IRF6-Related Disorders via the IRF6 Gene

IRF6-related disorders span a spectrum from isolated cleft lip and palate and Van der Woude syndrome (VWS; OMIM#119300) at the mild end to popliteal pterygium syndrome (PPS; OMIM 119500) at the more severe end. Anomalies found in individuals with VWS include congenital, usually bilateral, paramedian lower-lip fistulae (pits), cleft lip (CL), and cleft palate (CP). The PPS phenotype includes CL/CP, fistulae of the lower lip, webbing of the skin extending from the ischial tuberosities to the heels, bifid scrotum and cryptorchidism in males, hypoplasia of the labia majora in females, syndactyly of fingers or toes, and anomalies of the skin around the nails. Filiform synechiae may connect the upper and lower jaws (syngnathia) or the upper and lower eyelids (ankyloblepharon). A characteristic pyramidal fold of skin overlying the nail of the hallux is almost pathognomonic (Durda et al. GeneReviews 2011). In both VWS and PPS, growth and intelligence are normal.

Van der Woude syndrome (VWS) and popliteal pterygium syndrome (PPS) are inherited in an autosomal dominant manner. Most individuals with these two conditions have an affected parent; however, penetrance is incomplete and de novo variants have been reported. IRF6 is the only gene currently known to be associated with VWS and PPS. IRF6 encodes interferon regulatory factor 6, the function of which is currently unknown. However, IRF6 protein belongs to the interferon regulatory factor family of transcription factors. The IRFs are best known to regulate the expression of interferon-alpha and interferon-beta after viral infection (Taniguchi et al. Annu Rev Immunol 19:623-655, 2001). This protein family shares a highly-conserved helix-loop-helix DNA binding domain and a less well-conserved protein binding domain. Missense, nonsense, and frameshift variants as well as gross deletions in IRF6 have been reported to cause disease. The variants in individuals with VWS are consistent with haploinsufficiency. Those missense variants causing VWS are localized to the regions encoding the DNA binding domains (exons 3-4) and the protein binding domain (exons 7-9) and most likely result in loss of function. The variants in many individuals with PPS are localized to the DNA binding domain, which are predicted to abrogate DNA binding and likely have a dominant-negative effect on the protein function (Escalante et al. Nature 391:103–106, 1998; Kondo et al. Nat Genet 32:285–289, 2002; de Lima et al. Genet Med 11:241–247, 2009).

This test is predicted to detect disease variants in about 70% of individuals with the VWS and 97% of individuals with the PPS (Durda et al. 2011).

This test provides full coverage of all coding exons of the IRF6 gene 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 full 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).