Identification of IRF6 gene variants in three families with Van der Woude syndrome

Abstract

Abstract.Van der Woude syndrome is the most common cause of syndromic orofacial clefting. It is characterised by the presence of lip pits, cleft lip and/or cleft palate. It is transmitted in an autosomal dominant manner, with high penetrance and variable expressivity. Several mutations in the interferon regulatory factor 6 (IRF6) gene have been found in VWS families, suggesting that this gene is the primary locus. We screened for mutations in this gene in three families in our population. There was a recurrent nonsense mutation within exon 9 of the gene for a Malay family consisting of five affected members with different presentations. We also found a co-segregating rare polymorphism which would result in a non-synonymous change 23 bases downstream of the nonsense mutation. This polymorphism was present in <1% of the Malay subjects screened, but was not found among the Chinese and Indians in our population. For another family, a 396C¡T mutation (R45W in the DNA-binding domain) was found in the proband, although the possibility of a genetic defect elsewhere could not be excluded because his mother and twin sister (both unaffected) also had this variant. In the third case with complete absence of family history, a de novo deletion spanning the whole IRF6 gene was detected in the child with VWS. This case of haploinsufficiency caused disruption of orofacial development but not other organ systems as the child has no other medical or developmental abnormalities despite the deletion of at least five other genes.

Disease-associated mutations in IRF6 and RIPK4 dysregulate their signalling functions

“…Importantly, their mutation causes the congenital developmental syndromes, VWS and PPS, and the related but more severe BPS, respectively [5][6][7]. A p.Arg412X nonsense mutation immediately proximal to regulatory phosphorylation sites in IRF6 is prevalent in VWS, but less common in PPS [5,[15][16][17][18][19][20][21]. A nonsense mutation in the intermediate domain of RIPK4 (p.Ser376X) was recently identified in BPS [7].…”

“…However, a p.Arg412X nonsense mutation predicted to cause the truncation of IRF6 at Arg412 was the most common mutation identified in two geographically separate cohorts of N300 families with VWS [15]. The same mutation was also identified in other studies [5,[16][17][18][19][20][21], suggesting that it represents a mutational hotspot in VWS. A small number of RIPK4 mutations in BPS have been identified [6,7].…”

De novo 2.3 Mb microdeletion of 1q32.2 involving the Van der Woude Syndrome locus

“…The deletion started at a more telomeric position and extended further towards the telomere. Interestingly, it was also a de novo occurrence on the paternal chromosome as in the present case [4,12]. For family VWS1473, the deletion was on the maternally derived chromosome as the maternal allele was missing for D1S3753 [7].…”

“…The reduced gene dosage was confirmed by MLPA [4]. In this paper, we described the mapping of the deletion in this patient using a high resolution single nucleotide polymorphism (SNP) array.…”

A combined targeted mutation analysis of IRF6 gene would be useful in the first screening of oral facial clefts

“…They were detected in approximately 70% of VWS and 97% of PPS cases [16]. Microdeletion of 1q32–q41 is relatively rare, and only a few cases have been reported in the medical literature [24-26]. While the majority of the VWS mutations were spread over exons 3, 4, 7, 8 and 9, the majority of PPS mutations were concentrated in exons 3 and 4 [16,27].…”