1.BACKGROUND
Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant genetic disease with an incidence of 1:20000. Its main clinical symptoms are the developmental malformation of the binocular anterior segment, which is associated with craniofacial, umbilical and dental abnormalities (Sauer et al.,2012; Ito et al.,2014). There are three common clinical variants of this disease; defects that are limited to the peripheral part of the anterior eye segment are called Axenfeld anomalies. Abnormal iris hypoplasia combined with abnormalities in the periphery of the anterior eye segment is referred to as Rieger anomaly, and combined ocular abnormalities and systemic developmental defects are referred to as Axenfeld-Rieger syndrome.
ARS is often considered autosomal dominant; some sporadic cases have also been reported. ARS has genetic heterogeneity, and two pathogenic genes of ARS, FOXC1 and PITX2, are located in the chromosome 6p25 and 4q25 regions, respectively (Seifi et al.,2018; Seifi al.,2018b). Four families with diseases of the anterior eye segment (including ARS) were reported, all of which were associated with mutations in the FOXC1 gene located on chromosome 6p25. Through sequencing analysis, Nishimura et al. found three missense mutations and a small fragment deletion of 11 bp in the FOXC1 gene.
The FOXC1 gene is located in the region of chromosome 6p25, and the protein product of FOXC1 from the N end to the C end is the active domain 1 (AD1), forkhead domain (FHD) and active domain 2 (AD2) (Berryet al.,2007). The FHD is the DNA binding region for the FOXC1 protein. Missense mutations in FHD significantly reduce protein stability and transactivation capability and the ability of FOXC1 to bind to DNA. Transcriptional activity and protein expression of FOXC1 are largely regulated by posttranscriptional levels (Saleem et al.,2004).
Because of the heterogeneity of the ARS phenotype and genotype and the overlap with the clinical manifestation of anterior segment dysgenesis (ASD), challenges exist for accurate diagnosis and classification (Deml et al.,2014). A correct diagnosis is often established only when the mutation in one of the known associated genes is identified. In the Chinese population, FOXC1 mutations in patients with ARS have not been well described. Therefore, the purpose of this study was to identify a new heterozygous mutation of the FOXC1 gene with ARS by using targeted next-generation sequencing technology combined with bioinformatics and expression profiling.