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; Wasiu Lanre Adeyemo; Terri H Beaty; Azeez Butali; Carmen J Buxó; Wendy K Chung; David J Cutler; Michael P Epstein; Azeez Fashina; Brooklynn Gasser; Lord Jj Gowans; Jacqueline T Hecht; Lina Moreno Uribe; Daryl A Scott; Gary M Shaw; Mary Ann Thomas; Seth M Weinberg; Harrison Brand; Mary L Marazita; Robert J Lipinski; Jeffrey C Murray; Robert A Cornell; Elizabeth J Leslie-Clarkson

doi:10.1101/2025.01.17.25320742

Back

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

Preprint

Open access

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, Wasiu Lanre Adeyemo, Terri H Beaty, Azeez Butali, Carmen J Buxó, Wendy K Chung, David J Cutler, …

medRxiv : the preprint server for health sciences

Cold Spring Harbor Laboratory

01/17/2025

DOI: 10.1101/2025.01.17.25320742

PMCID: PMC11759255

PMID: 39867391

Files and links (1)

url

https://doi.org/10.1101/2025.01.17.25320742View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Van der Woude syndrome (VWS) is an autosomal dominant disorder characterized by lower lip pits and orofacial clefts (OFCs). With a prevalence of approximately 1 in 35,000 live births, it is the most common form of syndromic clefting and may account for ~2% of all OFCs. The majority of VWS is attributed to genetic variants in (~70%) or (~5%), leaving up to 25% of individuals with VWS without a molecular diagnosis. Both IRF6 and GRHL3 function in a transcriptional regulatory network governing differentiation of periderm, a single layer of epithelial cells that prevents pathological adhesions during palatogenesis. Disruption of this layer results in a spectrum of phenotypes ranging from lip pits and OFCs to severe pterygia and other congenital anomalies that can be incompatible with life. Understanding the mechanisms of peridermopathies is vital in improving health outcomes for affected individuals. We reasoned that genes encoding additional members of the periderm gene regulatory network, including kinases acting upstream of IRF6 (i.e., atypical protein kinase C family members, RIPK4, and CHUK), are candidates to harbor variants resulting in VWS. Consistent with this prediction, we identified 6 variants (DNs) and 11 rare variants in , an atypical protein kinase C, in 17 individuals with clinical features consistent with syndromic OFCs and peridermopathies. Of the identified DNs, 4 were identical p.(Asn383Ser) variants in unrelated individuals with syndromic OFCs, indicating a likely hotspot mutation. We also performed functional validation of 12 variants using the enveloping layer in zebrafish embryos, a structure analogous to the periderm. Three patient-specific alleles (p.Arg130His, p.(Asn383Ser), and p.Leu385Phe) were confirmed to be loss-of-function variants. In summary, we identified as a novel causal gene 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 University
Sunil K Singh - University of Washington
Rachel B Walkup - University of Wisconsin–Madison
Dorelle V Fawwal - Emory University
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
Azeez Fashina - University of Washington
Brooklynn Gasser - Ambry Genetics (United States)
Lord Jj Gowans - Kwame Nkrumah University of Science and Technology
Jacqueline T Hecht - The University of Texas Health Science Center at Houston
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
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: Preprint
Publication Details: medRxiv : the preprint server for health sciences
DOI: 10.1101/2025.01.17.25320742
PMID: 39867391
PMCID: PMC11759255
Publisher: Cold Spring Harbor Laboratory; United States
Grant note: R01 DE027983 / NIDCR NIH HHS HHSN268201700006C / NHLBI NIH HHS R01 DE030342 / NIDCR NIH HHS R01 DE028342 / NIDCR NIH HHS R01 DE032710 / NIDCR NIH HHS R01 DE032122 / NIDCR NIH HHS R01 DE016148 / NIDCR NIH HHS R01 DE008559 / NIDCR NIH HHS R37 DE008559 / NIDCR NIH HHS R01 DE028300 / NIDCR NIH HHS
Language: English
Date posted: 01/17/2025
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: 9984780352202771

Metrics

9 Record Views