Journal article
Distinguishing syndromic and nonsyndromic cleft palate through analysis of protein-altering de novo variants in 818 trios
American journal of human genetics, Vol.112(11), pp.2679-2692
11/06/2025
DOI: 10.1016/j.ajhg.2025.09.009
PMCID: PMC12808955
PMID: 41056948
Abstract
De novo variants (DNs) are sporadically occurring variants found in an offspring but absent in both parents. DNs most commonly arise in the germline and are not under selective pressure; therefore, they may be enriched for disease-causing alleles. In fact, DNs have been implicated in multiple rare genetic disorders. Cleft palate (CP) is a craniofacial congenital anomaly occurring in ∼1 in 1,700 live births. Genome-wide association studies have found fewer than a dozen CP-specific loci, while exome and targeted sequencing studies in family-based and case-control cohorts often lack statistical power to conclusively identify causal variants. We therefore hypothesized that CP probands would be enriched for protein-altering DNs, which may explain the relative dearth in discovery. A complicating factor in understanding CP, however, is its phenotypically heterogeneous nature. As such, we aggregated sequence data for 818 trios with CP representing a combination of subtypes and isolated and syndromic presentations. We identified global enrichment of protein-altering DNs (1.48, p = 1.28 × 10
) and exome-wide-significant (p < 1.3 × 10
) gene-specific enrichment for SATB2, MEIS2, COL2A1, ZC4H2, EFTUD2, KAT6B, and ANKRD11. We found a statistically significant higher enrichment of protein-altering DNs in syndromic (1.70, p = 6.95 × 10
) versus nonsyndromic (1.31, p = 8.51 × 10
) probands but no differences between subtypes. We explored differences in gene-specific enrichment, finding some unique to syndromic probands (ZC4H2) or nonsyndromic probands (IRF6), as well as some shared between groups (SATB2). Altogether, we show that DNs are a contributor to CP risk and that combined analysis can enhance our ability to find genetic associations that would otherwise be undetected.
Details
- Title: Subtitle
- Distinguishing syndromic and nonsyndromic cleft palate through analysis of protein-altering de novo variants in 818 trios
- Creators
- Kelsey R Robinson - Emory UniversitySarah W Curtis - Emory UniversityJustin E Paschall - Johns Hopkins MedicineWasiu Lanre Adeyemo - University of LagosTerri H Beaty - Johns Hopkins UniversityAzeez Butali - University of IowaCarmen J Buxó - University of Puerto Rico SystemDavid J Cutler - Emory UniversityMichael P Epstein - Emory UniversityLord J J Gowans - Kwame Nkrumah University of Science and TechnologyJacqueline T Hecht - The University of Texas Health Science Center at HoustonGary M Shaw - Stanford UniversityLina Moreno Uribe - University of Iowa, OrthodonticsJeffrey C Murray - University of IowaHarrison Brand - Massachusetts General HospitalSeth M Weinberg - University of PittsburghMary L Marazita - University of PittsburghKimberly F Doheny - Johns Hopkins MedicineElizabeth J Leslie-Clarkson - Emory University
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.112(11), pp.2679-2692
- DOI
- 10.1016/j.ajhg.2025.09.009
- PMID
- 41056948
- PMCID
- PMC12808955
- NLM abbreviation
- Am J Hum Genet
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Publisher
- Elsevier
- Grant note
- Center for Inherited Disease Research (CIDR)CIDRNational Institutes of Health (NIH): HHSN268201700006I NIH: X01-HG010835, X01-HL0132363, X01-HD100701, F31-DE032588, R01 DE027983, R01-DE028342, R01-DE030342, R01-DE028300, R00-DE024571, U54GM133807, R01-DE008559, R01-DE016148, R01-DE032122, R01-DE0332319, R01-DE011931, R01-DE031261 Centers for Disease Control and Prevention, Centers of Excellence: U01-DD001033
We are very thankful for the participants, their families, and colleagues who have made this research possible. Sequencing services for CPSeq were provided by the Center for Inherited Disease Research (CIDR) . CIDR is fully funded through a federal contract from the National Institutes of Health (NIH) to the Johns Hopkins University, contract number HHSN268201700006I. Additional WGS was funded by NIH grants X01-HG010835 (E.J.L.-C.. and M.L.M.) , X01-HL0132363 (M.L.M.) , and X01-HD100701 (E.J.L.-C., J.C.M., and M.L.M.) . Patient recruitment, assembly of phenotypic information, and data analysis were supported by NIH grants F31-DE032588 (K.R.R.) , R01 DE027983 (E.J.L.-C.) , R01-DE028342 (E.J.L.-C.) , R01-DE030342 (E.J.L.-C.) , R01-DE028300 (A.B.) , R00-DE024571 (C.J.B.) , U54GM133807 (C.J.B.) , U54GM133807 (C.J.B.) , R01-DE008559 (J.C.M.) , R01-DE016148 (M.L.M. and S.M.W.) , R01-DE008559 (J.C.M. and M.L.M.) , R01-DE032122 (M.L.M.) , R01-DE0332319 (M.L.M., E.J.L.-C., and S.M.W.) , R01-DE011931 (J.T.H.) , and R01-DE031261 (H.B.) . We thank the California Department of Public Health, Maternal Child and Adolescent Division, for providing data for these analyses. This work was supported by the Centers for Disease Control and Prevention, Centers of Excellence no. U01-DD001033 (G.M.S.) .
- Language
- English
- Electronic publication date
- 10/06/2025
- Date published
- 11/06/2025
- Academic Unit
- Orthodontics; Oral Pathology, Radiology and Medicine; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9985014894802771
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