Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Structural variants (SVs) are larger genetic rearrangements such as deletions, duplications, and insertions and other forms of structural alterations. Given their large size, they can have an outsized effect on phenotype, however, the contribution of SVs to the genetic architecture of orofacial clefts (OFCs) is not well understood. In this study, we sought to better understand the contribution SVs to OFC risk by characterizing de novo SVs (dnSVs) in 1,549 probands with an OFC. Overall, we called 375 dnSVs in 307 probands (0.242 dnSVs per genome). The dnSV rate per genome was highest among individuals with cleft lip (CL, 0.29), followed by cleft lip and palate (CLP, 0.25) and cleft palate only (CP, 0.20), though differences across subtypes were not statistically significant. There were also no differences between sex or syndromic status, but we did identify a significant difference in the rate of duplications across OFC subtypes (p=0.005). Compared to CP (0.028), duplication rates were significantly higher for both CL (0.121; p = 0.003) and CLP (0.096; p = 0.002), suggesting a potential etiologic mechanism for CL/P. We systematically curated each dnSV to classify its potential for influencing OFC risk by examining the genes and regulatory elements disrupted by the SV and evidence for their role in craniofacial development or OFCs. We identified 22 dnSVs in regions associated with recurrent genomic disorders, including seven deletions and one duplication of the well-established OFC risk locus 22q11.2. Additionally, we identified 12 large (>1Mb) SVs, with eight meeting criteria for a likely pathogenic classification based on total gene involvement, and seven dnSVs disrupting well-known genes associated with autosomal dominant forms of OFC. The most notable was SATB2, for which we found four dnSVs, all in individuals with CP. Next, by combining evidence from recurrent dnSVs and de novo single nucleotide variants with Hi-C contact maps and predicted chromatin states from developing craniofacial tissues, we found new candidate genes for OFC risk including FHAD1 , NBEA , NR3C2 , and SPHKAP . Overall, dnSVs classified as likely pathogenic accounted for putative molecular diagnoses in approximately 1.67% of the cohort, with an additional 0.96% having variants of unknown significance with plausible risk for OFCs. Our results support dnSVs as an important component of OFC etiology and suggest their inclusion in analyses may improve diagnostic yield for affected individuals.
Source: medRxiv
Authors: Kelsey R. Robinson, Sarah W. Curtis, Nehir E. Kurtas, Alba Sanchis-Juan, Alexandra Manchel, Wasiu Lanre Adeyemo, Terri H. Beaty, Azeez Butali, Carmen J. Buxó, David J. Cutler, Michael P. Epstein, Eleanor Feingold, Lord JJ Gowans, Jacqueline T. Hecht, Lina Moreno Uribe, Carmencita D. Padilla, Gary M. Shaw, Seth M. Weinberg, Jeffrey C. Murray, Justin Cotney, Michael Talkowski, Mary L. Marazita, Harrison Brand, Elizabeth J. Leslie-Clarkson
Institutions: Emory University, Broad Institute, Massachusetts General Hospital, Children's Hospital of Philadelphia, University of Lagos, Johns Hopkins University, University of Iowa, University of Puerto Rico System, University of Pittsburgh, Kwame Nkrumah University of Science and Technology, The University of Texas Health Science Center at Houston, Stanford University, University of North Carolina at Chapel Hill
Language: English
Subfield: Oral Surgery
Field: Dentistry
Domain: Health Sciences
Open Access status: green
Awards: Identifying novel genetic risks for cleft palate using whole genome sequencing, G1856920414, G2027230392, G2223542244, G3202355983, Extending the Phenotype of Nonsyndromic Orofacial Clefting, G3294076716, G3799963148, G3805145943, G391651506, G4165663431, G4614695615, Transfer 5R01DE027983 - Genomic and Functional Analysis of IRF6 Target Genes in Orofacial Cleft Pathogenesis, Mapping Nonsyndromic Cleft Lip and Palate Genetic Loci, G5637692172, G576193370, Molecular Genetic Epidemiology of Cleft Lip and Palate, G6520516100, G6914550155, G7411451994, G7504117239, G7974002463, G8081039027, G9000145211, G9000293956
OpenAlex ID: W7223122793