A heritable cause of cleft lip and palate—Van der Woude syndrome caused by a novel IRF6 mutation. Review of the literature and of the differential diagnosis

Ferrero, Giovanni Battista; Baldassarre, Giuseppina; Panza, Emanuele; Valenzise, Mariella; Pippucci, Tommaso; Mussa, Alessandro; Pepe, Ernesto; Seri, Marco; Silengo, Margherita

doi:10.1007/s00431-009-1011-3

Cited by 10 publications

(8 citation statements)

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“…Mutations in any of the coding or non‐coding exons of IRF6 result in VWS, whereas mutations predominantly affecting one residue encoded by exon 4 and a few other mutations in exons 3, 4, 6 and 9 have been reported to cause PPS (4, 6, 12–28). These mutations have been reported in patients of diverse nationalities but there are no reports of IRF6 mutations from South Asia.…”

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Epidemiology of Van der Woude syndrome from mutational analyses in affected patients from Pakistan

et al. 2010

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Mutations in IRF6 cause Van der Woude syndrome (VWS), one of the most common syndromes associated with cleft lip (CL) with or without cleft palate (CP). The presence of pits on the lower lip of patients is the most characteristic feature of the syndrome. We have identified three novel and seven previously reported IRF6 mutations in 12 of 16 unrelated families segregating VWS from Pakistan. The three newly identified mutations include a frameshift (c.568delG) and two missense mutations c.295G>A (p.G99S) and c.1219T>C (p.S407P). Recent functional studies on IRF6 and the three-dimensional structure of IRF5 carboxy (C) terminus, a protein encoded by a paralog of IRF6, shed light on the p.S407P substitution. Additionally, the identification of the same mutations responsible for VWS in Pakistan, as reported in other global populations worldwide, marks these residues as mutational hotspots and indicates their essential role in structural stability or function of IRF6. This is the first study of VWS in Pakistan and we estimate that 1 in 100 patients with CL with or without CP (CL/P) are affected in the Pakistani population predominantly from the Punjab area.

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Epidemiology of Van der Woude syndrome from mutational analyses in affected patients from Pakistan

et al. 2010

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“…This was followed by parametric linkage analysis, the trait model (mode of inheritance, disease-allele frequency, and penetrance of genotypes). 34 Since the parameters of the disease model were uncertain, in the initial genome scan, the evidence of linkage with a nonparametric, penetrance-independent, affected-only, and allele-sharing model was assessed. On finding significant evidence of linkage by exceeding the predetermined threshold (P.005) with an allele-sharing method, a range of parametric models to the data were fitted.…”

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Genomic expression in non syndromic cleft lip and palate patients: A review

Mehrotra

2015

Journal of Oral Biology and Craniofacial Research

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Cleft lip and palate are common congenital anomalies with significant medical, psychological, social, and economic ramifications, affecting one in seven hundred live births. Genetic causes of non syndromic cleft lip and/or palate (NSCLP) include chromosomal rearrangements, genetic susceptibility to teratogenic exposures, and complex genetic contributions of multiple genes. Development of the orofacial clefts in an individual will depend on the interaction of several moderately effecting genes with environmental factors. Several candidate genes have been genotyped in different population types, using case parent trio or case control design; also genes have been sequenced and SNPs have been reported. Quantitative and molecular analysis have shown linkage and association studies to be more relevant. Recent literature search shows genome wide association studies using microarray. The aim of this paper was to review the approaches to identify genes associated with NSCLP and to analyze their differential expressions. Although no major gene has been confirmed, a lot of research is ongoing to provide an understanding of the pathophysiology of the orofacial clefts.

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“…So far, globally available reports show that VWS is caused by mutations in the IRF6 gene located on chromosome 1q32·2 (Kondo et al, 2002;Ferrero et al, 2010;Leslie & Marazita, 2013). Recently, Indian studies on VWS reported that the critical region on Fig.…”

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confidence: 99%

Genome-wide copy number scan identifies IRF6 involvement in Van der Woude syndrome in an Indian family

et al. 2014

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Summary Van der Woude syndrome (VWS) is an autosomal dominant developmental malformation presenting with bilateral lower lip pits related to cleft lip, cleft palate and other malformations. We performed a whole-genome copy number variations (CNVs) scan in an Indian family with members suffering from VWS using 2·6 million combined SNP and CNV markers. We found CNVs affecting IRF6, a known candidate gene for VWS, in all three cases, while none of the non-VWS members showed any CNVs in the IRF6 region. The duplications and deletions of the chromosomal critical region in 1q32-q41 confirm the involvement of CNVs in IRF6 in South Indian VWS patients. Molecular network analysis of these and other cleft lip/palate related module genes suggests that they are associated with cytokine-mediated signalling pathways and response to interferon-gamma mediated signalling pathways. This is a maiden study indicating the involvement of CNVs in IRF6 in causing VWS in the Indian population.

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A heritable cause of cleft lip and palate—Van der Woude syndrome caused by a novel IRF6 mutation. Review of the literature and of the differential diagnosis

Abstract: This report emphasizes the role of the clinician in recognizing the clinical variability and the genetic heterogeneity of CL/P.

Cited by 10 publications

References 20 publications

Epidemiology of Van der Woude syndrome from mutational analyses in affected patients from Pakistan

Epidemiology of Van der Woude syndrome from mutational analyses in affected patients from Pakistan

Genomic expression in non syndromic cleft lip and palate patients: A review

Genome-wide copy number scan identifies IRF6 involvement in Van der Woude syndrome in an Indian family

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