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Distinguishing syndromic and nonsyndromic cleft palate through analysis of protein-altering de novo variants in 818 trios.

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Title: Distinguishing syndromic and nonsyndromic cleft palate through analysis of protein-altering de novo variants in 818 trios.
Authors: Robinson KR; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA., Curtis SW; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA., Paschall JE; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA., Adeyemo WL; Department of Oral and Maxillofacial Surgery, College of Medicine, University of Lagos, Lagos 101017, Nigeria., Beaty TH; Department of Epidemiology, Johns Hopkins University, Baltimore, MD 21218, USA., Butali A; Department of Oral Biology, Radiology, and Medicine, University of Iowa, Iowa City, IA 52242, USA., Buxó CJ; School of Dental Medicine, University of Puerto Rico, San Juan, PR 00925, USA., Cutler DJ; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA., Epstein MP; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA., Gowans LJJ; Department of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana., Hecht JT; Department of Pediatrics, McGovern Medical School University of Texas Health at Houston, Houston, TX 77030, USA., Shaw GM; Department of Pediatrics, Stanford University, Stanford, CA 94305, USA., Uribe LM; Department of Orthodontics and the Iowa Institute for Oral Health Research, University of Iowa, Iowa City, IA 52242, USA., Murray JC; Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA., Brand H; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA., Weinberg SM; Department of Oral and Craniofacial Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA., Marazita ML; Department of Oral and Craniofacial Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA., Doheny KF; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA., Leslie-Clarkson EJ; Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: ejlesli@emory.edu.
Source: American journal of human genetics [Am J Hum Genet] 2025 Nov 06; Vol. 112 (11), pp. 2679-2692. Date of Electronic Publication: 2025 Oct 06.
Publication Type: Journal Article; Research Support, N.I.H., Extramural
Language: English
Journal Info: Publisher: Cell Press Country of Publication: United States NLM ID: 0370475 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1537-6605 (Electronic) Linking ISSN: 00029297 NLM ISO Abbreviation: Am J Hum Genet Subsets: MEDLINE
Imprint Name(s): Publication: 2008- : [Cambridge, MA] : Cell Press
Original Publication: Baltimore, American Society of Human Genetics.
MeSH Terms: Cleft Palate*/genetics , Cleft Palate*/diagnosis , Cleft Palate*/pathology , Genetic Variation*, Exome/genetics ; Transcription Factors/genetics ; Humans ; Female ; Male ; Genome-Wide Association Study ; Syndrome ; Genetic Predisposition to Disease ; Phenotype ; Exome Sequencing ; Peptide Elongation Factors ; Ribonucleoprotein, U5 Small Nuclear
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 × 10-28) and exome-wide-significant (p < 1.3 × 10-6) 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 × 10-26) versus nonsyndromic (1.31, p = 8.51 × 10-8) 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.
(Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of interests The authors declare no competing interests.
Comments: Update of: medRxiv. 2025 Mar 04:2025.03.03.25323233. doi: 10.1101/2025.03.03.25323233.. (PMID: 40093200)
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Grant Information: R01 DE032332 United States DE NIDCR NIH HHS; U01 DD001033 United States DD NCBDD CDC HHS; U54 GM133807 United States GM NIGMS NIH HHS; R01 DE030342 United States DE NIDCR NIH HHS; R01 DE032319 United States DE NIDCR NIH HHS; R01 DE032122 United States DE NIDCR NIH HHS; R01 DE027983 United States DE NIDCR NIH HHS; R01 DE028300 United States DE NIDCR NIH HHS; R01 DE031261 United States DE NIDCR NIH HHS; R01 DE008559 United States DE NIDCR NIH HHS; R01 DE028342 United States DE NIDCR NIH HHS; R37 DE008559 United States DE NIDCR NIH HHS; R01 DE011931 United States DE NIDCR NIH HHS; R00 DE024571 United States DE NIDCR NIH HHS; R01 DE016148 United States DE NIDCR NIH HHS; F31 DE032588 United States DE NIDCR NIH HHS; HHSN268201700006C United States HL NHLBI NIH HHS
Contributed Indexing: Keywords: cleft palate; de novo; genetic architecture; phenotypic heterogeneity; variation
Substance Nomenclature: 0 (Transcription Factors)
0 (EFTUD2 protein, human)
0 (Peptide Elongation Factors)
0 (Ribonucleoprotein, U5 Small Nuclear)
Entry Date(s): Date Created: 20251007 Date Completed: 20251107 Latest Revision: 20260920
Update Code: 20260920
PubMed Central ID: PMC12808955
DOI: 10.1016/j.ajhg.2025.09.009
PMID: 41056948
Database: MEDLINE
Description
ISSN:1537-6605
DOI:10.1016/j.ajhg.2025.09.009