Dominant Gene Mutations Causes Van der Woude Syndrome

A new gene has been identified that is related to the Van der Woude syndrome, the most common syndrome with cleft lip and palate.

There are more than 350 syndromes with clefts, of which Van der Woude syndrome (VWS) is the most common and approximately 70% of the individuals with VWS have a mutation in a gene called interferon regulatory factor 6 (IRF6).


An international team led by scientists from the Karolinska Institute (Huddinge, Sweden) collected DNA samples from 45 families of multiple ethnicities who were completely sequenced for IRF6 without identifying a causative mutation. A total of 360 unrelated individuals without a history of oral cleft from the Philippines were used as controls.

The team started by executing a genetic linkage study of a large family from Finland. The family had been diagnosed with VWS, although no IRF6 mutations had been found. By comparing the DNA of affected individuals with DNA from healthy family members, the scientists identified another gene, called Grainy-head like 3 (GRHL3), which was mutated only in the affected family members. The same gene was found to be altered in seven additional families with VWS where no IRF6 mutations had been found previously.

Genomic DNA from eight affected and three healthy individuals from the VWS Finnish family underwent SureSelect Target Enrichment (Agilent Technologies, Santa Clara, CA, USA) in order to perform sequence capture of the exome. Enriched samples were sequenced on an Illumina HiSeq instrument (San Diego, CA, USA). Genotyping, mutation screening by Sanger sequencing, phenotyping, and other studies were also performed. The authors conclude that both genes are required for a proper formation of the palate, probably functioning in separate but convergent molecular pathways. The study highlights the importance of studying even rare patients to increase our understanding of disease mechanisms.

Myriam Peyrard-Janvid, PhD, the senior author of the study said, “The discovery of a new gene, GRHL3, responsible for the most common of the syndromic forms of cleft lip and palate means that clinicians with collections of families or isolated cases with cleft lip and palate, syndromic or non-syndromic, now will be able to look for mutations in this gene. As it has been shown for IRF6, one or several polymorphisms in GRHL3 might be found to be associated with increased risk of clefts in nonsyndromic cases.” The study was published on December 19, 2013, in the American Journal of Human Genetics.

Related Links:
Karolinska Institute
Agilent Technologies
Illumina