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Haploinsufficiency of GRHL2 is associated with orofacial clefting in humans.

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Τίτλος: Haploinsufficiency of GRHL2 is associated with orofacial clefting in humans.
Συγγραφείς: Curtis SW; Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301 Atlanta, GA 30322, United States., Yang C; Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301 Atlanta, GA 30322, United States., Sanchis-Juan A; Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, United States.; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, 415 Main St., Cambridge, MA 02142, United States., Singleton K; Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301 Atlanta, GA 30322, United States., Beaty TH; Department of Epidemiology, Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, United States., Erger F; Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Straße 34, 50931 Cologne, Germany., Epstein MP; Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301 Atlanta, GA 30322, United States., Feingold E; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, 3501 Terrace Street, Pittsburgh, PA 15261, United States.; Department of Human Genetics, School of Public Health, University of Pittsburgh, 130 De Soto Street, Pittsburgh, PA 15261, United States., Krause M; Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Straße 34, 50931 Cologne, Germany., Moreno Uribe LM; The Iowa Institute for Oral Health Research, College of Dentistry, University of Iowa, 801 Newton Rd., Iowa City, IA 52242, United States.; Department of Orthodontics, College of Dentistry, University of Iowa, 801 Newton Rd., Iowa City, IA 52242, United States., Netzer C; Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Straße 34, 50931 Cologne, Germany., Padilla CD; College of Medicine, University of the Philippines Manila, 547 Pedro Gil Street, Ermita Manila, Philippines.; Newborn Screening Reference Center, National Institutes of Health (Philippines), 1579 F.T. Benitez St., Malate Manila,Philippines., Shaffer JR; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, 3501 Terrace Street, Pittsburgh, PA 15261, United States.; Department of Human Genetics, School of Public Health, University of Pittsburgh, 130 De Soto Street, Pittsburgh, PA 15261, United States., Weinberg SM; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, 3501 Terrace Street, Pittsburgh, PA 15261, United States.; Department of Human Genetics, School of Public Health, University of Pittsburgh, 130 De Soto Street, Pittsburgh, PA 15261, United States., Carlson JC; Department of Human Genetics, School of Public Health, University of Pittsburgh, 130 De Soto Street, Pittsburgh, PA 15261, United States.; Department of Biostatistics and Health Data Science, School of Public Health, University of Pittsburgh, 130 De Soto Street, Pittsburgh, PA 15261, United States., Velmans C; Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Kerpener Straße 34, 50931 Cologne, Germany., Murray JC; Department of Pediatrics, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, United States., Dworkin S; Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Plenty Road, Bundoora, VIC 3086, Australia., Marazita ML; Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, 3501 Terrace Street, Pittsburgh, PA 15261, United States.; Department of Human Genetics, School of Public Health, University of Pittsburgh, 130 De Soto Street, Pittsburgh, PA 15261, United States., Brand H; Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, United States.; Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, 415 Main St., Cambridge, MA 02142, United States., Leslie-Clarkson EJ; Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301 Atlanta, GA 30322, United States.
Πηγή: Human molecular genetics [Hum Mol Genet] 2025 Dec 04; Vol. 34 (24), pp. 2088-2098.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: IRL Press at Oxford University Press Country of Publication: England NLM ID: 9208958 Publication Model: Print Cited Medium: Internet ISSN: 1460-2083 (Electronic) Linking ISSN: 09646906 NLM ISO Abbreviation: Hum Mol Genet Subsets: MEDLINE
Imprint Name(s): Original Publication: Oxford, England ; New York : IRL Press at Oxford University Press, c1992-
Ιατρικοί όροι (MeSH): Cleft Palate*/genetics , Cleft Palate*/pathology , Transcription Factors*/genetics , Transcription Factors*/metabolism , DNA-Binding Proteins*/genetics , DNA-Binding Proteins*/metabolism , Cleft Lip*/genetics , Cleft Lip*/pathology , Haploinsufficiency*/genetics, Humans ; Animals ; Female ; Male ; Mice ; Philippines ; Genetic Predisposition to Disease ; Whole Genome Sequencing ; Loss of Function Mutation
Περίληψη: Orofacial clefts (OFCs) are one of the most common structural birth defects, with the prevalence of OFC varying across populations, and studies on the causes of OFCs in diverse populations are necessary, but still limited. We analyzed whole genome sequencing data on 419 parent-child trios from the Philippines, a population with a particularly high rate of OFC. To identify novel genes for OFCs, we studied both common variation and de novo variants (DNVs). We identified a significant enrichment in both loss-of-function (N = 62; P = 8.34 × 10-5) and protein-altering DNVs (N = 394; P = 1.49 × 10-7) among OFC probands. Among the genes individually enriched for DNVs was GRHL2 (P = 6.60 × 10-6), where there were two DNVs, a stop-gain and a frameshift deletion. We then queried OFC trios from other cohorts in the Gabriella Miller Kids First program (total N = 1254) and GeneMatcher and identified an 89 kb de novo deletion in GRHL2 and a de novo 8q22.3 microdeletion with one breakpoint in GRHL2. Additionally, within the common variant analyses we found significant gene x gene interactions with GRHL2. GRHL2 is a conserved transcription factor involved in embryonic development, with truncating mutations causing autosomal dominant progressive hearing loss and missense variants causing autosomal recessive ectodermal dysplasia. Heterozygous variation in its homolog, GRHL3, causes Van der Woude syndrome and isolated cleft palate. Additionally, mice deficient for either Grhl2 or Grhl3 have craniofacial anomalies, including facial and palatal clefts, strongly supporting GRHL2 as a risk locus for OFCs.
(© The Author(s) 2025. Published by Oxford University Press.)
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Grant Information: R37 DE008559 United States DE NIDCR NIH HHS; R01-DE028342 (EJL) United States NH NIH HHS; R01-DE027983 (EJL) United States NH NIH HHS; X01-DE032472 (PI: MLM, EJL) United States NH NIH HHS; R01-DE016148 (MLM, SMW) United States NH NIH HHS; T32 GM149422 United States GM NIGMS NIH HHS; R01 DE032319 United States DE NIDCR NIH HHS; T32-GM149422 (KS) United States NH NIH HHS; X01-HD100701 (EJL, MJM, JCM) United States NH NIH HHS; R01 DE008559 United States DE NIDCR NIH HHS; R01-DE031261 (HB) United States NH NIH HHS; R01 DE028342 United States DE NIDCR NIH HHS; X01-HG010835 (EJL, MLM) United States NH NIH HHS; X01-HL132363 (MLM, EF) United States NH NIH HHS; R01 DE016148 United States DE NIDCR NIH HHS; R01-DE032319 (MLM, EJL, SMW, JRS) United States NH NIH HHS; X01-HL136465 (MLM, EF) United States NH NIH HHS; R01 DE027983 United States DE NIDCR NIH HHS; R01/R37-DE008559 (JCM) United States NH NIH HHS; X01-DE030062 (MLM, EF) United States NH NIH HHS; R01 DE031261 United States DE NIDCR NIH HHS
Contributed Indexing: Keywords: association; gene-by-gene interaction; orofacial cleft; rare variants
Substance Nomenclature: 0 (Transcription Factors)
0 (DNA-Binding Proteins)
0 (GRHL2 protein, human)
Entry Date(s): Date Created: 20251031 Date Completed: 20251206 Latest Revision: 20251209
Update Code: 20260130
PubMed Central ID: PMC12680603
DOI: 10.1093/hmg/ddaf163
PMID: 41172132
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1460-2083
DOI:10.1093/hmg/ddaf163