Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome

Lima, Renata Lúcia Leite Ferreira de; Hoper, Sarah A; Ghassibé, Michella; Cooper, Margaret E.; Rorick, Nicholas K.; Kondo, Shinji; Katz, L.A.; Marazita, Mary L.; Compton, John G.; Bale, Sherri J.; Hehr, Ute; Dixon, Michael J.; Daack-Hirsch, Sandra; Boute, Odile; Bayet, Bénédicte; Revençu, Nicole; Verellen‐Dumoulin, Christine; Vikkula, Miikka; Richieri-Costa, Antônio; Moretti-Ferreira, Danilo; Murray, Jeffrey C.; Schutte, Brian C.

doi:10.1097/gim.0b013e318197a49a

Cited by 124 publications

(189 citation statements)

References 47 publications

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“…We also identified a c.1234C>t mutation leading to p.R412X, a nonsense mutation in exon 9 (VWS4; Fig. 3A) that has been previously described in Brazilian and Northern European populations (6). No unique exonic missense, nonsense or frameshift mutations were found in our fifth family (VWS5), although a c.921C>t mutation resulting in a conserved serine to serine mutation was found in exon 7 in the affected sibling pair (p.S307S).…”

Section: Irf6 Mutationssupporting

confidence: 63%

“…using a protein structure damage predictor (Polyphen), this p.N88I mutation is thought to be damaging to the IRF6 protein structure. Asparagine 88 to histidine, tyrosine and serine mutations were previously described in VWS patients (5,6), further suggesting that this is an important conserved residue. Mutations at this site may alter IRF6 gene function, likely through dna-binding ability.…”

Section: Discussionmentioning

confidence: 69%

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Novel IRF6 mutations in Honduran Van Der Woude syndrome patients

et al. 2011

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Abstract. Van der Woude syndrome (VWS) is an autosomal dominant inherited disease characterized by lower lip pits, cleft lip and/or cleft palate. Missense, nonsense and frameshift mutations in IRF6 have been revealed to be responsible for VWS in european, asian, north american and Brazilian populations. However, the mutations responsible for VWS have not been studied in central american populations. Here, we investigated the role of IRF6 in patients with VWS in a previously unstudied Honduran population. IRF6 mutations were identified in four out of five VWS families examined, which strongly suggests that mutations in IRF6 are responsible for VWS in this population. We reported three novel mutations and one previously described mutation. In the first family, a mother and daughter both exhibited a p.N88I mutation in the dna-binding region of IRF6 that was not present in unaffected family members. in the second, we found a unique p.K101QfsX15 mutation in the affected patient, leading to a frameshift and early stop codon. In the third, we identified a p.Q208X mutation occurring in exon 6. In the fourth, we found a nonsense mutation in exon 9 (p.R412X), previously described in Brazilian and northern european populations. In the fifth, we did not identify any unique exonic missense, nonsense or frameshift mutations. This study reports the first cases of IRF6 mutations in VWS patients in a central American population, further confirming that the causal link between IRF6 and VWS is consistent across multiple populations.

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Section: Irf6 Mutationssupporting

confidence: 63%

Section: Discussionmentioning

confidence: 69%

Novel IRF6 mutations in Honduran Van Der Woude syndrome patients

et al. 2011

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“…Primer sequences that were used to amplify exons 1 to 9 of IRF6 (RefSeq NM_006147.3) and PAX7 (RefSeq NM_001135254.1) have been published elsewhere (Ferreira de Lima et al. 2009; Butali et al. 2014a,b).…”

Section: Methodsmentioning

confidence: 99%

“…These variants are usually concentrated in the highly conserved DNA‐binding domain (exons 3 and 4) and less conserved transactivation domain (exons 7 and 9) (Ferreira de Lima et al. 2009). Recent sequence analyses of these four exons in VWS and PPS patients from Africa confirmed that these four exons are mutational “hot‐spots” in IRF6 (Butali et al.…”

Section: Introductionmentioning

confidence: 99%

The prevalence, penetrance, and expressivity of etiologicIRF6variants in orofacial clefts patients from sub‐Saharan Africa

Gowans

Busch

Mossey

et al. 2017

Molec Gen & Gen Med

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BackgroundOrofacial clefts are congenital malformations of the orofacial region, with a global incidence of one per 700 live births. Interferon Regulatory Factor 6 (IRF6) (OMIM:607199) gene has been associated with the etiology of both syndromic and nonsyndromic orofacial clefts. The aim of this study was to show evidence of potentially pathogenic variants in IRF6 in orofacial clefts cohorts from Africa.MethodsWe carried out Sanger Sequencing on DNA from 184 patients with nonsyndromic orofacial clefts and 80 individuals with multiple congenital anomalies that presented with orofacial clefts. We sequenced all the nine exons of IRF6 as well as the 5′ and 3′ untranslated regions. In our analyses pipeline, we used various bioinformatics tools to detect and describe the potentially etiologic variants.ResultsWe observed that potentially etiologic exonic and splice site variants were nonrandomly distributed among the nine exons of IRF6, with 92% of these variants occurring in exons 4 and 7. Novel variants were also observed in both nonsyndromic orofacial clefts (p.Glu69Lys, p.Asn185Thr, c.175‐2A>C and c.1060+26C>T) and multiple congenital anomalies (p.Gly65Val, p.Lys320Asn and c.379+1G>T) patients. Our data also show evidence of compound heterozygotes that may modify phenotypes that emanate from IRF6 variants.ConclusionsThis study demonstrates that exons 4 and 7 of IRF6 are mutational ‘hotspots’ in our cohort and that IRF6 mutants‐induced orofacial clefts may be prevalent in the Africa population, however, with variable penetrance and expressivity. These observations are relevant for detection of high‐risk families as well as genetic counseling. In conclusion, we have shown that there may be a need to combine both molecular and clinical evidence in the grouping of orofacial clefts into syndromic and nonsyndromic forms.

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“…Mutations in interferon regulatory factor 6 (IRF6), located on 1q32.2, are responsible for the two autosomal dominant orofacial cleft syndromes, Van Der Woude and popliteal pterygium syndrome [1][2][3]. It was also the first identified nonsyndromic orofacial cleft (NSOFC) susceptibility locus [4] and has been the only candidate gene consistently found to have a significant association with NSOFC across multiple studies in many regions of the world, for example, China and Europe [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Interferon Regulatory Factor 6 (IRF6) and Gene – Environment Interactions in Non-Syndromic Orofacial Cleft Cases in Saudi Arabia-A Case Control Study

Alamoudi¹,

Sabbagh²,

Innes³

et al. 2018

J Oral Hyg Health

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The association between interferon regulatory factor 6 (IRF6) and nonsyndromic orofacial cleft (NSOFC) is affected by ethnicity. Also, gene-environment interactions (GEI) may play an important role in its etiology.Objectives: This case-control study investigated whether IRF6 gene variants were associated with NSOFC in Saudi Arabian population and whether the gene was affected by maternal environmental exposures. Methods:We extracted DNA from saliva samples obtained from 171 infant-parent triad cases and 189 matched controls (age, gender, and location) from January 2010-December 2011; this study included a total of 11 referral hospitals in Saudi Arabia. IRF6 (rs2013162, rs2235375, and rs2235371) polymorphisms were genotyped using restriction-digestion polymerase chain reaction. Data on environmental exposures, for GEI analyses, were collected through questionnaire-led interviews with parents. Results:We found statistically significant over transmission of the common IRF6 rs2013162 allele among cleft lip with or without palate CL(P) cases. No associations were found for either of the other two IRF6 SNPs. Maternal exposure to antipyretics, folic acid, fever, antibiotics, illnesses, common cold/flu, paternal water pipe smoking, stress, x-rays, and/or chemicals could significantly interact with the maternal IRF6 (rs2013162 and rs2235375) gene variants, affecting the likelihood of having an offspring with NSOFC. Conclusion:The common allele at IRF6 rs2013162 was significantly over transmitted among CL(P) cases. This study provides hypotheses for future investigations into genetic and environmental factors and their interaction in the etiology of NSOFC.

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Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome

Cited by 124 publications

References 47 publications

Novel IRF6 mutations in Honduran Van Der Woude syndrome patients

Novel IRF6 mutations in Honduran Van Der Woude syndrome patients

The prevalence, penetrance, and expressivity of etiologicIRF6variants in orofacial clefts patients from sub‐Saharan Africa

Interferon Regulatory Factor 6 (IRF6) and Gene – Environment Interactions in Non-Syndromic Orofacial Cleft Cases in Saudi Arabia-A Case Control Study

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