Associated disorders

The IRF6 gene is associated with autosomal dominant popliteal pterygium syndrome (MedGen UID: 78543) and autosomal dominant van der Woude syndrome (MedGen UID:61233). Additionally, the IRF6 gene has preliminary evidence supporting a correlation with non-syndromic orofacial cleft (MedGen UID: 332391).

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Interferon regulatory transcription factor 6 (IRF6) is a member of a family of transcription factors with a conserved helix-turn-helix DNA binding domain and a C-terminal protein domain that is not conserved. IFR6 may regulate transcription of WD-repeat domain 65 gene (WDR65) and thereby affect craniofacial development.


Clinical condition
IRF6 is the causative gene for many cases of PPS and VDWS.

Patients with PPS most often exhibit clefting, popliteal pterygia, syndactyly, and intra-oral adhesions. Some patients also have abnormalities of the genitalia. 97% of individuals with PPS have a heterozygous pathogenic variant in IRF6 (PMID: 19282774).

Patients with VDWS most commonly have cleft lip with or without cleft palate, isolated cleft palate, or a submucous cleft palate with the finding of lip pits. VDWS is an autosomal dominant disorder with clinical variability. 15% of VDWS patients do not have lip pits. 72% of individuals with VDWS have a heterozygous pathogenic variant (2% del/dup). In both VDWS and PPS, affected individuals do not have motor delay or intellectual deficits (PMID: 20301581).

If VDWS patient is negative for IRF6, GHRL3 should be considered. 17% of individuals with clinical features of VDWS who test negative for a IRF6 variant have a pathogenic variant in GRHL3 (PMID: 24360809).

Differential diagnosis
Many patients with Kabuki syndrome (KS) have cleft palate and some have lip pits. In contrast to VDWS, most individuals with KS have distinctive facial features and intellectual disability. The causative genes for KS are KMT2D and KDM6A. If testing with Invitae, these genes can be added to an order when clinically relevant.

Gene information
IRF6 disorders have high but incomplete penetrance. The IRF6 gene encodes a protein transcription factor that plays a role in the early development of tissues in the head, face, skin, and genitals. A large variety of pathogenic changes have been described in IRF6, including exonic deletions. The Invitae Van Der Woude Panel includes full gene sequencing and deletion/duplication testing of IRF6 and GHRL3 in a single test.

IRF6 related disorders exhibit clinical variability and high but incomplete penetrance. The disorders are inherited in an autosomal dominant fashion. Recurrence risk to affected individuals is 50%.

Individuals affected with the clefting manifestations of VDWS are closely followed for feeding issues and weight gain in the first few weeks or months of life. Surgical repair of the clefts are done with multidisciplinary teams of surgeons, dentists, orthodontists, otolaryngologists, speech pathologists, and audiologists. Individuals with PPS are also seen by orthopedists, physical therapists and occupational therapists to address issues involving the pterygia and syndactyly. For some individuals with abnormal genitalia, further evaluations are necessary.

Review Date: April 2016

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
IRF6 NM_006147.3