Journal article
Haploinsufficiency of GRHL2 is associated with orofacial clefting in humans
Human molecular genetics, Vol.34(24), pp.2088-2098
12/04/2025
DOI: 10.1093/hmg/ddaf163
PMCID: PMC12680603
PMID: 41172132
Abstract
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.
Details
- Title: Subtitle
- Haploinsufficiency of GRHL2 is associated with orofacial clefting in humans
- Creators
- Sarah W Curtis - Emory UniversityCinderella Yang - Emory University School of MedicineAlba Sanchis-Juan - Broad InstituteKatherine Singleton - Emory UniversityTerri H Beaty - Johns Hopkins UniversityFlorian Erger - University Hospital CologneMichael P Epstein - Emory UniversityEleanor Feingold - University of PittsburghMax Krause - University Hospital CologneLina M Moreno Uribe - University of IowaChristian Netzer - University of CologneCarmencita D Padilla - University of the Philippines ManilaJohn R Shaffer - University of PittsburghSeth M Weinberg - University of PittsburghJenna C Carlson - University of PittsburghClara Velmans - University Hospital CologneJeffrey C Murray - University of IowaSeb Dworkin - La Trobe UniversityMary L Marazita - University of PittsburghHarrison Brand - Massachusetts General HospitalElizabeth J Leslie-Clarkson - Emory University School of Medicine
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.34(24), pp.2088-2098
- DOI
- 10.1093/hmg/ddaf163
- PMID
- 41172132
- PMCID
- PMC12680603
- NLM abbreviation
- Hum Mol Genet
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Publisher
- Oxford University Press
- Grant note
- X01-HL136465 (MLM, EF) / NIH HHS X01-DE032472 (PI: MLM, EJL) / NIH HHS R01/R37-DE008559 (JCM) / NIH HHS R01-DE027983 (EJL) / NIH HHS X01-DE030062 (MLM, EF) / NIH HHS R01-DE032319 (MLM, EJL, SMW, JRS) / NIH HHS X01-HD100701 (EJL, MJM, JCM) / NIH HHS R01-DE016148 (MLM, SMW) / NIH HHS T32-GM149422 (KS) / NIH HHS R01-DE028342 (EJL) / NIH HHS
- Language
- English
- Electronic publication date
- 10/31/2025
- Date published
- 12/04/2025
- Academic Unit
- Orthodontics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9985024249002771
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