Evidence for craniofacial enhancer variation underlying nonsyndromic cleft lip and palate

Abstract

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 Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. https://www.springer.com/aamterms-v1 *

DNA Methylation Variation Is Identified in Monozygotic Twins Discordant for Non-syndromic Cleft Lip and Palate

“…Six monozygotic twin pairs discordant for NSCLP were ascertained and characterized as part of the larger genetic study of NSCLP that has been previously described ( Chiquet et al, 2007 ; Morris et al, 2020 ). Briefly, participants were recruited at the craniofacial clinics affiliated with the UTHealth Science Center at Houston under IRB-approved protocols and written informed consent was obtained from parents and assents from the children.…”

Genetic models and approaches to study orofacial clefts

“…Although the analysis of rare variants using methods for combining multiple variants within a gene or region yielded mixed results, two regions ( NOG and NTN1 ) showed some statistical evidence that rare variants within the region are important for OFC risk. Other targeted sequencing approaches have focused on craniofacial enhancers and identified individual enhancers in which rare variants may be associated with OFC interest (Morris et al, 2020; Thieme et al, 2021).…”

How orthodontic research can be enriched and advanced by the novel and promising evolutions in biomedicine

“…Although the clinical practice of orthodontics is gradually supported by an increasing evidence-based component, still significant part of the subjects of aetiology of dentofacial deformities and malocclusions, facial growth modification, biology of tooth movement and post-treatment stability are characterised by incomplete understanding, limited knowledge or controversial concepts. In recent years, an increase of biomedical innovations that have been used in a variety of disciplines, including cancer, cardiovascular disease and craniofacial medicine, has taken place (Morris et al, 2020;Wilmes et al, 2013). These innovations include remarkable discoveries and advancements in computational and systems biology, bioinformatics, CRISPR, multi-omics sequencing, the mining of databases of clinical phenotypes, animal models, gene therapy and protein therapy, which are not widely used in orthodontic research (Jheon et al, 2017).…”

“…The implementation of multi-omics technologies in orthodontics can supply clinicians with a substantial understanding of the flow of many clinical conditions, from the aetiology of malocclusions or dental abnormalities (genetic, environmental or developmental) to the functional repercussions or relevant interactions (Civelek and Lusis, 2014). Morris et al (2020) investigated whether or not variation in craniofacial enhancers contributes to non-syndromic cleft lip and palate (NSCLP) (Morris et al, 2020). Using NGS, they sequenced 20 craniofacial enhancers in NSCLP probands.…”