Rare variants in PRKCI cause Van der Woude syndrome and other features of peridermopathy

Kelsey Robinson; Sunil K Singh; Rachel B Walkup; Dorelle V Fawwal; Kendra M Vilfort; Amanda Koloskee; Azeez Fashina; Wasiu Lanre Adeyemo; Terri H Beaty; Azeez Butali; Carmen J Buxó; Wendy K Chung; David J Cutler; Michael P Epstein; Brooklynn Gasser; Lord J J Gowans; Jacqueline T Hecht; Anuj Mankad; Lina Moreno Uribe; Daryl A Scott; Gary M Shaw; Mary Ann Thomas; Seth M Weinberg; Eric C Liao; Harrison Brand; Mary L Marazita; Robert J Lipinski; Jeffrey C Murray; Robert A Cornell; Elizabeth J Leslie-Clarkson

doi:10.1016/j.ajhg.2025.08.008

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Rare variants in PRKCI cause Van der Woude syndrome and other features of peridermopathy

Journal article

Peer reviewed

Rare variants in PRKCI cause Van der Woude syndrome and other features of peridermopathy

Kelsey Robinson, Sunil K Singh, Rachel B Walkup, Dorelle V Fawwal, Kendra M Vilfort, Amanda Koloskee, Azeez Fashina, Wasiu Lanre Adeyemo, Terri H Beaty, Azeez Butali, …

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

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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.

periderm

cleft palate

kinase

cleft lip and palate

neurodevelopmental disorders

Details

Title: Subtitle: Rare variants in PRKCI cause Van der Woude syndrome and other features of peridermopathy
Creators: Kelsey Robinson - Emory University
Sunil K Singh - University of Washington
Rachel B Walkup - University of Wisconsin–Madison
Dorelle V Fawwal - Emory University
Kendra M Vilfort - Emory University
Amanda Koloskee - Emory University
Azeez Fashina - University of Washington
Wasiu Lanre Adeyemo - University of Lagos
Terri H Beaty - Johns Hopkins University
Azeez Butali - University of Iowa
Carmen J Buxó - University of Puerto Rico System
Wendy K Chung - Boston Children's Hospital
David J Cutler - Emory University
Michael P Epstein - Emory University
Brooklynn Gasser - Ambry Genetics (United States)
Lord J J Gowans - Kwame Nkrumah University of Science and Technology
Jacqueline T Hecht - The University of Texas Health Science Center at Houston
Anuj Mankad - University of Iowa
Lina Moreno Uribe - University of Iowa, Orthodontics
Daryl A Scott - Baylor College of Medicine
Gary M Shaw - Stanford University
Mary Ann Thomas - University of Calgary
Seth M Weinberg - University of Pittsburgh
Eric C Liao - Children's Hospital of Philadelphia
Harrison Brand - Massachusetts General Hospital
Mary L Marazita - University of Pittsburgh
Robert J Lipinski - University of Wisconsin–Madison
Jeffrey C Murray - University of Iowa
Robert A Cornell - University of Washington
Elizabeth 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

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