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IRF6-Related Disorders

Includes: Popliteal Pterygium Syndrome (PPS), Van der Woude Syndrome (VWS)

, MS, , PhD, and , MD.

Author Information
, MS
Pediatrics Department
University of Iowa
Iowa City, Iowa
, PhD
Department of Microbiology and Molecular Genetics
Department of Pediatrics and Human Development
Michigan State University
East Lansing, Michigan
, MD
Pediatrics Department
University of Iowa
Iowa City, Iowa

Initial Posting: ; Last Update: March 1, 2011.

Summary

Disease characteristics. IRF6-related disorders span a spectrum from isolated cleft lip and palate and Van der Woude syndrome (VWS) at the mild end to popliteal pterygium syndrome (PPS) at the more severe end. Individuals with VWS show one or more of the following anomalies:

  • Congenital, usually bilateral, paramedian lower-lip fistulae (pits) or sometimes small mounds with a sinus tract leading from a mucous gland of the lip
  • Cleft lip (CL)
  • Cleft palate (CP)

Both cleft types — cleft lip with or without cleft palate (CL±P) and CP only — occur in individuals with VWS in the same proportions as in the general population, about two to one respectively.

The PPS phenotype includes CL±P, 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 and/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.

In both phenotypes, growth and intelligence are normal.

Diagnosis/testing. Diagnosis is based on clinical findings. Mutations in IRF6 are known to be associated with IRF6-related disorders. Genetic variants in IRF6 contribute risk for isolated cleft lip and palate. Sequence analysis detects mutations in approximately 72% of individuals with the Van der Woude syndrome phenotype and approximately 74% of individuals with the popliteal pterygium syndrome phenotype.

Management. Treatment of manifestations: Supportive/symptomatic treatment may include surgery, orthodontia, speech therapy, feeding and hearing evaluation, physical therapy, and orthopedic care.

Genetic counseling. IRF6-related disorders are inherited in an autosomal dominant manner. Most individuals diagnosed with an IRF6-related disorder have an affected parent; however, penetrance is incomplete and de novo mutations have been reported. The risk to the sibs of the proband depends on the genetic status of the proband's parents. If a parent of the proband is affected or has an IRF6 mutation, the risk to the sibs of inheriting the mutation is 50%. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing allele in the family member is known. Prenatal ultrasound examination may detect a cleft lip in some fetuses later in pregnancy, but it is less likely to detect a cleft palate or lip pits.

Diagnosis

Clinical Diagnosis

IRF6-related disorders span a spectrum from isolated cleft lip and palate and Van der Woude syndrome (VWS) at the mild end to popliteal pterygium syndrome (PPS) at the more severe end.

To make the diagnosis of Van der Woude syndrome, at least one of the following findings must be present:

  • Lip pits and cleft lip AND/OR palate (CLP). Lip pits must be paramedian on the lower lip, and can include mounds with a sinus tract leading from a mucous gland of the lip.
  • Lip pits alone and a first-degree relative with CLP
  • CLP and a first-degree relative with lip pits

Note: Presence of psychomotor delay does not exclude Van der Woude syndrome or popliteal pterygium syndrome and suggests the presence of a microdeletion involving 1q32.2; however, microdeletions are an uncommon cause of Van der Woude syndrome and popliteal pterygium syndrome. Furthermore, psychomotor delay (observed in multiple family members in only 1 of >350 reported families studied) may be the result of an unrelated cause [Sander et al 1994].

To make the diagnosis of popliteal pterygium syndrome, an individual must have one or more of the following in addition to features of Van der Woude syndrome listed above:

  • Popliteal pterygia
  • Syndactyly
  • Abnormal external genitalia
  • Ankyloblepharon
  • Pyramidal skin on the hallux
  • Intraoral adhesions

Molecular Genetic Testing

Gene. Mutations in IRF6 are known to be associated with Van der Woude syndrome and popliteal pterygium syndrome. Genetic variants in IRF6 contribute risk for isolated cleft lip and palate.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in IRF6-Related Disorders

Gene SymbolPhenotypeTest MethodMutations DetectedMutation Detection Frequency by Test Method 1, 2
IRF6VWSSequence analysis Sequence variants 3 in exons 1-9~72%
Deletion / duplication analysis 4Exonic, multiexonic, and whole-gene deletions 5<2% (7/448)
PPSSequence analysis of select exonsSequence variants 3 in exon 4~74%
Deletion / duplication analysis 4Exonic, multiexonic, and whole-gene deletions 5Unknown 6

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Schutte & Murray [personal communication]

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. Extent of deletions detectable may vary by method and by laboratory.

6. Unknown, but likely rare because causative mutations were identified on sequence analysis in 7/7 individuals by Schutte et al [1999] and in 36/37 individuals by de Lima et al [2009].

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

To confirm/establish the diagnosis in a proband

  • Van der Woude syndrome should be considered in every child born with an orofacial cleft and clinical evaluation by a medical geneticist is generally performed to document all relevant clinical findings. In addition, the parents should be examined for isolated lip pits, submucous cleft palate, and hypodontia.
  • In families in which lip pits are present in at least one family member, molecular genetic testing of IRF6 is appropriate.

    Note: Since lip pits are not present in15% of persons with VWS, it is possible that rare individuals with a de novo IRF6 mutation will not have lip pits or a family member with lip pits.
  • Sequence analysis of IRF6 is performed first. If no mutation is identified, deletion/duplication analysis can be considered.
  • Presence of cleft lip (CL) or cleft lip and palate (CL+P) together with cleft palate (CP) only in the same family should also suggest VWS and should prompt a close search for lip pits and consideration of molecular genetic testing even in the absence of these physical findings. In "mixed" families in which some members have cleft palate only and others have clefts of the lip with/without cleft palate, MSX1 molecular genetic testing would be an additional consideration if molecular genetic testing does not identify an IRF6 mutation [van den Boogaard et al 2000]. (See Differential Diagnosis.)

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

The craniofacial features of popliteal pterygium syndrome (PPS) and Van der Woude syndrome (VWS) form a continuum such that it is often difficult to distinguish between mildly affected individuals with PPS and those with VWS [Bixler et al 1973, Soekarman et al 1995, Lees et al 1999, Kondo et al 2002].

Van der Woude syndrome. Individuals with VWS show one or more of three anomalies: congenital, usually bilateral, paramedian lower-lip fistulae (pits) or sometimes small mounds with a sinus tract leading from a mucous gland of the lip; cleft lip (CL); or cleft palate (CP) [Van der Woude 1954].

Van der Woude [1954] observed that 27% of the offspring of affected parents had lip fistulae alone and 21% had fistulae associated with CL and/or CP. Burdick et al [1985] gathered information on 864 affected individuals from 164 families. In this population, 44% had lip pits only, 37% had cleft lip (with/without lip pits and with/without cleft palate), 16% had cleft palate only (with/without lip pits), and 3% had no apparent phenotype. Overall, lip pits were observed in 86% of affected individuals.

Both cleft types, cleft lip with or without cleft palate (CL±P) and CP only, occur in individuals with VWS in the same proportions as in the general population, about two to one respectively [Burdick et al 1987]. The IRF6-related disorders are especially interesting as it is unusual for a single syndrome or genetic disorder to include both types of clefting. This type of mixed clefting can also occur with mutation of MSX1 [van den Boogaard et al 2000] and FGFR1.

The sex ratio is nearly equal in VWS for CP and CL±P, as well as for the presence of lip pits. It was also noted that CL±P and CP co-occur both vertically and horizontally in pedigrees. Forty percent of families with at least three affected individuals have both forms of clefting; in those, 75% have both forms of clefting in sibs.

Oberoi & Vargervik [2005] suggest that individuals with VWS are more likely to have hypoplasia of the mandible and maxilla than isolated cases with the same cleft phenotype.

Non-classic forms of the VWS phenotype that have been described [Soricelli et al 1966, Ranta et al 1983, Ranta & Rintala 1983, Schinzel & Klausler 1986, Burdick et al 1987, Kantaputra et al 2002] include:

  • Conical elevations (CE) of the lip
  • Single unilateral lip pits
  • Bulges located below the vermilion border
  • Hypodontia
  • Submucous cleft
  • Bifid uvula
  • Ankyloglossia
  • Limb abnormalities
  • Hearing loss

Growth and intelligence are normal. The single exception is a family in which affected individuals have developmental delay and a large contiguous gene deletion that spans IRF6 [Sander et al 1994]. Rarely developmental delay may be presumed to be unrelated in a family that also segregates VWS [Zechi-Ceide et al 2007]. In two other families, individuals with large deletions have normal intelligence [Schutte et al 1999, Kayano et al 2003]. In one of the latter cases, the deletion is even larger than the deletion described by Sander et al [1994], suggesting that developmental delay in the family of Sander et al [1994] is not related to deletion of IRF6.

In a recent small study, Jones et al [2010] found that following surgery for their clefts, eight (47%) of 17 individuals with VWS had wound complications compared to 13 (19%) of 68 individuals with nonsyndromic cleft lip and/palate (NSCLP).

Popliteal pterygium syndrome. The PPS phenotype includes cleft lip and/or palate (91%-97% of individuals); fistulae of the lower lip (45.6% [Froster-Iskenius 1990]); 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 and/or toes, and anomalies of the skin around the nails [Lewis 1948, Rintala et al 1970]. A characteristic pyramidal fold of skin overlying the nail of the hallux is almost pathognomonic.

Filiform synechiae may connect the upper and lower jaws (syngnathia) or the upper and lower eyelids (ankyloblepharon).

Growth and intelligence are normal.

Genotype-Phenotype Correlations

Van der Woude syndrome. Whole-gene deletions and nearly all protein truncation mutations cause a VWS phenotype. Missense mutations that cause VWS are evenly divided between the two protein domains encoded in exons 3, 4, and 7-9. Two missense mutations at arginine 84, p.Arg84Gly [Item et al 2005] and p.Arg84Pro [de Lima et al 2009], are found only in individuals with VWS, suggesting that p.Arg84Gly and p.Arg84Pro affect IRF6 function differently from p.Arg84His and p.Arg84Cys, which are seen most commonly in PPS.

Popliteal pterygium syndrome. Most missense mutations that cause PPS are located in exon 4.

It appears likely that certain mutations (p.Arg84His, p.Arg84Cys) are more apt to cause PPS than VWS. A cluster of missense mutations in the DNA binding domain are more commonly seen in families with PPS (p<0.01; e.g., p.Trp60, p.Lys66, p.Gln82, p.Arg84, p.Lys89). However, families may include individuals with features of only VWS and other members with the additional features of PPS.

Penetrance

Murray et al [personal communication] note that about 70% of individuals with an IFR6 mutation have an orofacial cleft requiring surgical intervention

Van der Woude syndrome. Additional studies have supported Van der Woude's observation of dominant inheritance with variable expressivity and high, but incomplete, penetrance [Cervenka et al 1967, Janku et al 1980, Shprintzen et al 1980, Burdick et al 1985]. In the most current and extensive literature review of VWS [Burdick et al 1985], a citation list search and manual search of Index Medicus starting from 1965 revealed data on 864 affected individuals in 164 families reported since Demarquay [1845] first observed VWS. Based on these data, penetrance was estimated at 92% [Burdick et al 1985].

Lip pit phenotype. The penetrance of the lip pit phenotype is estimated at 86%.

Prevalence

Van der Woude syndrome. VWS represents the most common single-gene cause of cleft lip and cleft palate, accounting for about 2% of all individuals with CL+P [Cohen & Bankier 1991, Murray et al 1997] or roughly one in 35,000 to one in 100,000 in the European and Asian populations [Cervenka et al 1967, Rintala & Ranta 1981, Burdick 1986].

Popliteal pterygium syndrome. A prevalence of approximately one in 300,000 has been suggested [Froster-Iskenius 1990].

Differential Diagnosis

Pits of the lower lip similar to those seen in VWS also occur in the following disorders:

Van der Woude syndrome should be considered in every child born with an orofacial cleft, even in the absence of lip pits, and the parents should be examined for isolated lip pits, submucous cleft palate, and hypodontia. Because lip pits are absent in 15% of persons with VWS it is possible to find a person with a de novo IRF6 mutation and no lip pits. Jehee et al [2009] found a likely disease-causing mutation in IRF6 in two small families in which no lip abnormality was reported.

Isolated CLP. Ranta & Rintala [1983] examined the lower lips of 397 children with CP, 518 with CL+P, and 1000 with no cleft phenotype. In addition to lip pits in these groups, 39.3% of CP, 0.8% of CL+P, and 0.7% of noncleft cases had conical elevations (CE) of the lower lip [Ranta & Rintala 1983]. The finding was interesting in that the familial occurrence of clefts among those in the CP group with CE (30%) was statistically higher than in those without them (20.7%). In addition, the incidence of hypodontia was significantly higher among 251 children with CP and CE (40%) than in those without them (25%) [Ranta et al 1983]. In all, 56% of children with CP had an associated hypodontia or CE phenotype. It is unknown how many of these may represent an IRF6-related disorder.

Mixed clefting (cleft lip with or without cleft palate (CL±P) and CP only). The mixed clefting seen in IFR6-related disorders can also occur with disorders caused by mutations in MSX1 [van den Boogaard et al 2000], TP63, and FGFR1. Although lip pits are absent in these disorders, they lack sufficient additional features to exclude VWS without lip pits [van den Boogaard et al 2000, Dode et al 2003, Jezewski et al 2003]. These disorders should be considered in evaluating any family in which multiple members have orofacial clefts.

Wong et al [2001] described a family in which ten of 11 affected family members had CP and one had cleft lip and palate; only one of the 11 affected individuals clinically examined had lip pits. Two of the affected individuals had a "wave-like" lower lip in addition to CP. Although the authors suggested that this could be a novel finding of VWS, linkage to IRF6 at 1q32-q41 was excluded (multipoint lod scores < -13.0 for markers across this region). The locus was subsequently mapped to a 30-cM region on the short arm of chromosome 1 in 1p32-p36 [Koillinen et al 2001].

Ankyloblepharon. Ankyloblepharon (or eyelid synechiae) present at birth are seen occasionally in PPS. These may also be seen in ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, Rapp-Hodgkin syndrome (OMIM 129400), ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 1 (OMIM 129900), curly hair-ankyloblepharon-nail dysplasia syndrome (OMIM 214350), and trisomy 18.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to these disorders, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with an IRF6-related disorder, the following evaluations are recommended:

  • Individuals diagnosed with VWS should be evaluated for the characteristic features of PPS: webbing behind the knee, syndactyly of the toes, and the pyramidal skin-fold on the nail of the hallux.
  • Feeding and hearing should be evaluated.

Treatment of Manifestations

Individuals with a cleft lip and/or palate should be evaluated and treated by a multidisciplinary team of specialists. The American Cleft Palate-Craniofacial Association [1993] has published parameters for evaluation and treatment of patients with cleft lip/palate or other craniofacial anomalies that can guide treatment of these patients [revised 2009]. Click Image guidelines.jpg for full text.

Management is supportive/symptomatic.

  • Cleft lip. Management is surgical and orthodontic.
  • Cleft palate. In addition to surgery and orthodontics, speech therapy and audiologic evaluation are usually needed.
  • Lip pits. Surgery may be indicated for cosmetic purposes or for lip function.
  • Popliteal pterygium. Management is surgical and orthopedic.
  • Eyelid synechiae (ankyloblepharon) may require surgical removal.
  • Abnormal genitalia rarely require surgery but may result in infertility.
  • Syndactyly may require surgery.
  • Orthopedic care and physical therapy may be needed.

Prevention of Secondary Complications

Timely treatment of otitis media secondary to cleft palate is indicated to prevent secondary hearing loss. Some individuals may have pressure-equalizing tubes placed.

Evaluations by a speech-language pathologist can aid in determining if speech therapy or other interventions are appropriate for a child with secondary hearing loss.

Surveillance

The following surveillance guidelines are adapted from the American Cleft Palate-Craniofacial Association [1993] parameters for evaluation and treatment of patients with cleft lip/palate or other craniofacial anomalies [revised 2009]. Click Image guidelines.jpg for full text.

Neonatal period and infancy

  • Weekly assessment of nutritional intake and weight gain during the first month of life
  • Otolaryngologic evaluation
  • Audiologic evaluation
  • Assessment of prelinguistic speech-language development
  • Dental evaluation
  • Consultation with other specialists as applicable

Longitudinal evaluation and treatment

  • Audiologic evaluation as soon as possible in a neonate and again at the time of an infant’s first visit to the Cleft Clinic. The timing and frequency of follow-up evaluations should be based on the individual’s history of ear disease or hearing loss. These evaluations should be carried out routinely through adolescence.
  • Dental evaluation at an infant’s first visit to the Cleft Clinic and within six months of the first tooth erupting, no later than age 12 months. Routine dental evaluation should continue throughout life.
  • Otolaryngologic evaluation at an infant’s first visit to the Cleft Clinic and within the first six months of life. These evaluations should continue throughout adolescence.
  • Speech-language pathology evaluation at an infant’s first visit to the Cleft Clinic to provide parents with information about speech and language development. By age six months, infants should be seen for assessment of prelinguistic speech-language development. During the first two years of life, children should be evaluated at least twice, and then at least annually until age six years. After age six years, evaluations should be at least annually until after adenoid involution, and then at least every two years until dental and skeletal maturity.
  • Consultation with other specialist as applicable

Evaluation of Relatives at Risk

Offspring and/or sibs of an affected individual should be clinically examined for evidence of cleft palate including submucous cleft, given the reduced penetrance of VWS.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

IRF6-related disorders are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with an IRF6-related disorder have an affected parent. However, penetrance is incomplete.
  • A proband with an IRF6-related disorder may have the disorder as the result of a de novo mutation.
    • In a study of 16 families with VWS and one family with PPS, the single affected individual in each of two families with VWS had de novo IRF6 mutations [Peyrard-Janvid et al 2005].
    • A female born with ankyloblepharon and lip pits, diagnosed as a mild form of PPS, had a de novo mutation [Houweling et al 2009].
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include physical examination of both parents with special attention to evaluation for lip pits and/or clefts, especially submucous clefts that may be asymptomatic, and molecular genetic testing if the family-specific mutation is known.

Note: Although most individuals diagnosed with an IRF6-related disorder have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members or incomplete penetrance.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected or has an IRF6 mutation, the risk to the sibs of inheriting the mutation is 50%. Approximately 92% of individuals with an IRF6 mutation manifest the phenotype [Burdick et al 1985]. About 70% of individuals with a mutation have an orofacial cleft requiring surgical intervention [Murray, personal communication]. However, the clinical manifestations of IRF6-related disorders are variable and cannot be predicted in the sibs.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low but the possibility of incomplete penetrance in a parent or of germline mosaicism needs to be considered.
  • If a disease-causing mutation found in the proband cannot be detected in the DNA extracted from the leukocytes of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband.

Offspring of a proband. Each child of an individual with an IRF6 mutation has a 50% chance of inheriting the mutation. The clinical manifestations of IRF6-related disorders are variable and cannot be predicted in the offspring.

Other family members. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has an IRF6 mutation, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of transmitting the disorder.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Ultrasound examination. Prenatal ultrasound examination may detect a cleft lip later in pregnancy, but it is less likely to detect a cleft palate or lip pits. A level 2 targeted ultrasound examination at a center that routinely performs such procedures is most accurate.

Requests for prenatal testing for conditions such as IRF6-related disorders are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate. Prenatal testing may provide the benefit of preparing the parents and family for a child with a facial difference or disability. However, the clinical manifestations of IRF6-related disorders are variable and cannot be predicted in the offspring.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Canada
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
    Email: info@aboutfaceinternational.org
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free); 214-570-9099
    Fax: 214-570-8811
    Email: contactCCA@ccakids.com
  • Cleft Palate Foundation (CPF)
    1504 East Franklin Street
    Suite 102
    Chapel Hill NC 27514-2820
    Phone: 800-242-5338 (toll-free); 919-933-9044
    Fax: 919-933-9604
    Email: info@cleftline.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. IRF6-Related Disorders: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
IRF61q32​.2Interferon regulatory factor 6IRF6 homepage - Mendelian genesIRF6

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for IRF6-Related Disorders (View All in OMIM)

119300VAN DER WOUDE SYNDROME 1; VWS1
119500POPLITEAL PTERYGIUM SYNDROME; PPS
607199INTERFERON REGULATORY FACTOR 6; IRF6

Molecular Genetic Pathogenesis

Further functional analyses to identify downstream target genes and interacting proteins is important to the understanding of the role of IRF6 in palatal development, especially given the overlap of murine Irf6 expression at the medial edge of the palatal shelves immediately before and during fusion with that of murine Tgfb3 and the proposed role of the SMIR domain of IRF6 in mediating interactions between IRFs and Smads, a family of transcription factors known to transduce TGF-beta signals [Fitzpatrick et al 1990, Brivanlou & Darnell 2002].

Normal allelic variants. There are nine exons and eight introns. Two common SNPs were found in the coding sequence for IRF6: c.459G>T (p.Ser153Ser), c.820G>A (p.Val274Ile). Rare variants found in unaffected controls include c.9C>T (p.Leu3Leu), c.55G>A (p.Asp19Asn), c.181C>G (p.Ala61Pro), c.339G>T (Val113Val), c.671C>T (p.Thr224Ser), c.726C>T (p.Thr242Thr), and c.1153T>C (p.Leu385Leu) [de Lima et al 2009].

Pathologic allelic variants. Protein truncation (nonsense and frameshift) mutations, missense mutations, and whole-gene deletions are known to cause disease. Mutations have now been identified in more than 334 of 448 families with VWS and PPS, representing 229 different alleles [Sander et al 1994, Schutte et al 1999, Kondo et al 2002, Kayano et al 2003, Kim et al 2003, Shotelersuk et al 2003, Wang et al 2003, Gatta et al 2004, Ghassibe et al 2004, Kantaputra et al 2004, Matsuzawa et al 2004, Item et al 2005, Mostowska et al 2005, Peyrard-Janvid et al 2005, Wang et al 2005, Ye et al 2005, Du et al 2006, Brosch et al 2007, Birnbaum et al 2008, de Medeiros et al 2008, Osoegawa et al 2008, Tan et al 2008, de Lima et al 2009, Jehee et al 2009, Yeetong et al 2009, Desmyter et al 2010, Ferrero et al 2010, Matsuzawa et al 2010].

Table 2. Selected IRF6 Allelic Variants

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change
(Alias 12
Reference Sequences
Normalc.820G>Ap.Val274Ile 3NM_006147​.2
NP_006138​.1
c.9C>Tp.=
(Leu3Leu)
c.55G>Ap.Asp19Asn
c.181G>Cp.Ala61Pro
c.339G>Tp.=
(Val113Val)
c.671C>Gp.Thr224Ser
c.711C>Tp.=
(T237T)
c.726C>Tp.=
(T242T)
c.1153T>Cp.=
(L385L)
Pathologicc.250C>Gp.Arg84Gly 4
c.251G>Cp.Arg84Pro 5
c.251G>Ap.Arg84His 5
c.250C>Tp.Arg84Cys 5

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. p.= indicates that protein has not been analyzed, but no change is expected.

3. Some evidence suggests an association with isolated CLP.

4. Seen only in individuals with VWS

5. Most commonly seen in individuals with PPS

Normal gene product. The function of the normal gene product of IRF6 is currently unknown. However, IRF6 protein belongs to the interferon regulatory factor family of transcription factors. This protein family shares a highly conserved helix-loop-helix DNA binding domain (amino acids 13-113) and a less well-conserved protein binding domain (amino acids 226-394). The DNA binding domain contains a unique penta-tryptophan motif. The IRFs form homo- and heterodimers through the protein binding domain, called IRF association domain (IAD). This domain is also called the SMIR (SMAD/IRF) domain because the secondary structure of this protein binding domain is shared in the two families [Eroshkin & Mushegian 1999]. Most IRFs, including IRF6, are broadly, but not ubiquitously, expressed. The expression of IRF4 and IRF8 is restricted to hematopoietic cells.

The IRFs are best known to regulate the expression of interferon-alpha and interferon-beta after viral infection [Taniguchi et al 2001]. Following a viral infection, the latent IRF proteins in the cytoplasm are activated by multiple phosphorylation events at serine residues in the C terminus. They form homo- and heterodimers, accumulate in the nucleus, bind to the promoters of the interferon and interferon-stimulated genes, and are active in transcription [Lin et al 1998].

Mouse knockout studies support the role for Irf1, Irf2, Irf3, Irf4, Irf5, Irf7, Irf8, and Irf9 in the immune response, and none of these mutant strains has embryologic abnormalities [Matsuyama et al 1993, Holtschke et al 1996, Kimura et al 1996, Mittrucker et al 1997, Sato et al 2000, Honda et al 2005, Takaoka et al 2005]. However, IRF1, IRF2, IRF3, IRF4, and IRF7 also regulate cell growth or arrest [Iida et al 1997, Harada et al 1998, Heylbroeck et al 2000, Zhang & Pagano 2002]. Although IRF6 was identified as a homolog of IRF4, which is required for B- and T-cell development and homeostasis [Mittrucker et al 1997], its function in immune response remains unknown. Mice deficient for Irf6 have abnormal skin, limb, and craniofacial development [Ingraham et al 2006, Richardson et al 2006].

Abnormal gene product. The mutations in individuals with VWS are consistent with haploinsufficiency. The missense mutations that cause VWS localize to the regions encoding the DNA binding domains (exons 3 and 4) and the protein binding domain (exons 7, 8, and 9) and most likely result in loss of function.

The mutations found in many individuals with PPS are highly localized to amino acid residues in the DNA binding domain (exons 3 and 4). Based on structural similarity to IRF1 [Escalante et al 1998], these residues (including p.Trp60, p.Lys66, p.Gln82, p.Arg84, p.Lys89) are predicted to directly contact the DNA target. Missense mutations at these positions abrogate DNA binding in IRF1 [Escalante et al 1998] but do not affect protein binding. Consequently, these mutations are predicted to have a dominant-negative effect on IRF function and may explain the broader phenotype observed in PPS [Kondo et al 2002, de Lima et al 2009]. Not all missense mutations at p.Arg84 are highly associated with PPS; p.Arg84Gly and p.Arg84Pro are found only in individuals with VWS, suggesting a different effect on IRF6 function for these mutations.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Published Guidelines/Consensus Statements

  1. American Cleft Palate-Craniofacial Association. Parameters for evaluation and treatment of patients with cleft lip/palate or other craniofacial anomalies (pdf). Available online. 1993; revised 2009. Accessed 10-25-12.

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Chapter Notes

Author Notes

Bryan Cary Bjork, PhD; Harvard Medical School (2003-2011)
Kate M Durda, MS (2011-present)
Katherine Nash Krahn, MS; University of Iowa (2003-2011)
Jeffrey C Murray, MD (2003-present)
Brian C Schutte, PhD (2003-present)

Revision History

  • 1 March 2011 (me) Comprehensive update posted live
  • 15 May 2006 (me) Comprehensive update posted to live Web site
  • 30 October 2003 (me) Review posted to live Web site
  • 27 May 2003 (jcm) Original submission
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