2025 DOHG News

A team of researchers has identified a new gene mutated in Van der Woude syndrome, an inherited disorder perturbing the development of the face and mouth. People with Van der Woude syndrome often have a cleft lip or cleft palate, combined with lower lip pits. 

Emory geneticists teamed up with clinicians across North America to identify the new gene, called PRKCI (protein kinase C-I). In collaboration with scientists at the University of Washington, they also tested the effects of variants of PRKCI on zebrafish embryos.

The results were published on Sept. 2 in American Journal of Human Genetics.

The prevalence of Van der Woude syndrome is about 1:35,000 live births. In total, the team identified de novo PRKCI variants in 7 individuals with Van der Woude syndrome or syndromic cleft lip or palate. They found additional PRKCI variants in clinical databases. 

“One of the unique things about PRKCI is that there are neurodevelopmental phenotypes in some of the individuals with pathogenic variants in this gene, which is not a phenotype typically associated with Van der Woude syndrome or peridermopathies,” says lead author Elizabeth Leslie-Clarkson, PhD, associate professor of human genetics at Emory University School of Medicine. 

Van der Woude syndrome is one of a related set of disorders called peridermopathies arising due to defects of the periderm: a layer of cells that lines the oral cavity and other structures in the developing embryo. The broader peridermopathy spectrum also includes limb, digit, and dental phenotypes.

The other genes for Van der Woude syndrome are IRF6 and GRHL3. These genes promote the differentiation of the periderm. Mutations in IRF6 are responsible for about 70 percent of Van der Woude cases, mutations in GRHL3 are responsible for another 5%, while mutations in PRKCI cause a smaller fraction, 2-3%.

Leslie-Clarkson and her colleagues showed that PRKCI acts upstream of IRF6. PRKCI also acts in other pathways, influencing the development of multiple tissues besides the periderm. This could explain effects on the heart or brain seen in some cases they studied. The precise relationship between PRKCI and IRF6 still has to be worked out, she said.

“When I was a graduate student, I was part of the discovery of GRHL3 as the second gene for Van der Woude syndrome, about 10 years after IRF6 was discovered. It’s been another 10 years or so to discover PRKCI. We estimate that now ~10% of families with Van der Woude syndrome lack a molecular diagnosis and we’re very hopeful it won’t take another 10 years to get them an answer.”

Co-first authors of the paper are Emory postdoctoral fellow Kelsey Robinson, and research scientist Sunil Singh, now at University of Wisconsin-Madison. 

A photo of a patient affected by Van der Woude syndrome is available here (from Gowans et al 2017, Creative Commons/open access).