Preprint
Multi-omic analyses of a twin pair with mirror image cleft lip identifies pathogenic variant in FGF20 modified by differential methylation upstream of ZFP57
medRxiv : the preprint server for health sciences
Cold Spring Harbor Laboratory
11/18/2024
DOI: 10.1101/2024.11.16.24317351
PMCID: PMC11601713
PMID: 39606391
Abstract
Disturbances in the intricate processes that control craniofacial morphogenesis can result in birth defects, most common of which are orofacial clefts (OFCs). Nonsyndromic cleft lip (nsCL), one of the phenotypic forms amongst OFCs, has a non-random laterality presentation with the left side being affected twice as often compared to the right side. This study investigates the etiology of nsCL and the factors contributing to its laterality using a pair of monozygotic twins with mirror-image cleft lip.
We conducted whole-genome sequencing (WGS) analyses in a female twin pair with mirror image nsCL, their affected mother and unaffected father to identify etiopathogenic variants. Additionally, to identify possible cleft lip laterality modifiers, DNA-methylome analysis was conducted to test for differential methylation patterns between the mirror twins. Lastly, DNA methylation patterns were also analyzed on an independent cohort of female cases with unilateral cleft lip (left=22; right=17) for replication purposes.
We identified a protein-altering variant in
(p.Ile79Val) within the fibroblast growth factor interacting family domain segregating with the nsCL in this family. Concurrently, DNA-methylome analysis identified differential methylation regions (DMRs) upstream of Zinc-finger transcription factor
(Δβ > 5%). Replication of these results on an independent cohort, confirmed these DMRs, emphasizing their biological significance (p<0.05). Enrichment analysis indicated that these DMRs are involved in DNA methylation during early embryo development (FDR adjusted p-value = 1.3241E-13). Further bioinformatics analyses showed one of these DMRs acting as a binding site for transcription factor
(
), a key player in craniofacial development. Interactome analysis also suggested a potential role for
in left/right axis specification, thus emphasizing its significance in cleft laterality.
This study provides novel insights into the etiology of nsCL and its laterality, suggesting an interplay between etiopathogenic variants and DNA methylation in cleft laterality. Our findings elucidate the intricate mechanisms underlying OFCs development. Understanding these factors may offer new tools for prevention and management of OFCs, alleviating the burden on affected individuals, their families and global health.
Details
- Title: Subtitle
- Multi-omic analyses of a twin pair with mirror image cleft lip identifies pathogenic variant in FGF20 modified by differential methylation upstream of ZFP57
- Creators
- Waheed Awotoye - University of IowaLigiane A Machado-Paula - University of Iowa, Dental ResearchLuke Hovey - University of IowaHenry Keen - University of IowaMichael Chimenti - University of Iowa, Iowa Institute of Human GeneticsBenjamin Darbro - University of IowaShareef Dabdoub - University of IowaJames C Thomas - University of IowaJeff Murray - University of IowaShankar Rengasamy Venugopalan - Tufts UniversityLina Moreno-Uribe - University of Iowa, OrthodonticsAline L Petrin - University of Iowa
- Resource Type
- Preprint
- Publication Details
- medRxiv : the preprint server for health sciences
- DOI
- 10.1101/2024.11.16.24317351
- PMID
- 39606391
- PMCID
- PMC11601713
- Publisher
- Cold Spring Harbor Laboratory; United States
- Language
- English
- Date posted
- 11/18/2024
- Academic Unit
- Orthodontics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Medical Genetics and Genomics; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research; Periodontics; Iowa Institute of Human Genetics
- Record Identifier
- 9984751758302771
Metrics
55 Record Views