Journal article
Rare variants in PRKCI cause Van der Woude syndrome and other features of peridermopathy
American journal of human genetics, Vol.112(10), pp.2422-2439
10/2025
DOI: 10.1016/j.ajhg.2025.08.008
PMCID: PMC12510259
PMID: 40902599
Abstract
Van der Woude syndrome (VWS) is an autosomal dominant disorder characterized by lower lip pits and orofacial clefts (OFCs). With a prevalence of ∼1 in 35,000 live births, it is the most common form of syndromic clefting. Most VWS is attributed to variants in IRF6 (∼70%) or GRHL3 (∼5%), leaving up to 25% of individuals without a molecular diagnosis. Both IRF6 and GRHL3 function in a transcriptional regulatory network (TRN) governing differentiation of periderm, a single epithelial cell layer preventing pathological adhesions during palatogenesis. Periderm disruption can elicit a spectrum of phenotypes, including lip pits and OFCs, pterygia, and severe or fatal congenital anomalies. Understanding these mechanisms is vital in improving health outcomes for individuals with peridermopathies. We hypothesized genes encoding members of the periderm TRN, including kinases such as atypical protein kinase C (aPKC) acting upstream of IRF6, could harbor variants resulting in VWS. Consistent with this hypothesis, we identified 7 de novo variants (DNs) and 11 rare variants in PRKCI in 18 individuals with clinical features of syndromic OFCs and peridermopathies. Among the identified DNs, c.1148A>G (p.Asn383Ser) was found in five unrelated individuals, indicating a hotspot mutation. We functionally tested 12 proband-specific alleles in a zebrafish model. Three alleles, c.389G>A (p.Arg130His), c.1148A>G (p.Asn383Ser), and c.1155A>C (p.Leu385Phe), were confirmed loss-of-function variants. We also show that phosphomimetic Irf6 can rescue the effects of aPKC inhibition, supporting placement of PRKCI within this TRN. In summary, we identified PRKCI variants as causative for VWS and syndromic OFC with other features of peridermopathies.
Details
- Title: Subtitle
- Rare variants in PRKCI cause Van der Woude syndrome and other features of peridermopathy
- Creators
- Kelsey Robinson - Emory UniversitySunil K Singh - University of WashingtonRachel B Walkup - University of Wisconsin–MadisonDorelle V Fawwal - Emory UniversityKendra M Vilfort - Emory UniversityAmanda Koloskee - Emory UniversityAzeez Fashina - University of WashingtonWasiu Lanre Adeyemo - University of LagosTerri H Beaty - Johns Hopkins UniversityAzeez Butali - University of IowaCarmen J Buxó - University of Puerto Rico SystemWendy K Chung - Boston Children's HospitalDavid J Cutler - Emory UniversityMichael P Epstein - Emory UniversityBrooklynn Gasser - Ambry GeneticsLord J J Gowans - Kwame Nkrumah University of Science and TechnologyJacqueline T Hecht - The University of Texas Health Science Center at HoustonAnuj Mankad - University of IowaLina Moreno Uribe - University of Iowa, OrthodonticsDaryl A Scott - Baylor College of MedicineGary M Shaw - Stanford UniversityMary Ann Thomas - University of CalgarySeth M Weinberg - University of PittsburghEric C Liao - Children's Hospital of PhiladelphiaHarrison Brand - Massachusetts General HospitalMary L Marazita - University of PittsburghRobert J Lipinski - University of Wisconsin–MadisonJeffrey C Murray - University of IowaRobert A Cornell - University of WashingtonElizabeth J Leslie-Clarkson - Emory University
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.112(10), pp.2422-2439
- DOI
- 10.1016/j.ajhg.2025.08.008
- PMID
- 40902599
- PMCID
- PMC12510259
- NLM abbreviation
- Am J Hum Genet
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Publisher
- CELL PRESS
- Grant note
- R01 DE027983 / NIDCR NIH HHS
- Language
- English
- Electronic publication date
- 08/29/2025
- Date published
- 10/2025
- 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
- 9984958291502771
Metrics
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