Identification of functional non-coding variants associated with orofacial cleft

Priyanka Kumari, Ryan Z. Friedman, Sarah W. Curtis, Lira Pi, Kitt Paraiso, Axel Visel, Lindsey Rhea, Martine Dunnwald, Anjali P. Patni, Daniel Mar, Karol Bomsztyk, Julie Mathieu, Hannele Ruohola-Baker, Elizabeth J. Leslie-Clarkson, Michael A. White, Barak A. Cohen and Robert A. Cornell ()
Additional contact information
Priyanka Kumari: University of Washington
Ryan Z. Friedman: Washington University School of Medicine
Sarah W. Curtis: Emory University School of Medicine
Lira Pi: Cencora-PharmaLex
Kitt Paraiso: Lawrence Berkeley National Laboratory
Axel Visel: Lawrence Berkeley National Laboratory
Lindsey Rhea: University of Iowa
Martine Dunnwald: University of Iowa
Anjali P. Patni: University of Washington
Daniel Mar: University of Washington School of Medicine
Karol Bomsztyk: University of Washington School of Medicine
Julie Mathieu: University of Washington School of Medicine
Hannele Ruohola-Baker: University of Washington
Elizabeth J. Leslie-Clarkson: Emory University School of Medicine
Michael A. White: Washington University School of Medicine
Barak A. Cohen: Washington University School of Medicine
Robert A. Cornell: University of Washington

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Oral facial cleft (OFC) comprises cleft lip with or without cleft palate (CL/P) or cleft palate only. Genome wide association studies (GWAS) of isolated OFC have identified common single nucleotide polymorphisms (SNPs) in many genomic loci where the presumed effector gene (for example, IRF6 in the 1q32 locus) is expressed in embryonic oral epithelium. To identify candidates for functional SNPs at eight such loci we conduct a massively parallel reporter assay in a fetal oral epithelial cell line, revealing SNPs with allele-specific effects on enhancer activity. We filter these SNPs against chromatin-mark evidence of enhancers and test a subset in traditional reporter assays, which support the candidacy of SNPs at loci containing FOXE1, IRF6, MAFB, TFAP2A, and TP63. For two SNPs near IRF6 and one near FOXE1, we engineer the genome of induced pluripotent stem cells, differentiate the cells into embryonic oral epithelium, and discover allele-specific effects on the levels of effector gene expression, and, in two cases, the binding affinity of transcription factors FOXE1 or ETS2. Conditional analyses of GWAS data suggest the two functional SNPs near IRF6 account for the majority of risk for CL/P at this locus. This study connects genetic variation associated with OFC to mechanisms of pathogenesis.

Date: 2025
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DOI: 10.1038/s41467-025-61734-w

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