Characterization of de novo structural variants in trios with orofacial clefts
- 1Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA
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.
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BibTeX
@misc{robinson2026characterization,
title = {{Characterization of de novo structural variants in trios with orofacial clefts}},
author = {K. R. Robinson and S. W. Curtis and N. E. Kurtas and A. Sanchis-Juan and A. Manchel and W. L. Adeyemo and T. H. Beaty and A. Butali and C. J. Buxo Martinez and D. J. Cutler and M. P. Epstein and E. Feingold and L. J. Gowans and J. T. Hecht and L. Moreno Uribe and C. D. Padilla and G. M. Shaw and S. M. Weinberg and J. C. Murray and J. Cotney and M. Talkowski and M. L. Marazita and H. Brand and E. J. Leslie-Clarkson},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.16.26365772},
url = {https://www.medrxiv.org/content/10.64898/2026.10.16.26365772v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Characterization of de novo structural variants in trios with orofacial clefts
AU - K. R. Robinson
AU - S. W. Curtis
AU - N. E. Kurtas
AU - A. Sanchis-Juan
AU - A. Manchel
AU - W. L. Adeyemo
AU - T. H. Beaty
AU - A. Butali
AU - C. J. Buxo Martinez
AU - D. J. Cutler
AU - M. P. Epstein
AU - E. Feingold
AU - L. J. Gowans
AU - J. T. Hecht
AU - L. Moreno Uribe
AU - C. D. Padilla
AU - G. M. Shaw
AU - S. M. Weinberg
AU - J. C. Murray
AU - J. Cotney
AU - M. Talkowski
AU - M. L. Marazita
AU - H. Brand
AU - E. J. Leslie-Clarkson
PY - 2026
DA - 2026/10/16
PB - medRxiv
DO - 10.64898/2026.10.16.26365772
UR - https://www.medrxiv.org/content/10.64898/2026.10.16.26365772v1
AB - 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.
ER -