Clinical Guidance

VWS. Whole-gene deletions and nearly all protein truncation variants cause a VWS phenotype. Missense variants that cause VWS are evenly divided between the two protein domains encoded in exons 3, 4, and 7-9. Two pathogenic missense variants at arginine 84, and , are found only in individuals with VWS, suggesting that p.Arg84Gly and p.Arg84Pro differ from and (which are seen most commonly in PPS) in their effect on IRF6 protein function. PPS. Most PPS-associated variants are missense (78%) and are located in exon 4 (72%). It appears likely that certain pathogenic variants (, ) are more apt to cause PPS than VWS. A cluster of pathogenic missense variants in the DNA binding domain that are predicted to directly contact the DNA are more commonly seen in families with PPS (p0.

Source: GeneReviews — "IRF6-Related Disorders"

Penetrance

IRF6-related disorders have high, but incomplete, penetrance. VWS. A citation list search and manual search of Index Medicus starting from 1965 revealed data on 864 affected individuals in 164 families reported since first observed VWS. Based on these data, penetrance was estimated at 92% . PPS. Of approximately 40 pedigrees with individuals diagnosed with PPS, there were no instances of incomplete penetrance.

Source: GeneReviews — "IRF6-Related Disorders"

Diagnostic Criteria

Suggestive Findings Van der Woude syndrome (VWS) • Lip pits* in combination with one of the following: • Cleft lip with or without cleft palate (CL±P) • Cleft palate (CP) • Submucous cleft palate (SMCP) • Lip pits* alone and a first-degree relative with CL±P, CP, or SMCP • CL±P, CP, or SMCP and a first-degree relative with lip pits* • CL or CL+P and CP in the same family * Lip pits are most often paramedian on the lower lip, and can include mounds with a sinus tract leading from a mucous gland of the lip. Popliteal pterygium syndrome (PPS) • Popliteal pterygia • Syndactyly • Abnormal external genitalia • Ankyloblepharon • Pyramidal skin on the hallux • A spectrum of intraoral adhesions, the most severe of which is complete syngnathia • Musculoskeletal anomalies are rarely reported (e.g., talipes equinovarus, digital reduction, spina bifida occulta, bifid ribs, short sternum). IRF6-related neural tube defect. Two individuals with an IRF6 pathogenic variant and spina bifida have been reported. Neural tube defects due to an IRF6 pathogenic variant cannot be clinically distinguished from neural tube defects of other etiologies. IRF6-related orofacial cleft. Eighteen individuals with an IRF6 pathogenic variant and orofacial cleft have been reported. Orofacial cleft due to an IRF6 pathogenic variant cannot be clinically distinguished from orofacial clefts of other etiologies. Establishing the Diagnosis The diagnosis of an IRF6-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in IRF6 identified by molecular genetic testing . Molecular genetic testing approaches include single-gene testing or a multigene panel. • Single-gene testing. Sequence analysis of IRF6 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants; analysis of the IRF6 regulatory region should be included . Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. • A multigene panel that includes sequence analysis and gene-targeted deletion/duplication analysis of IRF6 , GRHL3, and other genes of interest is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here. Table 1. Molecular Genetic Testing Used in IRF6-Related Disorders

Source: GeneReviews — "IRF6-Related Disorders"

Differential Diagnosis

Table 3. Genes of Interest in the Differential Diagnosis of IRF6-Related Disorders

Management Guidelines

No clinical practice guidelines for IRF6-related disorders have been published. Individuals with a cleft lip and/or palate should be evaluated and treated by a multidisciplinary team of craniofacial specialists. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with an IRF6-related disorder, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with IRF6-Related Disorders

Source: GeneReviews — "IRF6-Related Disorders"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "IRF6-Related Disorders"

Surveillance Guidelines

The following surveillance guidelines are adapted from the parameters for evaluation and treatment of individuals with cleft lip/palate or other craniofacial anomalies. Click here for full text.

Table 6.

Recommended Surveillance for Individuals with IRF6-Related Disorders

System/Concern | Evaluation | Frequency

Cleft lip/palate

| Assessment of nutritional intake weight gain | Weekly during 1st mo of life

Otolaryngologic eval | • Follow-up eval w/in 1st 6 mos of life

• Continue evals throughout adolescence.

Audiologic eval | • Follow-up eval w/infant's 1st visit to cleft clinic

• Timing frequency of follow-up evals based on person's history of ear disease or hearing loss

• Routine evals through adolescence

Speech-language pathology eval | • Follow up by age 6 mos for assessment of prelinguistic speech-language development

• During 1st 2 yrs of life, evaluate children at least twice, then at least annually until adenoid involution.

• After adenoid involution, evaluate at least every 2 yrs until dental skeletal maturity.

Dental eval | • Follow-up eval w/in 6 mos of 1st tooth erupting; no later than age 12 mos

• Continue routine dental eval throughout life.

Neural tube

defect | Assess walking/ mobility bowel/ bladder mgmt | At each visit throughout life in those w/history of meningocele or myelomeningocele

Source: GeneReviews — "IRF6-Related Disorders"