pregnant women (49 cases and 119 controls) in the Shanxi province of northern China from 2010 to 2015. Cord serum samples were obtained from all participants to analyze the levels of 32 elements using inductively coupled plasma-mass spectrometry. The study examined the independent correlation between element concentrations and OFCs using two machine screening models, Boruta and Least Absolute Shrinkage and Selection Operator. Bayesian kernel machine regression (BKMR) was utilized to determine the combined effects of key exposure elements on OFCs and to clarify the interaction between exposed elements through the generalized additive model (GAM). The screening models identified lead (Pb), tin (Sn), iron (Fe), and cesium (Cs) as the most significant risk factors for OFC development in offspring. In the BKMR model, the probability of OFCs increased with higher overall levels of these risk elements, with Pb emerging as the primary contributor to the combined effect of the mixture. The findings of the GAM indicated that the combined exposure to Pb and Sn had a synergistic effect on the risk of developing OFCs. Analysis of elemental exposure in umbilical cord serum suggested that Pb exposure may have detrimental effects on OFC development in offspring, which may be further intensified by a synergistic interaction between Sn and Pb in the occurrence of OFCs.

Maternal micronutrient biomarkers and risk of non-syndromic cleft lip/palate: A case-control study.

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. 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. 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. Higher maternal vitamin B12 levels are associated with a reduced risk of CL/P, while elevated homocysteine levels may increase the risk.

Custom Biomedical FAIR Data Analysis in the Cloud Using CAVATICA.

The historically fragmented biomedical data ecosystem has moved towards harmonization under the findable, accessible, interoperable, and reusable (FAIR) data principles, creating more opportunities for cloud-based research. This shift is especially opportune for scientists across diverse domains interested in implementing creative, nonstandard computational analytic pipelines on large and varied datasets. However, executing custom cloud analyses may present difficulties, particularly for investigators lacking advanced computational expertise. Here, we present an accessible, streamlined approach for the cloud compute platform CAVATICA that offers a solution. We outline how we developed a custom workflow in the cloud, for analyzing whole genome sequences of case-parent trios to detect sex-specific genetic effects on orofacial cleft risk, which required several programming languages and custom software packages. The approach involves just three components: Docker to containerize software environments, tool creation for each analysis step, and a visual workflow editor to weave the tools into a Common Workflow Language (CWL) pipeline. Our approach should be accessible to any investigator with basic computational skills, is readily extended to implement any scalable high-throughput biomedical data analysis in the cloud, and is applicable to other commonly used compute platforms such as BioData Catalyst. We believe our approach empowers versatile data reuse and promotes accelerated biomedical discovery in a time of substantial FAIR data.

Maternal Metabolic Status and Orofacial Cleft Risk: A Case-Control Study in Thailand

ObjectivesMetabolic 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). MethodsWe 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 odd 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. ResultsWhen compared to mothers of normal weight, the OR associated with OFCs were 2.44 (95% CI, 1.04–5.76, p=0.04) in overweight mothers, and 3.30 (95% CI, 1.14–9.57, p=0.03) in obese mothers. Low HDL-C raised the risk of OFCs 2.95 times (95% CI, 1.41–6.14, p=0.004) 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=0.28). Subgroup analyses showed similar results, uncovering an additional significant association between underweight mothers and OFCs. ConclusionsThe 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 can contribute to reducing the risk of OFCs.

A common cis-regulatory variant impacts normal-range and disease-associated human facial shape through regulation of PKDCC during chondrogenesis.

Genome-wide association studies (GWAS) identified thousands of genetic variants linked to phenotypic traits and disease risk. However, mechanistic understanding of how GWAS variants influence complex morphological traits and can, in certain cases, simultaneously confer normal-range phenotypic variation and disease predisposition, is still largely lacking. Here, we focus on rs6740960, a single nucleotide polymorphism (SNP) at the 2p21 locus, which in GWAS studies has been associated both with normal-range variation in jaw shape and with an increased risk of non-syndromic orofacial clefting. Using in vitro derived embryonic cell types relevant for human facial morphogenesis, we show that this SNP resides in an enhancer that regulates chondrocytic expression of PKDCC - a gene encoding a tyrosine kinase involved in chondrogenesis and skeletal development. In agreement, we demonstrate that the rs6740960 SNP is sufficient to confer chondrocyte-specific differences in PKDCC expression. By deploying dense landmark morphometric analysis of skull elements in mice, we show that changes in Pkdcc dosage are associated with quantitative changes in the maxilla, mandible, and palatine bone shape that are concordant with the facial phenotypes and disease predisposition seen in humans. We further demonstrate that the frequency of the rs6740960 variant strongly deviated among different human populations, and that the activity of its cognate enhancer diverged in hominids. Our study provides a mechanistic explanation of how a common SNP can mediate normal-range and disease-associated morphological variation, with implications for the evolution of human facial features.

Risk of orofacial clefts in relation to maternal body mass index, diabetes and hypertension.

To investigate if maternal body mass index, diabetes and hypertension are associated with orofacial clefts. Case-control study. Information from 53,188 live births with and without orofacial cleft registered at USA Vital Statistics Natality Birth Data between 2017 and 2021. Case group consisted of all affected live births diagnosed with orofacial clefts (13,297 cases). Comparison group consisted of 39,891 live births without clefts or any other congenital malformation. Information about orofacial cleft cases were compared with the comparison group. The unadjusted and adjusted Odds Ratios were estimated to evaluate the strength of association between mother's pre-pregnancy body mass index, maternal diabetes and hypertension and orofacial cleft occurrence, assuming a p value < 0.05 and 95% confidence intervals (95% C.I.) for statistically significant differences. Mother's pre-pregnancy body mass index, maternal diabetes and maternal hypertension are conditions associated with an increased risk of orofacial cleft development in the child (OR = 1.08, p = 0.004, 95% C.I. = 1.024-1.149; OR = 1.32, 95%, p = 0.000, 95% C.I. = 1.202-1.444; and OR = 1.35, p = 0.000, 95% C.I. = 1.239-1.484; respectively). Maternal ethnicity, sex of infant, and cigarette smoking pregnancy remained as covariates after adjustments in all logistic regression models. Due to the increased prevalence of obesity, diabetes, and hypertension, and also to their association with congenital malformations, such as clefts, it is recommended that mothers planning to become pregnant to follow healthy habits, maintain healthy weight, and be screened for possible diabetes or hypertension prior to conception and early in pregnancy.

Preconception folic acid supplementation for the prevention of birth defects: a prospective, population-based cohort study in mainland China

BackgroundFolic acid supplementation is recommended for reducing the risk of birth defects. We aimed to assess the protective association of periconception folic acid supplements with birth defects in real-world setting.MethodsThis prospective, population-based cohort study utilized national preconception registered data of married Chinese couples planning a pregnancy within 6 months between 2010 and 2012 in Mainland China. Participated women are freely provided folic acid starting 3 months before conception till 3 months after conception. Birth defects were self-reported at 42 days postpartumn followup. R software (v4.0.2) was applied for statistical analyses.ResultsComplete data of 567,547 couples with pregnancy outcomes and folic acid supplementation were extracted for final analysis. A total of 74.7% women were with folic acid supplementation, and 599 birth defects were self-reported. The odd of birth defects was lower among women taking folic acid compared to their counterparts not taking (0.102% vs 0.116%, P < 0.001). In the multiple logistic regression analyses, the odd of birth defects was lower among couples with maternal folic acid supplementation (OR = 0.78, 95%CI: 0.66–0.95, P = 0.011), especially decreased odd of neural tube defects (NTDs) (OR = 0.56, 95%CI: 0.39–0.82, P = 0.003). This association was confirmed by 1:4 and 1:10 case control analysis. Odds of birth defects were significantly lower among women with folic acid supplementation more than 3 months before pregnancy (P < 0.001), and moreover, the odds of cleft (P = 0.007) and NTDs (P = 0.007) were of notable decrease.ConclusionThis retrospective case cohort study provides programmatic evidence for public health strategy-making to for reducing the risk of NTDs and clefts.

The Management of Nausea and Vomiting in Pregnancy and Hyperemesis Gravidarum (Green-top Guideline No. 69).

An objective and validated index of nausea and vomiting such as the Pregnancy-Unique Quantification of Emesis (PUQE) and HyperEmesis Level Prediction (HELP) tools can be used to classify the severity of NVP and HG. [Grade C] Ketonuria is not an indicator of dehydration and should not be used to assess severity. [Grade A] There are safety and efficacy data for first line antiemetics such as anti (H1) histamines, phenothiazines and doxylamine/pyridoxine (Xonvea®) and they should be prescribed initially when required for NVP and HG (AppendixIII). [Grade A] There is evidence that ondansetron is safe and effective. Its use as a second line antiemetic should not be discouraged if first line antiemetics are ineffective. Women can be reassured regarding a very small increase in the absolute risk of orofacial clefting with ondansetron use in the first trimester, which should be balanced with the risks of poorly managed HG. [Grade B] Metoclopramide is safe and effective and can be used alone or in combination with other antiemetics. [Grade B] Because of the risk of extrapyramidal effects metoclopramide should be used as second-line therapy. Intravenous doses should be administered by slow bolus injection over at least 3 minutes to help minimise these. [Grade C] Women should be asked about previous adverse reactions to antiemetic therapies. If adverse reactions occur, there should be prompt cessation of the medications. [GPP] Normal saline (0.9% NaCl) with additional potassium chloride in each bag, with administration guided by daily monitoring of electrolytes, is the most appropriate intravenous hydration. [Grade C] Combinations of different drugs should be used in women who do not respond to a single antiemetic. Suggested antiemetics for UK use are given in AppendixIII. [GPP] Thiamine supplementation (either oral 100 mg tds or intravenous as part of vitamin B complex (Pabrinex®)) should be given to all women admitted with vomiting, or severely reduced dietary intake, especially before administration of dextrose or parenteral nutrition. [Grade D] All therapeutic measures should have been tried before considering termination of pregnancy. [Grade C].

12-Year Trends of Orofacial Clefts in the United States: Highlighting Racial/Ethnic Differences in Prevalence of Cleft Lip and Cleft Palate.

Discrepancies in prevalence among infants with orofacial clefts are public health research priorities. Our objective was to calculate updated estimated prevalence of orofacial clefts in the United States, with sub-analyses by racial/ethnic group. The National Birth Defect Prevention Network database was used to evaluate trends in cases with orofacial cleft in the United States from 2006 to 2018. Cases with cleft lip with and without cleft palate (CL ± P) and cleft palate (CP) alone were sub-stratified by racial/ethnic category. Estimated prevalence was calculated using the total live births reported in each maternal racial/ethnic group. The odds ratio (OR) was calculated to measure the strength of association between racial/ethnic group and risk of orofacial clefts. Estimated prevalence rates show that maternally-reported Native American/Alaskan Native individuals were 43.8% (p < 0.0001) and 36.0% (p < 0.0001) more likely to have CL ± P and CP alone, respectively, compared to maternally-reported non-Hispanic White individuals. Estimated prevalence of CL ± P in maternally-reported non-Hispanic Black individuals (OR = 0.64) and maternally-reported Asians/Pacific Islander individuals were significantly lower than in maternally-reported non-Hispanic White individuals (OR = 0.63, p < 0.0001). Estimated prevalence of CP alone was significantly lower in maternally-reported non-Hispanic Black individuals (OR = 0.64, p < 0.0001), maternally-reported Asians/Pacific Islander individuals (OR = 0.69, p < 0.0001), and maternally-reported Hispanic individuals (OR = 0.81, p < 0.0001). Across the total population, there was no significant change in estimated orofacial cleft prevalence. However, there were significant disproportions in estimated orofacial cleft prevalence across racial/ethnic groups, which may guide further discussion among craniofacial health care providers and centers and their patients regarding differences in cleft risk factors.

Association between gestational exposure and risk of orofacial clefts: a systematic review and meta-analysis

BackgroundThe occurrence of orofacial Clefts (OFCs) is a congenital disease caused by many factors. According to recent studies, air pollution has a strong correlation with the occurrence of OFCs. However, there are still some controversies about the current research results, and there is no relevant research to review the latest results in recent years.ObjectiveIn this paper, the authors conducted a systematic review and meta-analysis to explore the correlation between ambient air pollution and the occurrence of neonatal OFCs deformity.MethodsWe searched Pubmed, Web of science, and Embase databases from the establishment of the database to May 2023. We included observational studies on the relationship between prenatal exposure to fine particulate matter 2.5 (PM2.5), fine particulate matter 10 (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), ozone (O3), carbon monoxide (CO) and the risk of cleft lip (CL), cleft palate (CP), cleft lip with or without palate (CL/P). the Newcastle-Ottawa quality assessment scale (NOS) was used to evaluate the quality of the literature. Funnel plot and Egger’s regression were used to verify the publication bias. Random effect model or fixed effect model was used to estimate the combined relative risk (RR) and 95% confidence interval (95%CI).ResultsA total of eleven studies were included in this study, including four cohort studies and seven case-control studies, including 22,453 cases of OFCs. Ten studies had low risk of bias and only one study had high risk of bias. Three studies reported that PM2.5 was positively correlated with CL and CP, with a combined RR and 95%CI of 1.287(1.174,1.411) and 1.267 (1.105,1.454). Two studies reported a positive correlation between O3 and CL, with a combined RR and 95%CI of 1.132(1.047,1.225). Two studies reported a positive correlation between PM10 and CL, with a combined RR and 95%CI of 1.108 (1.017,1.206). No association was found between SO2, CO, NO2 exposure during pregnancy and the risk of OFCs.ConclusionThe results of this study showed that there was a significant statistical correlation between exposure to PM10, PM2.5, O3 and the risk of OFCs in the second month of pregnancy. Exposure assessment, research methods and mechanisms need to be further explored.

A Systematic Literature Review on the Association Between Toxic and Essential Trace Elements and the Risk of Orofacial Clefts in Infants.

Orofacial clefts (OFCs) have been linked to various toxic and essential trace elements (TETEs) worldwide. However, review estimation is absent. Therefore, addressing the hypothesis that TETEs are associated with OFCs is the main area of this review. A systematic literature search was conducted using electronic databases through PubMed, Web of Science, Scopus, Science Direct, and Google Scholar between 2004 and August 2022. The "AND" and "OR" operators were used to make our search results inclusive and restrictive as follows: ("Toxic element*" OR "Heavy metal*") AND ("Toxic element*" OR "Lead OR Arsenic OR Mercury*")) AND ("Essential trace element*" OR "Zinc OR Selenium OR Copper*")) AND ("Orofacial cleft*" OR "Cleft lip*" OR "Cleft palate*") AND ("Infant*" OR "Newborn*" OR "Neonate*")). The presence of toxic elements was linked to the development of OFCs. The results showed that higher levels of toxic elements in various biological sample types were related to increased risks for OFCs. Increased concentrations of essential trace elements (ETEs) lowered the risk of OFCs. Maternal consumption of diets rich in ETEs, including zinc (Zn), selenium (Se), copper (Cu), cobalt (Co), and molybdenum (Mo), was linked to a more pronounced reduction in the risk of OFCs. Based on the findings, it is acceptable to infer that maternal exposure to toxic elements, whether through environmental contaminants or dietary sources, was associated with an elevated risk of OFCs. Furthermore, the study revealed that ETEs exhibited a potential protective role in reducing the incidence of OFCs. This observation highlights the importance of reducing exposure to toxic elements during pregnancy and suggests that optimizing maternal intake of ETEs could be an effective preventive strategy.

Risk Factors Associated with Cleft Etiology: A Multicenter Experience

Background: The etiology of cleft lip and palate is complex and thought to involve genetic influences with variable interactions from environmental factors. Although genetic and environmental triggers are important for syndromic cleft lip and palate, the etiology of the more common non-syndromic (isolated) forms remains poorly understood. Recognition of etiology, risk factors and natural history is essential to define how prevention and treatment should be planned and implemented. Objective: This study is aimed at assessing the possible risk factors in the etiology of patients presenting with cleft lip and palate. Materials and methods: A total of 254 children (children 12years and below) for cleft surgery at three surgical centers (Mercyland orthopedic Hospital, Galaxy Medical Center and shifa Royal Hospital) in the North Eastern under the Smile Train, project for a 2-year period (January 2021 to December 2022) were included in this study. A Self- administered questionnaire was prepared to fill in data about the patients' gender, family history of cleft, consanguineous marriages, maternal risk factors. Ages of the children were ascertained in months and years as told by the parents. Paternal and maternal ages were also recorded. Statistical analysis was done using the Statistical Package for Social Sciences (IBM) 23.0 version. The significant level was set at a p value of \0.05 at 95% confidence interval. Results: Median age at presentation was 4 month, varying from &lt;1 months to 12 years. The gender distribution was 133 (52.4%) males and 121 (47.6%) females (M:F = 1:0.9). Majority (214, 84.3%) of the affected children belonged to low socioeconomic group while only a few (12, 4.7%). High proportion of mothers between the age of 26 to 35 years (42.5%) was observed, but no association was found between maternal age and clefts (p=0.331). There was evidence of association between paternal age &gt;35years old and cleft (p=0.005). Conclusion: This study revealed a strong association between consanguineous marriage, low socioeconomic status and persistent maternal fever during the first trimester and cleft. Increasing paternal age was also found to increase the risk of cleft. The relevance of this study is for public health workers and clinicians to be equipped with adequate information to provide useful counseling to parents particularly those with history of cleft.it may also provide adequate information for policy makers when making policies of public health concerns.

Epigenetic implications in maternal diabetes and metabolic syndrome-associated risk of orofacial clefts.

Orofacial clefts (OFCs) are one of the most common types of structural birth defects. The etiologies are complicated, involving with genetic, epigenetic, and environmental factors. Studies have found that maternal diabetes and metabolic syndrome are associated with a higher risk of OFCs in offspring. Metabolic syndrome is a clustering of several disease risk factors, including hyperglycemia, dyslipidemia, obesity, and hypertension. Metabolic disease during pregnancy can increase risk of adverse outcomes and significantly influence fetal development, including orofacial formation and fusion. An altered metabolic state may contribute to developmental disorders or congenital defects including OFCs, potentially through epigenetic modulations, such as histone modification, DNA methylation, and noncoding RNA expression to alter activities of critical morphogenetic signaling or related developmental genes. This review summarizes the currently available evidence and underlying mechanisms of how the maternal metabolic syndrome is associated with OFCs in mostly human and some animal studies. It may provide a better understanding of the interactions between intrauterine metabolic status and fetal orofacial development which might be applied toward prevention and treatments of OFCs.

The relationship between maternal periconceptional micronutrient supplementation and non-syndromic cleft lip/palate in offspring.

This study aimed to explore the relationship between maternal periconceptional supplementation with folic acid only (FAO) or with multiple micronutrients containing folic acid (MMFA) and non-syndromic cleft lip/palate in offspring. The data came from a prenatal health care system and a birth defects surveillance system in Beijing, China, from 2013 to 2018. Information on maternal FAO/MMFA supplementation was collected by questionnaire in the first trimester, and data on cleft lip/palate were collected at delivery or termination of pregnancy. Inverse probability weighting (IPW) by the propensity score to adjust for the confounders and Poisson regression model was used to estimate risk ratios (RRs) and their 95% confidence intervals (CIs). A total of 63,969 participants were included in the study. Compared to the no-supplementation group, the adjusted RR for the supplementation group was 0.51 (95% CI: 0.40, 0.64). And the adjusted RRs for FAO and MMFA compared to the no-supplementation group were 0.56 (95% CI: 0.40, 0.76) and 0.48 (95% CI: 0.35, 0.65), respectively. Compared to supplement FAO and MMFA with less than 8 days out of 10 days, the adjusted RRs for FAO and MMFA with 8 or more days out of 10 days were 1.17 (95% CI: 0.78, 1.75), and 2.05 (95% CI: 1.37, 3.31), respectively. Maternal supplementation with micronutrients, either FAO or MMFA, during the periconceptional period can reduce the risk for non-syndromic cleft lip/palate in offspring. However, women should be more cautious with MMFA supplementation.

Brazilian Multiethnic Association Study of Genetic Variant Interactions among FOS, CASP8, MMP2 and CRISPLD2 in the Risk of Nonsyndromic Cleft Lip with or without Cleft Palate

Associations of CRISPLD2 (cysteine-rich secretory protein LCCL domain containing 2) and genes belonging to its activation pathway, including FOS (Fos proto-oncogene), CASP8 (caspase 8) and MMP2 (matrix metalloproteinase 2), with nonsyndromic orofacial cleft risk, have been reported, but the results are yet unclear. The aim of this study was to evaluate single nucleotide polymorphisms (SNPs) in FOS, CASP8 and MMP2 and to determine their SNP-SNP interactions with CRISPLD2 variants in the risk of nonsyndromic cleft lip with or without cleft palate (NSCL±P) in the Brazilian population. The SNPs rs1046117 (FOS), rs3769825 (CASP8) and rs243836 (MMP2) were genotyped using TaqMan allelic discrimination assays in a case-control sample containing 801 NSCL±P patients (233 nonsyndromic cleft lip only (NSCLO) and 568 nonsyndromic cleft lip and palate (NSCLP)) and 881 healthy controls via logistic regression analysis adjusted for the effects of sex and genomic ancestry proportions with a multiple comparison p value set at ≤0.01. SNP-SNP interactions with rs1546124, rs8061351, rs2326398 and rs4783099 in CRISPLD2 were performed with the model-based multifactor dimensionality reduction test complemented with a 1000 permutation-based strategy. Although the association between FOS rs1046117 and risk of NSCL±P reached only nominal p values, NSCLO risk was significantly higher in carriers of the FOS rs1046117 C allele (OR: 1.28, 95% CI: 1.10-1.64, p = 0.004), TC heterozygous genotype (OR: 1.59, 95% CI: 1.16-2.18, p = 0.003), and in the dominant model (OR: 1.50, 95% CI: 1.10-2.02, p = 0.007). Individually, no significant associations between cleft risk and the SNPs in CASP8 and MMP2 were observed. SNP-SNP interactions involving CRISPLD2 variants and rs1046117 (FOS), rs3769825 (CASP8) and rs243836 (MMP2) yielded several significant p values, mostly driven by FOS rs1046117 and CASP8 rs3769825 in NSCL±P, FOS rs1046117 in NSCLO and CRISPLD2 rs8061351 in NSCLP. Our study is the first in the Brazilian population to reveal the association of FOS rs1046117 with NSCLO risk, and to support that CRISPLD2, CASP8, FOS and MMP2 interactions may be related to the pathogenesis of this common craniofacial malformation.

Assessing medical product safety during pregnancy using parameterizable tools in the sentinel distributed database.

The US Food and Drug Administration established the Sentinel System to monitor the safety of medical products. A component of this system includes parameterizable analytic tools to identify mother-infant pairs and evaluate infant outcomes to enable the routine monitoring of the utilization and safety of drugs used in pregnancy. We assessed the feasibility of using the data and tools in the Sentinel System by assessing a known association between topiramate use during pregnancy and oral clefts in the infant. We identified mother-infant pairs using the mother-infant linkage table from six data partners contributing to the Sentinel Distributed Database from January 1, 2000, to September 30, 2015. We compared mother-infant pairs with first-trimester exposure to topiramate to mother-infant pairs that were topiramate-unexposed or lamotrigine-exposed and used a validated algorithm to identify oral clefts in the infant. We estimated adjusted risk ratios through propensity score stratification. There were 2007 topiramate-exposed and 1 066 086 unexposed mother-infant pairs in the main comparison. In the active-comparator analysis, there were 1996 topiramate-exposed and 2859 lamotrigine-exposed mother-infant pairs. After propensity score stratification, the odds ratio for oral clefts was 2.92 (95% CI: 1.43, 5.93) comparing the topiramate-exposed to unexposed groups and 2.72 (95% CI: 0.75, 9.93) comparing the topiramate-exposed to lamotrigine-exposed groups. We found an increased risk of oral clefts after topiramate exposure in the first trimester in the Sentinel database. These results are similar to prior published observational study results and demonstrate the ability of Sentinel's data and analytic tools to assess medical product safety in cohorts of mother-infant pairs in a timely manner.

Association of In Utero Antipsychotic Medication Exposure With Risk of Congenital Malformations in Nordic Countries and the US

Psychiatric disorders are common among female individuals of reproductive age. While antipsychotic medication use is increasing, the safety of such medications in pregnancy is an area with large evidence gaps. To evaluate the risk of first-trimester antipsychotic exposure with respect to congenital malformations, focusing on individual drugs and specific malformation subtypes. This cohort study used data from nationwide health registers from the 5 Nordic countries and the US and spanned 1996 to 2018. The Nordic cohort included all pregnancies resulting in singleton live-born infants, and the US cohort consisted of publicly insured mothers linked to their live-born infants nested in the nationwide Medicaid Analytic eXtract. Data were analyzed from November 2020 to April 2022. One or more first-trimester dispensing of any atypical, any typical, and individual antipsychotic drugs. Any major congenital malformation and specific malformation subtypes previously suggested to be associated with antipsychotic exposure in utero: cardiovascular malformations, oral clefts, neural tube defects, hip dysplasia, limb reduction defects, anorectal atresia/stenosis, gastroschisis, hydrocephalus, other specific brain anomalies, and esophageal disorders. Propensity score stratification was used to control for potential confounders. Pooled adjusted estimates were calculated using indirect standardization. A total of 6 455 324 unexposed mothers (mean maternal age range across countries: 24-31 years), 21 751 mothers exposed to atypical antipsychotic drugs (mean age range, 26-31 years), and 6371 mothers exposed to typical antipsychotic drugs (mean age range, 27-32 years) were included in the study cohort. Prevalence of any major malformation was 2.7% (95% CI, 2.7%-2.8%) in unexposed infants, 4.3% (95% CI, 4.1%-4.6%) in infants with atypical antipsychotic drug exposure, and 3.1% (95% CI, 2.7%-3.5%) in infants with typical antipsychotic drug exposure in utero. Among the most prevalent exposure-outcome combinations, adjusted relative risks (aRR) were generally close to the null. One exception was olanzapine exposure and oral cleft (aRR, 2.1 [95% CI, 1.1-4.3]); however, estimates varied across sensitivity analyses. Among moderately prevalent combinations, increased risks were observed for gastroschisis and other specific brain anomalies after atypical antipsychotic exposure (aRR, 1.5 [95% CI, 0.8-2.6] and 1.9 [95% CI, 1.1-3.0]) and for cardiac malformations after chlorprothixene exposure (aRR, 1.6 [95% CI, 1.0-2.7]). While the association direction was consistent across sensitivity analyses, confidence intervals were wide, prohibiting firm conclusions. In this study, considering the evidence from primary and sensitivity analyses and inevitable statistical noise for very rare exposure-outcome combinations, in utero antipsychotic exposure generally was not meaningfully associated with an increased risk of malformations. The observed increased risks of oral clefts associated with olanzapine, gastroschisis, and other specific brain anomalies with atypical antipsychotics and cardiac malformations with chlorprothixene requires confirmation as evidence continues to accumulate.

Damaging Mutations in AFDN Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate.

Novel or rare damaging mutations have been implicated in the developmental pathogenesis of nonsyndromic cleft lip with or without cleft palate (nsCL ± P). Thus, we investigated the human genome for high-impact mutations that could explain the risk of nsCL ± P in our cohorts. We conducted next-generation sequencing (NGS) analysis of 130 nsCL ± P case-parent African trios to identify pathogenic variants that contribute to the risk of clefting. We replicated this analysis using whole-exome sequence data from a Brazilian nsCL ± P cohort. Computational analyses were then used to predict the mechanism by which these variants could result in increased risks for nsCL ± P. We discovered damaging mutations within the AFDN gene, a cell adhesion molecule (CAMs) that was previously shown to contribute to cleft palate in mice. These mutations include p.Met1164Ile, p.Thr453Asn, p.Pro1638Ala, p.Arg669Gln, p.Ala1717Val, and p.Arg1596His. We also discovered a novel splicing p.Leu1588Leu mutation in this protein. Computational analysis suggests that these amino acid changes affect the interactions with other cleft-associated genes including nectins (PVRL1, PVRL2, PVRL3, and PVRL4) CDH1, CTNNA1, and CTNND1. This is the first report on the contribution of AFDN to the risk for nsCL ± P in humans. AFDN encodes AFADIN, an important CAM that forms calcium-independent complexes with nectins 1 and 4 (encoded by the genes PVRL1 and PVRL4). This discovery shows the power of NGS analysis of multiethnic cleft samples in combination with a computational approach in the understanding of the pathogenesis of nsCL ± P.

Identification of a new familial case of 3q29 deletion syndrome associated with cleft lip and palate via whole-exome sequencing.

Many unbalanced large copy number variants reviewed in the paper are associated with syndromic orofacial clefts, including a 1.6Mb deletion on chromosome 3q29. The current report presents a new family with this recurrent deletion identified via whole-exome sequencing and confirmed by array comparative genomic hybridization. The proband exhibited a more severe clinical phenotype than his affected mother, comprising right-sided cleft lip/alveolus and cleft palate, advanced dental caries, heart defect, hypospadias, psychomotor, and speech delay, and an intellectual disability. Data analysis from the 3q29 registry revealed that the 3q29 deletion increases the risk of clefting by nearly 30-fold. No additional rare and pathogenic nucleotide variants were identified that could explain the clefting phenotype and observed intrafamilial phenotypic heterogeneity. These data suggest that the 3q29 deletion may be the primary risk factor for clefting, with additional genomic variants located outside the coding sequences, methylation changes, or environmental exposure serving as modifiers of this risk. Additional studies, including whole-genome sequencing or methylation analyses, should be performed to identify genetic factors underlying the phenotypic variation associated with the recurrent 3q29 deletion.