Van der Woude Syndrome Panel

Van der Woude syndrome (VWS) is the most common form of syndromic orofacial cleft and is frequently associated with pathogenic variants in the IRF6 and GRHL3 genes. Although VWS is a highly penetrant disorder, expressivity is variable even within families. Individuals may present with lower-lip fistulae (pits), cleft lip, cleft palate, cleft uvula or a combination thereof (Angiero et al. 2018. PubMed ID: 29569458). Anodontia and hypodontia (partial anodontia) has also been reported (Lam et al. 2010. PubMed ID: 20415912). In addition, pathogenic variants in the IRF6 gene are reported to be associated with popliteal pterygium syndrome, a severe syndromic form of orofacial cleft accompanied by skin, genitourinary and skeletal features (Schutte et al. 2014. PubMed ID: 20301581).

Pathogenic variants associated with VWS may be inherited in an autosomal dominant (AD) manner, or arise de novo (Peyrard-Janvid et al. 2005. PubMed ID: 16160700; Peyrard-Janvid et al. 2014. PubMed ID: 24360809). VWS is frequently associated with pathogenic missense variants, as well as loss-of-function and copy number variants in the IRF6 gene (Peyrard-Janvid et al. 2005. PubMed ID: 16160700; Manjegowda et al. 2014. PubMed ID: 25579819). IRF6 encodes the interferon regulatory factor 6 protein. This protein is a transcription factor that is expressed in the palatal shelves in the developing embryo (Kondo et al. 2002. PubMed ID: 12219090). This protein is also expressed in the hair follicles, palatal rugae, tooth germ and thyroglossal duct, external genitalia, and skin. Pathogenic missense variants associated with VWS typically localize to the conserved IRF6 winged-helix DNA-binding domain (exons 3 and 4) or the IRF6 SMIR/IAD protein-binding domain (exons 7 through 9), and result in haploinsufficency (Kondo et al. 2002. PubMed ID: 12219090).

Pathogenic variants in the GRHL3 gene are the second most frequent cause of VWS. Pathogenic missense and loss of function variants in GRHL3 are associated with VWS and orofacial cleft phenotypes (Peyrard-Janvid et al. 2014. PubMed ID: 24360809). To date, no pathogenic copy number variants have been reported in GRHL3. GRHL3 encodes the drosophila grainyhead (grh) protein. This protein is also a transcription factor that is expressed in the developing embryo (Ting et al. 2003. PubMed ID: 12549979).

Approximately 70% of cases of Van der Woude syndrome (VWS) may be explained by pathogenic variants in the IRF6 gene (Desmyster et al. 2010. PubMed ID: 21045959). An additional 6% of cases of VWS may be explained by pathogenic variants in the GRHL3 gene (Peyrard-Janvid et al. 2014. PubMed ID: 24360809).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes listed plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).