Rare Variants in Prkci Cause Van Der Woude Syndrome and Other Features of Peridermopathy

Authors

• 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

Language

English

Publication Date

10-2-2025

Journal

American Journal of Human Genetics

DOI

10.1016/j.ajhg.2025.08.008

PMID

40902599

PMCID

PMC12510259

PubMedCentral® Posted Date

9-2-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Cleft Lip, Cleft Palate, Humans, Cysts, Zebrafish, Animals, Abnormalities, Multiple, Lip, Interferon Regulatory Factors, Female, Male, Mutation, Phenotype, Protein Kinase C, Transcription Factors, DNA-Binding Proteins, cleft palate, cleft lip and palate, neurodevelopmental disorders, kinase, periderm

Published Open-Access

yes

Recommended Citation

Robinson, Kelsey; Singh, Sunil K; Walkup, Rachel B; et al., "Rare Variants in Prkci Cause Van Der Woude Syndrome and Other Features of Peridermopathy" (2025). Faculty, Staff and Student Publications. 4933.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4933