Nonsyndromic Cleft Research Articles

Genome analysis using whole-exome sequencing of non-syndromic cleft lip and/ or palate from Malagasy trios identifies variants associated with cilia-related pathways and Asian genetic ancestry

Genome analysis using whole-exome sequencing of non-syndromic cleft lip and/ or palate from Malagasy trios identifies variants associated with cilia-related pathways and Asian genetic ancestry

The IRF6 AP-2α binding site polymorphism relate to the severity of non-syndromic orofacial cleft of Indonesian patients.

IRF6 AP-2α binding site polymorphism is known as IRF6 rs642961. It has been associated with a nonsyndromic orofacial cleft (NS OFC). This study aimed to determine the IRF6 rs642961 as a risk factor associated with NS OFC and its phenotypes. The case-control design used for 264 subjects consists of 158 NS CLP subjects (42 CU CLP, 34 CB CLP, 33 CLO, 49 CPOs) and 106 healthy controls. The DNA is extracted from venous blood. The segment of IRF6 rs642961 amplified by polymerase chain reaction (PCR) followed by restriction fragment length of polymorphisms (RFLPs) used the MspI digestion enzyme. The qPCR method to identify the mRNA expression levels of the IRF6 gene rs642961 was analyzed by the Livak method. The study results show that in NS CB CLP phenotype as the most severe phenotype of NS OFC, the Odds Ratio (OR) of A mutant allele was 5.094 (CI=1.456-17.820; P=0.011) and the OR of AA homozygous mutant genotype was 13.481 (CI=2.648-68.635; P=0.001). There are different levels of mRNA expression changes from NS OFC and its phenotypes. It is substantial among the 2-ΔΔCt and the group of AA, GA, and GG genotypes (P<0.05); in the NS CPO phenotype, it shows IRF6 mRNA under-expression in GA, AA genotypes while in other phenotypes it shows IRF6 mRNA overexpression. The IRF6 AP-2α binding site polymorphism is strongly associated with the severity of NS OFC, and this polymorphism has a functional role in affecting IRF6 mRNA expression that is variable in each phenotype.

Dento-skeletal Sequel of Hyrax in Nonsyndromic Cleft Lip and Palate: A Systematic Review and Meta-analysis.

To critically evaluate and review the dento-skeletal outcomes of hyrax with or without nonsurgical protraction therapy in nonsyndromic cleft lip and palate (CLP) patients. Electronic databases were searched from PubMed, Cochrane, Scopus, SciELO, Lilacs, and Google Scholar from January 2005 to April 2022 to identify studies reporting on the dento-skeletal effect of hyrax with or without nonsurgical protraction therapy among children aged 7-15 years with CLP before the secondary alveolar bone grafting (SABG) procedure. Abstracts and subsequently eligible full-text articles were screened. The risk of bias in the included randomized and nonrandomized studies was assessed using Cochrane collaboration's risk of bias tool. The random-effects meta-analyses of the mean difference were carried out. A total of 423 studies were identified. After a thorough screening, 19 studies met the inclusion criteria. Of these 19 studies, 13 studies were conducted with only hyrax appliances, six studies had hyrax with nonsurgical protraction therapy. Hyrax had increased intermolar width, anterior nasal cavity width, and posterior maxillary width compared to inverted mini hyrax with p-values = 0.027, 0.004, and 0.03, respectively. Inverted mini hyrax had more canine inclination on noncleft than hyrax. Hyrax and fan-type expanders had an equivalent effect on the dento-skeletal structures indicating that hyrax can be used as an alternative to fan-type expanders. Hyrax with protraction therapy had a remarkable change in ANB angle compared to noncleft patients. Deepika U, Ray P, Nayak A, et al. Dento-skeletal Sequel of Hyrax in Nonsyndromic Cleft Lip and Palate: A Systematic Review and Meta-analysis. Int J Clin Pediatr Dent 2023;16(6):882-896.

Ultra-Rare Variants Identify Biological Pathways and Candidate Genes in the Pathobiology of Non-Syndromic Cleft Palate Only.

In recent decades, many efforts have been made to elucidate the genetic causes of non-syndromic cleft palate (nsCPO), a complex congenital disease caused by the interaction of several genetic and environmental factors. Since genome-wide association studies have evidenced a minor contribution of common polymorphisms in nsCPO inheritance, we used whole exome sequencing data to explore the role of ultra-rare variants in this study. In a cohort of 35 nsCPO cases and 38 controls, we performed a gene set enrichment analysis (GSEA) and a hypergeometric test for assessing significant overlap between genes implicated in nsCPO pathobiology and genes enriched in ultra-rare variants in our cohort. GSEA highlighted an enrichment of ultra-rare variants in genes principally belonging to cytoskeletal protein binding pathway (Probability Density Function corrected p-value = 1.57 × 10-4); protein-containing complex binding pathway (p-value = 1.06 × 10-2); cell adhesion molecule binding pathway (p-value = 1.24 × 10-2); ECM-receptor interaction pathway (p-value = 1.69 × 10-2); and in the Integrin signaling pathway (p-value = 1.28 × 10-2). Two genes implicated in nsCPO pathobiology, namely COL2A1 and GLI3, ranked among the genes (n = 34) with nominal enrichment in the ultra-rare variant collapsing analysis (Fisher's exact test p-value < 0.05). These genes were also part of an independent list of genes highly relevant to nsCPO biology (n = 25). Significant overlap between the two sets of genes (hypergeometric test p-value = 5.86 × 10-3) indicated that enriched genes are likely to be implicated in physiological palate development and/or the pathological processes of oral clefting. In conclusion, ultra-rare variants collectively impinge on biological pathways crucial to nsCPO pathobiology and point to candidate genes that may contribute to the individual risk of disease. Sequencing can be an effective approach to identify candidate genes and pathways for nsCPO.

Cupid's Bow Leveling and Preservation of Lip Height and Width: A Modified Rotation-Advancement Technique.

Several methods for cleft lip repair have been developed over time, with no clear method considered the standard. In the authors' department, the use of a modified rotation-advancement technique rather than the traditional rotation-advancement technique in unilateral complete cleft lip repair has increased over the past decade. This study aimed to determine which technique provides better outcomes. This retrospective study was conducted by analyzing the preoperative and postoperative aesthetic nasal and labial anthropometric measurements of the frontal and basal views of 213 consecutive patients treated between October of 2013 and June of 2019. A total of 141 participants were treated with the traditional rotation-advancement technique, and 72 with the modified rotation-advancement technique. The inclusion criteria were nonsyndromic unilateral complete cleft lip repair with high-resolution, good-quality photographs; no presurgical nasoalveolar molding; no revision in the lip or nose areas; and at least 1 year of follow-up. Patients who received the modified rotation-advancement technique had significantly improved Cupid's bow position and orientation ( P < 0.02 and P < 0.01, respectively) and enhanced vertical lip height symmetry ( P < 0.01) while preserving the lip width. The columellar length ( P < 0.03) and angulation ( P < 0.045) were also significantly improved, with enhanced nostril inclination in this group ( P < 0.06). According to the findings of the current study, modified rotation-advancement technique assisted surgeons in improving symmetrical leveling of the Cupid's bow and significantly aided in correcting lip height without compromising lip width. Moreover, the modified rotation-advancement technique resulted in better aesthetic nasal outcomes. Therapeutic, III.

Managing Chronic otitis media with Effusion in Children with non-Syndromic Cleft Palate: Short-Term Ventilation Tubes Versus Surveillance.

To compare the effectiveness of short-term ventilation tubes compared to surveillance on conductive hearing loss in children with non-syndromic orofacial clefting involving the muscular palate. Chronic otitis media with effusion is a common finding in children with cleft palate. The accepted convention is insertion of short-term ventilation tubes at the time of palate repair, but some centres are choosing conservative management. Each approach has its advantages but there is currently no consensus on the most appropriate management in children with non-syndromic cleft palate. Children <18 years with cleft lip and palate, or isolated cleft palate, not associated with a genetic syndrome, who have been diagnosed with chronic otitis media with effusion. A systematic search of MEDLINE, CINAHL, Embase and Scopus databases was conducted. Grey literature searches were conducted through Central Register of Controlled Trials, Clinicaltrials.gov and ProQuest. Two reviewers screened the studies, conducted critical appraisal, assessed the methodological quality, and extracted the data. Where possible, studies were pooled in statistical meta-analysis with heterogeneity being assessed using the standard Chi-squared and I2 tests. Four studies met the inclusion criteria but were of low quality with a moderate risk of bias. Only data on hearing thresholds could be pooled for analysis which found no statistically significant difference. Other outcomes were presented in narrative form. Certainty of evidence for all outcomes was deemed low to very low using GRADE criteria. No definitive conclusions can be drawn regarding most effective management at improving conductive hearing loss. Missing data and inconsistent reporting of outcomes limited capacity for pooled analysis.

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.

Evaluation of growth status of children with non-syndromic oral clefts.

To assess the growth status of children with non-syndromic oral clefts (NSOC) and explore potential influencing factors. The data of NSOC children aged ≤5 years hospitalized between December 2018 and June 2020 were retrieved and evaluated, including their height, weight, NSOC subtypes and demographic characteristics before reparative surgeries. The growth status of the children was assessed using height-for-age Z-score (HAZ), weight-for-age Z-score (WAZ) and weight-for-height Z-score (WHZ). In total, 504 NSOC children (271 females & 233 males) were included. The proportion of stunting (HAZ <-2), underweight (WAZ <-2) and wasting (WHZ <-2) was 4.96%, 5.16% and 3.97%, respectively. In addition, we observed that HAZ and WAZ decreased with increasing age (both p < 0.01). Moreover, non-syndromic cleft palate only (NSCP) and non-syndromic cleft lip and palate (NSCLP) were associated with lower HAZ and WAZ compared with non-syndromic cleft lip only (NSCL) (all p < 0.01), while NSCLP was associated with a lower WHZ compared with NSCL (p < 0.01). The growth retardation and low weight rate of NSOC children under 5 years old were higher than the national average level and differed by the age of NSOC children and disease subtypes. Further improvements are warranted to promote the growth status of the NSOC-affected children.

Genetic Analysis of the Single-Nucleotide Polymorphisms rs880810, rs545793, rs80094639, and rs13251901 in Nonsyndromic Oral Clefts: A Case-Parent Trio Study.

Oral clefts, including cleft lip (CL), cleft palate (CP), and cleft lip and palate (CLP), are the most common types of congenital anomalies of the human face. Various genetic and environmental factors play a role in developing oral clefts. Several studies have shown the association of the PAX7 gene and the 8q24 region with these oral clefts in different populations worldwide. However, there are no reported studies on the possible connection between the PAX7 gene and the 8q24 region nucleotide variants and the risk of developing nonsyndromic oral clefts (NSOC) in the Indian population. Hence, this study aimed to test the possible association between PAX7 gene single-nucleotide polymorphisms (SNPs) rs880810, rs545793,rs80094639, and rs13251901 of the 8q24 region using a case-parent trio design. Forty case-parent trios were selected from the CLP center. Genomic DNA was isolated from the cases and their parents. The rs880810, rs545793, rs80094639, and rs13251901 were genotyped by the MassARRAY technique. PLINK software was used for statistical analysis. All the SNPs were tested for Hardy-Weinberg equilibrium. No statistical significance was found with any SNPs, as none of the genotyped SNPs showed a p -value of less than 0.05. Hence, the rs880810, rs545793, and rs80094639 of the PAX7 gene, and rs13251901 of the 8q24 region are not associated with NSOC in the Indian population.

A retrospective study on clinical and epidemiological profile of nonsyndromic cleft lip and palate patients admitted in a large Comprehensive Cleft Care Centre in West Bengal, India

Aim: The aim of this study is to observe the clinical and epidemiological profile of nonsyndromic cleft lip (CL) and/or palate patients admitted to a cleft care center in West Bengal from May 2021 to April 2022. Materials and Methods: A retrospective epidemiological study had been done by preparing a master data sheet to record the patient's data from a Comprehensive Cleft Care Centre in West Bengal. The study variables included were patient's age reporting at the hospital, type of cleft, sex distribution of patients, residential address of the parents, socioeconomic status through parents' education, occupation, and monthly income, and consanguineous marriage history of the family. Results: A total of 276 nonsyndromic cleft patients during the time period (May 2021 to April 2022) were considered. Among these, 164 were male and 112 were female patients. The mean age of patients reporting to this hospital on average was 13–18 months. CL with palate patients (62%) predominated than any other type and was mostly seen in male patients (69.59%); isolated CL (22%) cases were more in females (56.25%), whereas isolated cleft palate (16%) cases were seen more in males (62.79%); unilateral (77%) and left-sided cleft (67%) were found predominantly than bilateral cases (23%) and seen mostly in females, whereas bilateral cleft cases were more in males. Most of the patients belonged to North 24 Parganas District which is an adjacent district of Kolkata, and most of the families belonged to a low socioeconomic group, and interestingly, most of them had consanguineous marriage history (61%) with at least one generation. Conclusion: The results of this study provided that CL with palate type is more common among all types of clefts and predominantly found in males than females in West Bengal. The unilateral left-sided cleft is predominant among all other varieties. Most of the parents belonged to low socioeconomic status and are having consanguineous marriage history. We need to spread awareness among the public through ads and banners, social media, and medical free camps about the deformity of CL and/or palate and also possible preventive measures, make arrangements for free treatment among the CL and/or CL and palate population for better life of cleft patients and their parents.

Acesso e utilização de serviço de saúde bucal em centro de referência em fissura oral no estado da Bahia

ABSTRACT This study aimed to determine the access and utilization of dental services in a reference center for orofacial defects in the state of Bahia, Brazil. In an interview, a questionnaire was done about socio-demographic information, cleft type, specialized treatments, scheduling time and return of the consultation of 101 patients with nonsyndromic cleft lip with or without cleft palate and 101 healthy controls. In both groups the age was between 5 to 12 years old. It was observed that individuals with cleft had faster access to the dental service in relation to the control group and shorter scheduling time between the first consultation and their return. Different needs in the use of dental services were observed in the study groups with differences in relation to the specialties (p=0.000). The nonsyndromic cleft lip with or without cleft palate individuals showed socialization difficulties in the age group between 9 and 12 years and did not present difficulties in accessing primary dental care in specialized service. In conclusion, in this study NSCL±P individuals did not present difficulties in accessing the specialized dental center. To complement the comprehensive care, it is suggested the performance of educational activities of oral health, not yet fully implemented in this multidisciplinary treatment center.

Prioritization of non-coding elements involved in non-syndromic cleft lip with/without cleft palate through genome-wide analysis of de novo mutations.

Non-syndromic cleft lip with/without cleft palate (nsCL/P) is a highly heritable facial disorder. To date, systematic investigations of the contribution of rare variants in non-coding regions to nsCL/P etiology are sparse. Here, we re-analyzed available whole-genome sequence (WGS) data from 211 European case-parent trios with nsCL/P and identified 13,522 de novo mutations (DNMs) in nsCL/P cases, 13,055 of which mapped to non-coding regions. We integrated these data with DNMs from a reference cohort, with results of previous genome-wide association studies (GWASs), and functional and epigenetic datasets of relevance to embryonic facial development. A significant enrichment of nsCL/P DNMs was observed at two GWAS risk loci (4q28.1 (p= 8×10-4) and 2p21 (p= 0.02)), suggesting a convergence of both common and rare variants at these loci. We also mapped the DNMs to 810 position weight matrices indicative of transcription factor (TF) binding, and quantified the effect of the allelic changes in silico. This revealed a nominally significant overrepresentation of DNMs (p= 0.037), and a stronger effect on binding strength, for DNMs located in the sequence of the core binding region of the TF Musculin (MSC). Notably, MSC is involved in facial muscle development, together with a set of nsCL/P genes located at GWAS loci. Supported by additional results from single-cell transcriptomic data and molecular binding assays, this suggests that variation in MSC binding sites contributes to nsCL/P etiology. Our study describes a set of approaches that can be applied to increase the added value of WGS data.

A systematic review of auditory processing abilities in children with non-syndromic cleft lip and/or palate

Abstract Purpose: The present systematic review aims to understand auditory processing abilities in children with nonsyndromic cleft lip and/or palate (NSCL/P). The review summarizes questionnaire, behavioral, and electrophysiological findings of auditory processing abilities in children with NSCL/P. Method: The study used a literature search of electronic databases (e.g., Pub Med, Google Scholar, J Stage, Research Gate, ScienceDirect) and the AIISH repository from 2000 to 2021. The retrieved articles were assessed in two stages: title and abstract screening, followed by a full-length article review. About 13 articles were selected after the full-length review of 17 shortlisted articles. All selected studies used cohort design. Result: The review showed that speech perception in noise and temporal processing were the majorly affected processing abilities in children with NSCL/P. The review also showed that cleft palate children are more prone to auditory processing deficits than other cleft subgroups. These auditory processing deficits in NSCL/P children may cause delayed speech and language skills, reading, and learning disabilities, which are highly reported in these children. Conclusion: Auditory processing evaluation should be a part of the audiological test battery for these children to promote early diagnosis and management.

Role of SATB2 5' Untranslated Region Promoter Methylation in Formation of Non-syndromic Cleft Palate Only

Role of SATB2 5' Untranslated Region Promoter Methylation in Formation of Non-syndromic Cleft Palate Only

Short-term surgical outcomes in patients with unilateral complete cleft lip and palate after presurgical nasoalveolar molding therapy: A three-dimensional anthropometric study.

This brief research report aimed to evaluate the short-term efficacy of presurgical nasoalveolar molding (PNAM) therapy on the nasolabial morphology three dimensionally in patients with non-syndromic complete unilateral cleft lip and palate (UCLP). Thirty-six patients with non-syndromic complete unilateral complete cleft lip and palate were enrolled retrospectively and categorized into 2 groups: 18 patients who had received PNAM treatment (PNAM group) and 18 age-matched patients who have not receive PNAM treatment (no PNAM group) from 2017 to 2021. The average starting age for PNAM therapy was 18.33 days, and the average PNAM treatment duration was 99.08 days. Twelve nasolabial parameters were measured to compare the postsurgical outcomes of two groups. In PNAM groups, cleft width, vertical distance between double Crista philtri and columellar deviation were reduced compared to that in no PNAM group. And nostril height was larger than that in no PNAM group. The differences between two groups were statistically significant (p < .05). There were no statistical differences in columellar length, nostril width and bi-alar width between two groups. However, the nostril width on cleft side in PNAM group was decreased by an average of 1.1 mm. Our result indicated that PNAM therapy decreased cleft width and vertical distance between Crista philtri. It also increased nasal symmetry by decreasing columellar deviation, increasing nostril height.

Utility of Screening for Obstructive Sleep Apnea with the Pediatric Sleep Questionnaire (PSQ) in Children with Craniofacial Anomalies.

To determine the accuracy of the Pediatric Sleep Questionnaire (PSQ) as a screening tool for obstructive sleep apnea in children with craniofacial anomalies. Retrospective cohort study. Multidisciplinary cleft and craniofacial clinic at a tertiary care center. Children with craniofacial anomalies 2 to ≤18 years of age who both completed a PSQ screen and underwent polysomnography (PSG) without interval surgery. Sensitivity and specificity of the PSQ in detecting an obstructive apnea-hypopnea index (AHI) ≥ 5 events/hour. Fifty children met study criteria, with 66% (n = 33) having an associated syndrome. Mean patient age at time of PSQ was 9.6 + 4.0 years. Overall, 33 (64%) screened positive on the PSQ, while 20 (40%) had an AHI ≥ 5. The sensitivity and specificity for identifying AHI ≥ 5 was 70% and 40%, respectively. With subgroup analysis, the sensitivity and specificity were higher (100% and 50%) in children with non-syndromic palatal clefting but lower (65% and 31%) in children with a syndrome or chromosomal anomaly. There was no correlation detected between PSQ score and AHI severity (p = 0.25). The mean obstructive AHI in the study population was 10.1 ± 22.7 despite 44% (n = 22) undergoing prior adenotonsillectomy. The PSQ was less sensitive and specific in detecting an AHI ≥ 5 in children with craniofacial anomalies than in a general population, and particularly poor in for children with syndrome-associated craniofacial conditions. Given the high prevalence of OSA in this patient population, a craniofacial-specific validated screening tool would be beneficial.

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.

Poor reporting quality of observational studies in children with non-syndromic cleft palate makes evidence synthesis difficult

Objective To assess the reporting quality of observational studies included in a systematic review of the management of chronic otitis media with effusion in children with non-syndromic cleft lip and palate using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist. Methods Medline, CINAHL, Scopus and Embase, were searched for studies comparing the use of ventilation tubes to surveillance. Two reviewers screened potential eligible articles, extracted data independently and assessed reporting quality using the STROBE checklist. Results The median compliance rate with individual STROBE items was low at 25% (range:0-100%) with 11 of the 22 items not reported in any of the studies. Items reported inconsistently pertained to potential sources of bias, sample size calculations, how loss to follow-up was addressed and management of missing data. Conclusion The development of this systematic review highlights the inadequate reporting standards in this field. Differences in the way the outcomes are defined, reported, and measured leads to variability in the observed intervention effects and difficulty in interpreting the true effect size. Future researchers are encouraged to use STROBE guidelines for the design and reporting of observational studies in this field.

Influence of Cleft Lip and Palate on Oral Health-Related Quality of Life in Northern Italy: Exploring Both the Children's and Caregivers' Perspectives.

The aim of this cross-sectional study was to examine whether parents/caregivers' perceptions of oral health-related quality of life (OHRQoL) differ from that of their cleft children, exploring the impact of demographic variables and cleft type on their agreement. Fifty-three primary and secondary schoolchildren, with non-syndromic orofacial cleft, and their parents answered the Child Oral Health Impact Profile (COHIP) questionnaire. Concordance between caregivers' and children's reports was low to moderate. Parents/caregivers had worse perceptions of OHRQoL compared to that of their children, peer interaction and functional well-being domains being statistically significantly different (p = 0.033 and p = 0.005, respectively). Cleft type, gender and parents' country of origin seemed to be potential contributing factors of disagreement. Parents overestimated the impact of unilateral (p = 0.047) and bilateral cleft lip and palate (p = 0.021) on OHRQoL, and they rated more poorly than their male children did. Italian parents were more concerned about the functional well-being of their children (p = 0.014), and foreign parents about peer interaction (p = 0.010) and school environment (p = 0.012) dimensions. These findings suggest that parental assessment of OHRQoL cannot replace that of school-aged children, but they are complementary as they cover different, but equally relevant perspectives.

Genome-wide analysis of copy-number variation in humans with cleft lip and/or cleft palate identifies COBLL1, RIC1, and ARHGEF38 as clefting genes

Cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex, heterogeneous etiology. It is well established that common and rare sequence variants contribute to the formation of CL/P, but the contribution of copy-number variants (CNVs) to cleft formation remains relatively understudied. To fill this knowledge gap, we conducted a large-scale comparative analysis of genome-wide CNV profiles of 869 individuals from the Philippines and 233 individuals of European ancestry with CL/P with three primary goals: first, to evaluate whether differences in CNV number, amount of genomic content, or amount of coding genomic content existed within clefting subtypes; second, to assess whether CNVs in our cohort overlapped with known Mendelian clefting loci; and third, to identify unestablished Mendelian clefting genes. Significant differences in CNVs across cleft types or in individuals with non-syndromic versus syndromic clefts were not observed; however, several CNVs in our cohort overlapped with known syndromic and non-syndromic Mendelian clefting loci. Moreover, employing a filtering strategy relying on population genetics data that rare variants are on the whole more deleterious than common variants, we identify several CNV-associated gene losses likely driving non-syndromic clefting phenotypes. By prioritizing genes deleted at a rare frequency across multiple individuals with clefts yet enriched in our cohort of individuals with clefts compared to control subjects, we identify COBLL1, RIC1, and ARHGEF38 as clefting genes. CRISPR-Cas9 mutagenesis of these genes in Xenopus laevis and Danio rerio yielded craniofacial dysmorphologies, including clefts analogous to those seen in human clefting disorders.