MMP16 as NSCL ± P Susceptible Gene in Western Han Chinese.

OBJECTIVE: The role of MMP16 in lip development is unclear. This study aimed to identify nonsyndromic cleft lip with or without palate (NSCL ± P) susceptible loci of MMP16 in western Han Chinese. DESIGN: We performed targeted sequencing around MMP16 combined with a 2-phase association analysis on common variants. Phase 2 association analysis was performed with NSCL ± P specific subphenotypes (NSCL and NSCLP). Then we used rare variants burden analysis and genotyping, accompanied by motif analysis. SETTING: This study was completed in a tertiary medical center. PATIENTS, PARTICIPANTS: Phase 1 targeted sequencing included 159 patients with NSCL ± P and 542 normal controls; phase 2 included 1626 patients with NSCL ± P (1047 NSCL and 579 NSCLP) and 2255 normal controls. INTERVENTIONS: Venous blood samples were collected from patients and used to extract DNA. MAIN OUTCOME MEASURES: After Bonferroni correction, phase 1 significant threshold of p-value was 4.28 × 10-5 (0.05/1167 single nucleotide polymorphisms [SNPs]), and phase 2 was .00025 (0.05/200 SNPs). Burden analysis significant threshold p-value was .05. RESULTS: Common variants phase 1 association analysis identified 11 statistically significant SNPs (lowest p = 1.90 × 10-9, odds ratio (OR) = 0.27, 95% CI: 0.17-0.44), phase 2 replication identified 16 SNPs in NSCL ± P (lowest p = 6.26 × 10-6, OR = 0.77, 95% CI: 0.69-0.86) and 9 in NSCL (lowest p = 8.44 × 10-5, OR = 0.76, 95% CI: 0.66-0.87). Rare variants burden analysis showed no significant results, genotyping results showed they were maternally inherited. CONCLUSIONS: Our study identified MMP16 susceptible SNPs in NSCL ± P and NSCL, emphasizing its potential role in lip development. Our study also highlighted the importance to perform association analysis with subphenotypes divided.

Relationship Between Stigma Experience and Self-Perception Related to Facial Appearance in Young Japanese Patients with Cleft lip and/or Palate.

OBJECTIVE: To examine the relationship between stigma experience related to facial appearance in Japanese youths with cleft lip and/or palate (CL/P) and their self-perception. DESIGN: A cross-sectional study. PARTICIPANTS: Sixty-nine Japanese youths with CL/P (11-18 years old). OUTCOME MEASURES: The participants' stigma experience in relation to facial appearance (measured with 7 single contextual scale items) and their self-perception (measured with 5 domain scores based on 30 perceptual items) were assessed using the Japanese version of the Youth Quality of Life Instrument-Facial Differences Module. Participants were categorized into high and low self-perception subgroups with a threshold of 1 standard deviation for each domain. The frequency of stigma experiences was compared between the following 2 subgroups: age, sex, cleft palate only versus other cleft, and high versus low self-perception. Correlations between the responses regarding stigma and all domain scores were examined. RESULTS: Sixteen percent of the participants reported experiencing stigma. Hearing others say something about their face occurred significantly more frequently in youths 15 to 18 years of age than in youths 11 to 14 years of age. Stigma frequency was not found to differ by sex or cleft type. Stigma experiences were significantly more frequent for youth with higher scores across negative self-perception domains as well as higher coping skills. Significant correlations were identified between responses regarding stigma items and all domain scores (r = 0.27-0.63, p < .05). CONCLUSIONS: It was found that stigma experiences related to facial appearance may influence negative self-perceptions of facial differences as well as higher coping skills among Japanese youths with CL/P.

Evidence for craniofacial enhancer variation underlying nonsyndromic cleft lip and palate.

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect for which only ~ 20% of the underlying genetic variation has been identified. Variants in noncoding regions have been increasingly suggested to contribute to the missing heritability. In this study, we investigated whether variation in craniofacial enhancers contributes to NSCLP. Candidate enhancers were identified using VISTA Enhancer Browser and previous publications. Prioritization was based on patterning defects in knockout mice, deletion/duplication of craniofacial genes in animal models and results of whole exome/whole genome sequencing studies. This resulted in 20 craniofacial enhancers to be investigated. Custom amplicon-based sequencing probes were designed and used for sequencing 380 NSCLP probands (from multiplex and simplex families of non-Hispanic white (NHW) and Hispanic ethnicities) using Illumina MiSeq. The frequencies of identified variants were compared to ethnically matched European (CEU) and Los Angeles Mexican (MXL) control genomes and used for association analyses. Variants in mm427/MSX1 and hs1582/SPRY1 showed genome-wide significant association with NSCLP (p ≤ 6.4 × 10-11). In silico analysis showed that these enhancer variants may disrupt important transcription factor binding sites. Haplotypes involving these enhancers and also mm435/ABCA4 were significantly associated with NSCLP, especially in NHW (p ≤ 6.3 × 10-7). Importantly, groupwise burden analysis showed several enhancer combinations significantly over-represented in NSCLP individuals, revealing novel NSCLP pathways and supporting a polygenic inheritance model. Our findings support the role of craniofacial enhancer sequence variation in the etiology of NSCLP.

Prevalence rates study of selected isolated non-Mendelian congenital anomalies in the Hutterite population of Alberta, 1980-2016.

A study of the prevalence rates for selected isolated non-Mendelian congenital anomalies in the Hutterite Brethren of Alberta, Canada was undertaken to further examine longitudinal data in this isolated community that was last reported in 1985 (Lowry et al., 1985), although there are numerous publications on recessive disorders (Boycott et al., 2008; Triggs-Raine et al., 2016). Cases were ascertained from the Alberta Congenital Anomaly Surveillance System for the years 1997-2016. Since our initial results showed some surprising findings in the Hutterite Brethren, such as zero cases of spina bifida, cleft lip and palate, gastroschisis, and omphalocele, and a significant excess of cases with hypospadias, we extended the study to prior years (1980-1996) for selected anomalies. For the extended study period (1980-2016), there was a significant increased prevalence of hypospadias, tetralogy of Fallot and tricuspid atresia in the Hutterite population, and although not statistically significant, zero cases of cleft lip with cleft palate, gastroschisis and omphalocele were confirmed. Further research is needed to determine the precise effects of rural environmental exposures, lifestyle factors, and genetic associations for selected multifactorial congenital anomalies.

Palatal evaluation and treatment in 22q11.2 deletion syndrome.

Palatal involvement occurs commonly in patients with 22q11.2 Deletion Syndrome (22qDS), and includes palatal clefting and velopharyngeal dysfunction in the absence of overt or submucous clefts. The reported incidence and distribution of palatal abnormalities vary in the literature. The aim of this article is to revisit the incidence and presenting features of palatal abnormalities in a large cohort of patients with 22qDS, summarize the surgical treatments performed in this cohort, and provide an overview of surgical treatment protocols and management guidelines for palatal abnormalities in this syndrome. Charts of 1,121 patients seen through the 22q and You Center at the Children's Hospital of Philadelphia were reviewed for palatal status, demographic factors, deletion size, and corrective surgical procedures. Statistical analysis was performed using Pearson's chi-squared test to identify differences between gender, deletion size, and palatal abnormality. Of the patients with complete evaluations, 67% were found to have a palatal abnormality. The most common finding was velopharyngeal dysfunction in 55.2% of patients, and in 33.3% of patients, this occurred in the absence of palatal clefting. There was no significant difference in the incidence of palatal abnormalities by gender; however, a difference was noted among race (p < 0.01) and deletion sizes (p < 0.01). For example, Caucasian and Asian patients presented with a much higher prevalence of palatal abnormalities, and conversely those with nested deletions presented with a much lower rate of palatal defects. Overall, 26.9% of patients underwent palatal surgery, and the most common indication was velopharyngeal dysfunction. Palatal abnormalities are a hallmark feature of 22q11.2 Deletion Syndrome; understanding the incidence, presenting features, and treatment protocols are essential for practitioners counseling and treating families affected with this disorder.

Interaction between interferon regulatory factor 6 and glycine receptor beta shows a protective effect on developing nonsyndromic cleft lip with or without cleft palate in the Han Chinese population.

Single-nucleotide polymorphisms (SNPs) in protein-coding regions of genes which were previously reported to be associated with nonsyndromic cleft lip, with or without palate involvement (NSCL/P), were investigated. Twelve candidate loci [platelet-derived growth factor C (PDGFC), platelet-derived growth factor subunit A (PDGFA), platelet-derived growth factor receptor alpha (PDGFRA), glycine receptor alpha 2 (GLRA2), glycine receptor beta (GLRB), ATP binding cassette subfamily A member 4 (ABCA4), MAF bZIP transcription factor B (MAFB), interferon regulatory factor 6 (IRF6), CCDC26 long non-coding RNA (CCDC26), paired box 7 (PAX7), ventral anterior homeobox 1 (VAX1), and netrin 1 (NTN1)] covering 1.5 Mbp were sequenced in 136 NSCL/P patients and 54 healthy controls. Twenty-five genomic variants identified were further validated in another 400 NSCL/P and 200 controls. Two SNPs in IRF6 showed a protective effect against the development of NSCL/P (rs12405750, OR = 0.54, 95% CI: 0.41-0.69; and rs2235371, OR = 0.55, 95% CI: 0.43-0.71). The missense variant, rs2235371, alters the conserved amino acid valine to isoleucine at codon 274 (V274I). We observed that SNPs at IRF6 (rs2235371 and rs12405750) and GLRB (rs73856838 and rs72685584) show consistent interaction effects. The association between the missense SNP rs2235371 in gene IRF6 and NSCL/P suggests that this SNP may play an important role as a risk factor for NSCL/P in the Han Chinese populations. The marginal signal near 4q31 detected in previous genome-wide association studies might be caused by an interaction between the IRF6 and GLRB genes. This interaction needs to be further validated by experimentation in follow-up studies.

PAX7 nucleotide variants and the risk of non-syndromic orofacial clefts in the Polish population.

OBJECTIVE: The etiology of non-syndromic cleft lip with or without cleft palate (nsCL/P) is multifactorial, heterogeneous, and still not completely understood. The aim of the present study was to examine the associations between common and rare PAX7 nucleotide variants and the risk of this common congenital anomaly in a Polish population. SUBJECTS AND METHODS: Eight top nsCL/P-associated PAX7 variants identified in our cleft genome-wide association study (GWAS) were selected for replication analysis in an independent group of patients and controls (n = 247 and n = 445, respectively). In addition, mutation screening of the PAX7 protein-coding region was conducted. RESULTS: Analysis of the pooled data from the GWAS and replication study confirmed that common PAX7 nucleotide variants are significantly associated with the increased risk of nsCL/P. The strongest individual variant was rs1339062 (c.586 + 15617T > C) with a p-value = 2.47E-05 (OR = 1.4, 95%CI: 1.20-1.64). Sequencing analysis identified a novel synonymous PAX7 substitution (c.87G > A, p.Val29Val) in a single patient with nsCLP. This transition located in the early exonic position was predicted to disrupt potential splice enhancer elements. CONCLUSION: Our study confirmed that PAX7 is a strong candidate gene for nsCL/P. Nucleotide variants of this gene contribute to the etiology of nsCL/P in the homogenous Polish population.

The Influence of Consanguinity on Familial Clefting Among Palestinians.

INTRODUCTION: Orofacial clefts (OFC) are the most common congenital craniofacial anomaly. The relationship between intermarriage (consanguinity) and positive family history for OFC is not well described. Consanguinity rates in developed countries are <1% but are considerably higher in the Middle East (45%). Familial clefting rates in developed countries are under 20% but in the Middle East are reported at 30% or higher. OBJECTIVE: To determine OFC demographics and to clarify the relationship between consanguinity and familial clefting among Palestinians. DESIGN: The Palestinian Congenial Anomalies Database is based on a 700-question survey administered to mothers of children with congenital anomalies. Orofacial clefts were diagnosed in 540 children. All demographic data were analyzed using χ2 tests with a level of significance at α < .05. RESULTS: Demographics for OFC among Palestinians were similar to other published reports. Overall consanguinity rate was 53% and familial clefting rate was 49%. Parental rates of consanguinity were significantly different for patients with cleft palate. Patients with consanguineous parents had a higher rate of positive family history of clefting (67%). Recurrence of clefts in siblings was significantly higher among those born to consanguineous parents (73%) when compared to nonconsanguineous parents. CONCLUSION: Consanguinity rates for Palestinians with OFC were higher than those reported in the Middle East. Familial clefting and sibling recurrence rates were also higher than expected. The risk of OFC may be mitigated with improved education about anticipated genetic consequences of consanguinity in high-risk populations such as the southern West Bank.

Association between PTCH1 and RAD54B single-nucleotide polymorphisms and non-syndromic orofacial clefts in a northern Chinese population.

BACKGROUND: Non-syndromic orofacial clefts (NSOC) is one of the most common congenital malformations, and its etiology involves both genetic and environmental factors. The present aimed to investigate the association of six single nucleotide polymorphisms (SNPs) (rs10512248 in PTCH1, rs12681366 and rs958447 in RAD54B, rs13317 in FGFR1, rs1838105 and rs4968247 in WNT9B) with NSOC in a Northern Chinese population. METHODS: In the present study, HI-SNP technology was used to conduct genotyping of the six SNPs (rs10512248, rs12681366, rs957448, rs13317, rs1838105 and rs4968247) in 596 patients with NSOC and 466 healthy individuals from a Northern Chinese population. RESULTS: The results obtained indicated that rs10512248 and rs12681366 minor allele frequencies were statistically significant (p = 0.020 and 0.015, respectively). Statistical analysis confirmed that the CT genotype of RAD54B rs12681366 was associated with a decreased risk of NSOC (odds ratio = 0.62, 95% confidence interval = 0.46-0.82, P = 0.001). After correcting for multiple testing, the associations remained significant. By contrast, nonsignificant differences were found for the rs957448, rs13317, rs1838105 and rs4968247 allele and genotype frequencies between cases and controls. CONCLUSIONS: These results demonstrate that the PTCH1 rs10512248 and RAD54B rs12681366 were significantly associated with NSOC in a Northern Chinese population. Additionally, the RAD54B rs12381366 CT genotype could decrease the risk of NSOC in a Northern Chinese population. We provide novel evidence for the development of NSOC in a Northern Chinese population.

Homozygote C/C at rs12543318 was risk factor for non-syndromic cleft lip only from Western Han Chinese population.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a complex disorder, and it results from both of the genetic modifiers and environmental factors, with genetic modifiers contributes to it more than environmental factors. GWASs made great progress in identifying the candidate genes for NSCL/P, but the findings need to be replicated in other populations. In this study, we selected eleven SNPs from recent GWASs and GWAS meta-analysis to investigate their associations among 308 NSCL/P trios (134 non-syndromic cleft lip only (NSCLO) trios and 174 non-syndromic cleft lip with cleft palate (NSCLP) trios) from Han Chinese population. All SNPs were genotyped using SNPscan method and analyzed the data with FBAT, PLINK, and R package. Allelic TDT analysis showed that allele A at rs12543318 was associated with NSCLO trios (P = .0032, OR = 0.57, 95% CI: 0.39-0.83), and parent-of-origin effect analysis indicated that allele A at rs12543318 was significantly maternally undertransmitted among NSCLO (P = .0046), which implied the potential influence of genomic imprinting; global TDT further confirmed this association. Individual genotypic TDT showed homozygote C/C at rs12543318 was overtransmitted among NSCLO (Z = 3.79, P = .00015) and NSCL/P groups (Z = 3.83, P = .00013), which indicated that it could increase the risk to have cleft babies. Our findings indicated that rs12543318 was associated with NSCLO from Western Han Chinese population, which will give new scientific evidence for later researches in the etiology of NSOCs.

MSH homeobox 1 polymorphisms and the risk of non-syndromic orofacial clefts: a meta-analysis.

MSH homebox 1 (MSX1) is a susceptibility gene for non-syndromic orofacial clefts (NSOCs). Here, a meta-analysis was conducted to assess their associations. A systematic search of PubMed to 1 September 2017, was performed to retrieve all eligible studies. Odds ratios (ORs) were used to calculate the associations. The stability of the results was evaluated by sensitivity analysis. Publication bias was assessed using Begg's funnel plots and the Egger test. In silico Msx1 expression during early mouse craniofacial development was evaluated by the Gene Expression Omnibus. In the overall analysis, MSX1 rs12532 (G>A) contributed to a decreased risk of NSOC. In an analysis stratified according to disease type, rs12532 was associated with the risk of cleft palate only (CPO) but not with the risk of cleft lip with or without cleft palate (CL/P). The association of rs12532 with the occurrence of NSOC in Asian and Caucasian populations but not South American populations was observed in an analysis stratified according to ethnicity. However, no significant associations were detected between any of the other MSX1 SNPs and the risk of NSOC in either the overall or subgroup analysis. The Msx1 gene was widely expressed in mouse craniofacial structures from embryonic day (E)8.5-E10.5. Taken together, the study indicates that MSX1 rs12532 is associated with the risk of NSOC.

Patterns of Orofacial Clefting in New York City From 1983 to 2010: Trends by Racial Background, Birthplace, and Public Health Strategies.

OBJECTIVE: To determine the role of racial background, public health initiatives, and residence on the prevalence of orofacial clefts (OFCs) in New York City (NYC). DESIGN/METHODS: Retrospective review of OFC cases from the New York State Congenital Malformations Registry. PATIENTS/PARTICIPANTS: Patients born with an OFC and all live births to mothers residing in NYC between 1983 and 2010. MAIN OUTCOME MEASURES: Orofacial cleft birth prevalence by cleft type, race, and borough of maternal residence for each year and by time period around the implementation of public health interventions including folate supplementation. RESULTS: A total of 3557 cases were reviewed. The prevalence remained stable for cleft palate and cleft lip with or without cleft palate (CL ± P) in sequential time periods of the study. Among CL ± P cases, cleft lip prevalence decreased early in the study compared to increases in cleft lip and palate prevalence. For most years, the prevalence of OFCs was lower among African Americans than whites. A total of 12% to 26% of mothers in 4 of the NYC boroughs deliver outside of their borough of residence, choosing to give birth in Manhattan most often. No difference in OFC prevalence was shown in any of the 5 NYC boroughs. CONCLUSIONS: The period prevalence remained relatively stable during the time periods before and after the implementation of folate supplementation for OFCs in NYC. Prevalence of OFC subtypes was lower for most time periods during this study among African Americans compared to whites. Several factors may explain the choice of birthplace outside of the mother's borough of residence.

Minority and Public Insurance Status: Is There a Delay to Alveolar Bone Grafting Surgery?

OBJECTIVE: This study sought to determine the timing of alveolar bone grafting (ABG) surgery among children with cleft lip with or without cleft palate (CL±P) with regard to race and insurance status. DESIGN: A retrospective chart review of consecutive patients receiving ABG surgery was conducted. A multivariate regression model was constructed using predetermined clinical and demographic variables. SETTING: A large, urban cleft referral center. PATIENTS, PARTICIPANTS: Nonsyndromic patients with CL±P were eligible for study inclusion. INTERVENTIONS: ABG surgery using autogenous bone harvested from the anterior iliac crest. MAIN OUTCOME MEASURE: The primary outcome of interest was age at ABG surgery. RESULTS: A total of 233 patients underwent ABG surgery at 8.1 ± 2.3 years of age. African American and Hispanic patients received delayed ABG surgery compared with Caucasian patients by approximately 1 year (P < .05). There was no difference in ABG surgery timing by insurance status (P > .05). CONCLUSIONS: The timing of ABG surgery varied by race but not by insurance status. Greater resources may be needed to ensure timely delivery of cleft care to African American and Hispanic children.

Ethics in Numbers: Auditing Cleft Treatment in Mexico and Beyond.

Plastic surgeons around the globe are implementing projects that mix audit with medical research to ensure and improve the level of care offered to patients with cleft lip and palate. Drawing on recent literature on "audit culture" and the global growth of "performance indicators" as a form of governance, I demonstrate the conjugation of ethics and the production of numerical indicators in cleft treatment. By standardizing documentation, cleft treatment audit programs facilitate evidence-based medicine and a form of reflexive self-governance. However, the abstraction that accompanies standardization is amplified as corollary data practices travel. In emerging as the answer to improving treatment, these projects lock out the politico-economic factors that mediate medical care in resource poor settings. This danger is compounded by the tendency of numerical governance to replace political conversation with technocratic expertise.

IRF6 mutation screening in non-syndromic orofacial clefting: analysis of 1521 families.

Van der Woude syndrome (VWS) is an autosomal dominant malformation syndrome characterized by orofacial clefting (OFC) and lower lip pits. The clinical presentation of VWS is variable and can present as an isolated OFC, making it difficult to distinguish VWS cases from individuals with non-syndromic OFCs. About 70% of causal VWS mutations occur in IRF6, a gene that is also associated with non-syndromic OFCs. Screening for IRF6 mutations in apparently non-syndromic cases has been performed in several modestly sized cohorts with mixed results. In this study, we screened 1521 trios with presumed non-syndromic OFCs to determine the frequency of causal IRF6 mutations. We identified seven likely causal IRF6 mutations, although a posteriori review identified two misdiagnosed VWS families based on the presence of lip pits. We found no evidence for association between rare IRF6 polymorphisms and non-syndromic OFCs. We combined our results with other similar studies (totaling 2472 families) and conclude that causal IRF6 mutations are found in 0.24-0.44% of apparently non-syndromic OFC families. We suggest that clinical mutation screening for IRF6 be considered for certain family patterns such as families with mixed types of OFCs and/or autosomal dominant transmission.

Association of single-nucleotide polymorphisms, rs2235371 and rs2013162, in the IRF6 gene with non-syndromic cleft palate in northeast China.

The aim of this study was to determine the association between two SNPs (rs2235371 and rs2013162) in the interferon regulatory factor 6 (IRF6) gene and non-syndromic cleft palate (NSCP) in northeast China. We genotyped these two SNPs in 104 NSCP cases, as well as in 178 parents and 300 controls. Case-control and case-parent analyses were performed using χ2 tests and family-based association tests (FBAT). Results indicated that there were significant differences in both genotypic and allelic distributions between patients and controls at rs2235371 and rs2013162 in the IRF6 gene. Case-parent analysis revealed over-transmission of the C allele in rs2235371 and the A allele in rs2013162. Lastly, FBAT showed over-transmission of the CA haplotype. This study demonstrated that the two SNPs, rs2235371 and rs2013162, are strongly associated with NSCP in the northeast Chinese population.

Epidemiological Study of Orofacial Clefts among Population of Eastern Slovakia during the Period 1996-2013.

BACKGROUND: Over the past 18 years, according to data from the Clinic of Plastic and Reconstructive Surgery, L. Pasteur University Hospital, there have been 493 cases of orofacial clefts (OC) reported in the area of Eastern Slovakia. The aim of this study was to map the occurrence of orofacial clefts reported in the area of Eastern Slovakia during the years 1996-2013. Also, we compared the occurrence of different types of clefts between the groups in relation to gender and ethnicity. METHODS AND RESULTS: The statistical analysis shows relationship between variables of location and gender and gender differences in the occurrence of various types of clefts. Moreover, in comparison with another study which analyzed the years 1985-2000 (1.29/10(3) live births), there was an increase in the incidence (1.42/10(3) live births) of OC in Eastern Slovakia. CONCLUSION: Our findings seem contradictive to similar studies which discuss ethnic differences in relation to OC. We recognize the relatively high occurrence of OC in Eastern Slovakia, and we link this phenomenon to several extrinsic factors, in particular socioeconomic status and embryotoxic factors.

Genetic risk factors for nonsyndromic cleft lip with or without cleft palate in a Brazilian population with high African ancestry.

Nonsyndromic cleft lip with or without cleft palate (NSCL ± P) is the most common orofacial birth defect, exhibiting variable prevalence around the world, often attributed to ethnic and environmental differences. Linkage analyses and genome-wide association studies have identified several genomic susceptibility regions for NSCL ± P, mostly in European-derived or Asian populations. Genetic predisposition to NSCL ± P is ethnicity-dependent, and the genetic basis of susceptibility to NSCL ± P likely varies among populations. The population of Brazil is highly admixed, with highly variable ancestry; thus, the genetic determinants of NSCL ± P susceptibility may be quite different. This study tested association of 8 single-nucleotide polymorphisms (SNPs), previously identified by genome-wide studies in other populations, with NSCL ± P in a Brazilian population with high African ancestry. SNPs rs560426, rs642961, rs1530300, rs987525, rs3758249, rs7078160, rs17085106, and rs13041247 were genotyped in 293 Brazilian patients with NSCL ± P and 352 unaffected Brazilian controls. Each sample was also genotyped for 40 biallelic short insertion/deletion polymorphic markers to characterize genetic ancestry. The average African ancestry background was 31.1% for the NSCL ± P group and 36.7% for the control group. After adjustment for ancestry and multiple testing, the minor alleles of rs3758249 (OR: 1.58, 95% CI: 1.25-2.01, P = 0.0001) and rs7078160 (OR: 1.59, 95% CI: 1.21-2.07, P = 0.0002) were significantly associated with risk of NSCL ± P. Polymorphisms located in IRF6 (rs642961) and 8q24 (rs1530300 and rs987525) showed marginal associations in this Brazilian population with high African ancestry. These results indicate that rs3758249 at 9q22 and rs7078160 at 10q25.3 represent risk loci for NSCL ± P in the Brazilian population with high African ancestry.

Epidemiology of twinning in the National Birth Defects Prevention Study, 1997 to 2007.

BACKGROUND: Our objective was to evaluate associations between twinning and maternal demographic factors and periconceptional exposures among infants with and without orofacial clefts. METHODS: We used data from the National Birth Defects Prevention Study; 228 twins and 8242 singletons without birth defects (controls), and 117 twins and 2859 singletons with orofacial clefts, born 1997 to 2007, were included in the analyses. Because of the occurrence of twinning due to the use of assisted reproductive technologies, logistic regression models were computed to estimate odds ratios and 95% confidence intervals for each exposure, stratified by fertility treatment use. To evaluate factors by zygosity, we used sex-pairing data and a simulation approach to estimate the zygosity of like-sex twin pairs for unassisted conceptions. RESULTS: Among control mothers who did not use fertility treatments, predictors of twinning included non-Hispanic black maternal race (adjusted odds ratio, 1.6; 95% confidence interval, 1.0-2.4), and tobacco smoking (adjusted odds ratio, 1.6; 95% confidence interval, 1.1-2.4). Among control mothers who used fertility treatments, older maternal age, higher income, and state of residence were associated with twinning. Associations were generally stronger among mothers of dizygotic (estimated) twins than monozygotic (estimated) twins. Results for mothers of infants with isolated orofacial clefts were similar to those of controls. CONCLUSION: We observed an increased twinning frequency with increasing maternal age, but factors such as maternal race/ethnicity and socioeconomic status may also contribute. Among women receiving fertility treatments, factors associated with twinning suggested a relation with treatment specifics (e.g., treatment type and number of embryos implanted) and availability of insurance coverage.

The need for orthognathic surgery in nonsyndromic patients with repaired isolated cleft palate.

OBJECTIVE: To determine the frequency of need for orthognathic surgery among nonsyndromic patients with isolated cleft palate repaired during infancy at The Hospital for Sick Children in Toronto, Canada. DESIGN: Retrospective cohort study. PATIENTS: PATIENTS with nonsyndromic isolated cleft palate born between 1970 and 1997 with available records including a lateral cephalometric radiograph taken at ≥15 years of age. METHODS: PATIENTS who had undergone or were being prepared for orthognathic surgery were automatically counted as requiring surgery. For the remaining patients, lateral cephalometric radiographs were traced and analyzed. Arbitrarily set cephalometric criteria were used to identify the "objective" need for orthognathic surgery. RESULTS: Of the 189 patients identified with nonsyndromic isolated cleft palate and for whom records were available, 25 (13.2%) were deemed to require orthognathic surgery. Of the surgical cohort, 92% required surgical correction for a Class III malocclusion. Similar percentages of males and females required orthognathic surgery. An apparently greater proportion of patients of Asian background (18.5%) than of white background (10.6%) required surgery, but this difference was not significant (P = .205). CONCLUSIONS: The current results suggest that approximately one in eight patients at our institution with nonsyndromic isolated cleft palate requires orthognathic surgery. There is a tendency for this to be higher in patients of Asian descent and lower in patients of white descent. Variability in extent, severity, and phenotype of the cleft, which may be attributed largely to genetics, may play an important role in dictating the need for orthognathic surgery.