Background The development of the face occurs during the early days of intrauterine life by the formation of facial processes from the first Pharyngeal arch. Derangement in these well‐organized fusion events results in Orofacial clefts (OFC). Van der Woude syndrome (VWS) is one of the most common causes of syndromic cleft lip and/or palate accounting for 2% of all cases. Mutations in the IRF6 gene account for 70% of cases with the majority of these mutations located in the DNA‐binding (exon 3, 4) or protein‐binding domains (exon 7–9). The current study was designed to update the list of IRF6 variants reported for VWS by compiling all the published mutations from 2013 to date as well as including the previously unreported VWS cases from Africa and Puerto Rico. Methods We used PubMed with the search terms; "Van der Woude syndrome," “Popliteal pterygium syndrome,” "IRF6," and "Orofacial cleft" to identify eligible studies. We compiled the CADD score for all the mutations to determine the percentage of deleterious variants. Results Twenty‐one new mutations were identified from nine papers. The majority of these mutations were in exon 4. Mutations in exon 3 and 4 had CADD scores between 20 and 30 and mutations in exon 7–9 had CADD scores between 30 and 40. The presence of higher CADD scores in the protein‐binding domain (exon 7–9) further confirms the crucial role played by this domain in the function of IRF6. In the new cases, we identified five IRF6 mutations, three novel missense mutations (p.Phe36Tyr, p.Lys109Thr, and p.Gln438Leu), and two previously reported nonsense mutations (p.Ser424*and p.Arg250*). Conclusion Mutations in the protein and DNA‐binding domains of IRF6 ranked among the top 0.1% and 1% most deleterious genetic mutations, respectively. Overall, these findings expand the range of VWS mutations and are important for diagnostic and counseling purposes.

Objectives Cleft lip with/without cleft palate and cleft palate only is congenital birth defects where the upper lip and/or palate fail to fuse properly during embryonic facial development. Affecting ~1.2/1000 live births worldwide, these orofacial clefts impose significant social and financial burdens on affected individuals and their families. Orofacial clefts have a complex etiology resulting from genetic variants combined with environmental covariates. Recent genome‐wide association studies and whole‐exome sequencing for orofacial clefts identified significant genetic associations and variants in several genes. Of these, we investigated the role of common/rare variants in SHH, RORA, MRPL53, ACVR1, and GDF11. Materials and Methods We sequenced these five genes in 1255 multi‐ethnic cleft lip with/without palate and cleft palate only samples in order to find variants that may provide potential explanations for the missing heritability of orofacial clefts. Rare and novel variants were further analyzed using in silico predictive tools. Results Ninteen total variants of interest were found, with variant types including stop‐gain, missense, synonymous, intronic, and splice‐site variants. Of these, 3 novel missense variants were found, one in SHH, one in RORA, and one in GDF11. Conclusion This study provides evidence that variants in SHH, RORA, MRPL53, ACVR1, and GDF11 may contribute to risk of orofacial clefts in various populations.

Individuals with orofacial clefting (OFC) have a higher prevalence of tooth agenesis (TA) overall. Neither the precise etiology of TA, nor whether TA occurs in patterns that differ by gender or cleft type is yet known. This meta-analysis aims to identify the spectrum of tooth agenesis patterns in subjects with non-syndromic OFC and controls using the Tooth Agenesis Code (TAC) program. An indexed search of databases (PubMed, EMBASE, and CINAHL) along with cross-referencing and hand searches were completed from May to June 2019 and re-run in February 2022. Additionally, unpublished TAC data from 914 individuals with OFC and 932 controls were included. TAC pattern frequencies per study were analyzed using a random effects meta-analysis model. A thorough review of 45 records retrieved resulted in 4 articles meeting eligibility criteria, comprising 2182 subjects with OFC and 3171 controls. No TA (0.0.0.0) was seen in 51% of OFC cases and 97% of controls. TAC patterns 0.2.0.0, 2.0.0.0, and 2.2.0.0 indicating uni- or bi-lateral missing upper laterals, and 16.0.0.0 indicating missing upper right second premolar, were more common in subjects with OFC. Subjects with OFC have unique TA patterns and defining these patterns will help increase our understanding of the complex etiology underlying TA.

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