Evidence map›Paper›PMID 40902599›Full record

ArticleAmerican journal of human genetics2025

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 and 20 more

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Article in American journal of human genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

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0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

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2 · The registry

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3 · Its place in the literature

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1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

30 authors.

Kelsey RobinsonDepartment of Human Genetics, Emory University, Atlanta, GA 30322, USA.
Sunil K SinghDepartment of Oral Health Sciences, University of Washington, Seattle, WA 98195, USA; Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
Rachel B WalkupDepartment of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
Dorelle V FawwalDepartment of Biology, Emory University, Atlanta, GA 30322, USA.
Kendra M VilfortDepartment of Human Genetics, Emory University, Atlanta, GA 30322, USA.
Amanda KoloskeeDepartment of Human Genetics, Emory University, Atlanta, GA 30322, USA.
Azeez FashinaDepartment of Oral Health Sciences, University of Washington, Seattle, WA 98195, USA.
Wasiu Lanre AdeyemoDepartment of Oral and Maxillofacial Surgery, College of Medicine, University of Lagos, Lagos, Nigeria.
Terri H BeatyDepartment of Epidemiology, Johns Hopkins University, Baltimore, MD 21218, USA.
Azeez ButaliDepartment of Oral Biology, Radiology, and Medicine, University of Iowa, Iowa City, IA 52242, USA.
Carmen J BuxóDental and Craniofacial Genomics Core, School of Dental Medicine, University of Puerto Rico, San Juan, PR 00925, USA.
Wendy K ChungBoston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
David J CutlerDepartment of Human Genetics, Emory University, Atlanta, GA 30322, USA.
Michael P EpsteinDepartment of Human Genetics, Emory University, Atlanta, GA 30322, USA.
Brooklynn GasserAmbry Genetics, Aliso Viejo, CA 92656, USA.
Lord J J GowansDepartment of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.
Jacqueline T HechtDepartment of Pediatrics, McGovern Medical School University of Texas Health at Houston, Houston, TX 77030, USA.
Anuj MankadDepartment of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA.
Lina Moreno UribeDepartment of Orthodontics & The Iowa Institute for Oral Health Research, University of Iowa, Iowa City, IA 52242, USA.
Daryl A ScottDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Gary M ShawDepartment of Pediatrics, Stanford University, Stanford, CA 94305, USA.
Mary Ann ThomasDepartment of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.
Seth M WeinbergCenter for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, and Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Eric C LiaoCenter for Craniofacial Innovation, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Harrison BrandCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Mary L MarazitaCenter for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, and Department of Human Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Robert J LipinskiDepartment of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
Jeffrey C MurrayDepartment of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
Robert A CornellDepartment of Oral Health Sciences, University of Washington, Seattle, WA 98195, USA.
Elizabeth J Leslie-ClarksonDepartment of Human Genetics, Emory University, Atlanta, GA 30322, USA. Electronic address: ejlesli@emory.edu.

Funding

Extending the Phenotype of Nonsyndromic Orofacial CleftsR01DE016148 · NIDCR · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI MARAZITA, MARY L., WEINBERG, SETH M · 2004 to 2018
$19.7M
Tracking and Evaluation CoreU54GM133807 · NIGMS · UNIVERSITY OF PUERTO RICO MED SCIENCES · PI LUCIANO, CARLOS A., MOROU-BERMUDEZ, EVANGELIA · 2020 to 2024
$17.7M
Comprehensive Training in Inter-Disciplinary Oral Health ResearchT90DE021984 · NIDCR · UNIVERSITY OF WASHINGTON · PI Robert Aaron Cornell · 2012 to 2026
$7.9M
Molecular Genetic Epidemiology of Cleft Lip and PalateR37DE008559 · NIDCR · UNIVERSITY OF IOWA · PI MURRAY, JEFFREY C · 2004 to 2013
$6.8M
Dissecting the transcriptional network governing differentiation of peridermR01DE023575 · NIDCR · UNIVERSITY OF WASHINGTON · PI CORNELL, ROBERT AARON, SCHUTTE, BRIAN C · 2013 to 2023
$4.3M
Whole Genome Sequencing for Orofacial Clefts, Incidental Findings and Role of Community GatekeepersR01DE028300 · NIDCR · UNIVERSITY OF IOWA · PI BUTALI, AZEEZ · 2020 to 2024
$3.9M
Genomics of Cleft PalateR01DE030342 · NIDCR · EMORY UNIVERSITY · PI ELIZABETH JANE LESLIE-CLARKSON · 2021 to 2026
$3.5M
Transfer 5R01DE027983 - Genomic and Functional Analysis of IRF6 Target Genes in Orofacial Cleft PathogenesisR01DE027983 · NIDCR · MASSACHUSETTS GENERAL HOSPITAL · PI LIAO, ERIC CHIEN-WEI · 2019 to 2023
$3.3M
Genetic modifiers of Van der Woude syndromeR01DE028342 · NIDCR · EMORY UNIVERSITY · PI LESLIE-CLARKSON, ELIZABETH JANE · 2019 to 2023
$2.7M
Investigating the role of genes, maternal exposures, and interactions on orofacial cleftsR01DE032122 · NIDCR · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI SHAFFER, JOHN R · 2022 to 2024
$2.1M
DNA methylation in orofacial cleftingR01DE032710 · NIDCR · UNIVERSITY OF WISCONSIN-MADISON · PI Robert Lipinski · 2023 to 2026
$1.9M
MOLECULAR GENETIC EPIDEMIOLOGY OF CLEFT LIP AND PALATER01DE008559 · NIDCR · UNIVERSITY OF IOWA · PI MURRAY, JEFFREY C · 1988 to 2003
$1.5M
NHLBI NIH HHS HHSN268201700006CNIDCR NIH HHS F31 DE032588NIDCR NIH HHS R00 DE024571NIDCR NIH HHS R01 DE008559NIDCR NIH HHS R01 DE016148NIDCR NIH HHS R01 DE023575NIDCR NIH HHS R01 DE027983NIDCR NIH HHS R01 DE028300NIDCR NIH HHS R01 DE028342NIDCR NIH HHS R01 DE030342NIDCR NIH HHS R01 DE032122NIDCR NIH HHS R01 DE032710NIDCR NIH HHS R37 DE008559NIDCR NIH HHS T90 DE021984NIGMS NIH HHS U54 GM133807
6 · The paper itself

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.

Indexed as

Abnormalities, MultipleCleft LipCleft PalateCystsLipProtein Kinase CAnimalsDNA-Binding ProteinsFemaleHumansInterferon Regulatory FactorsMaleMutationPhenotypeTranscription FactorsZebrafishDNA-Binding ProteinsInterferon Regulatory FactorsIRF6 protein, humanProtein Kinase CTranscription Factorscleft lip and palatecleft palatekinaseneurodevelopmental disordersperiderm

Identifiers

PMID40902599
PMCPMC12510259

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.