A Novel Homozygous Mutation in FOXC1 Causes Axenfeld Rieger Syndrome with Congenital Glaucoma

Abstract

BackgroundAnterior segment dysgenesis (ASD) disorders are a group of clinically and genetically heterogeneous phenotypes in which frequently cornea, iris, and lens are affected. This study aimed to identify novel mutations in PAX6, PITX2 and FOXC1 in families with anterior segment dysgenesis disorders.MethodsWe studied 14 Pakistani and one Mexican family with Axenfeld Rieger syndrome (ARS; n = 10) or aniridia (n = 5). All affected and unaffected family members underwent full ophthalmologic and general examinations. Total genomic DNA was isolated from peripheral blood. PCR and Sanger sequencing were performed for the exons and intron-exon boundaries of the FOXC1, PAX6, and PITX2 genes.ResultsMutations were identified in five of the 15 probands; four variants were novel and one variant was described previously. A novel de novo variant (c.225C>A; p.Tyr75*) was identified in the PAX6 gene in two unrelated probands with aniridia. In addition, a known variant (c.649C>T; p.Arg217*) in PAX6 segregated in a family with aniridia. In the FOXC1 gene, a novel heterozygous variant (c.454T>C; p.Trp152Arg) segregated with the disease in a Mexican family with ARS. A novel homozygous variant (c.92_100del; p.Ala31_Ala33del) in the FOXC1 gene segregated in a Pakistani family with ARS and congenital glaucoma.ConclusionsOur study expands the mutation spectrum of the PAX6 and FOXC1 genes in individuals with anterior segment dysgenesis disorders. In addition, our study suggests that FOXC1 mutations, besides typical autosomal dominant ARS, can also cause ARS with congenital glaucoma through an autosomal recessive inheritance pattern. Our results thus expand the disease spectrum of FOXC1, and may lead to a better understanding of the role of FOXC1 in development.

Gene‐specific facial dysmorphism in Axenfeld‐Rieger syndrome caused by FOXC1 and PITX2 variants

“…However, studies following the identification of the FOXC1 and PITX2 genes have seldom reported on the facial appearance of affected individuals. Hypertelorism, maxillary hypoplasia and a broad nasal bridge seem to be the most commonly reported traits in FOXC1 ‐associated ARS across different populations (D'Haene et al, 2011; Kawase et al, 2001; Kim et al, 2013; Micheal et al, 2016; Weisschuh et al, 2006), whereas maxillary hypoplasia and a thin upper lip are often reported in PITX2 ‐associated ARS (D'Haene et al, 2011; Reis et al, 2012; Weisschuh et al, 2006). No study has systematically assessed affected individuals for the presence or absence of facial traits.…”

Therapeutically Targeting Cancers That Overexpress FOXC1: A Transcriptional Driver of Cell Plasticity, Partial EMT, and Cancer Metastasis

“…The earliest reports on the biologic role and function of the FOXC1 TF implicated it in abnormal pathologic conditions like glaucoma (16)(17)(18)(19)(20)(21)(22)(23), congenital hydrocephalus (24), congenital renal defects (25,26), congenital heart defects (21,(27)(28)(29) and Axenfeld-Rieger Syndrome (21,30,31), a congenital disorder characterized by glaucoma and congenital heart defects.…”

Contribution of a Novel B3GLCT Variant to Peters Plus Syndrome Discovered by a Combination of Next-Generation Sequencing and Automated Text Mining

“…Disorders related to such a phenotype include Axenfeld Rieger syndrome (ARS), isolated Peters Anomaly, Peters plus syndrome (PPS), primary congenital glaucoma, congenital hereditary endothelial dystrophy, and iridogoniodysgenesis anomaly [3], all of which are registered as rare by Orphanet. The genetic background of ASD is only partially known and may be related to the disruption of many genes, e.g., CYP1B1 , BMP4 , FOXC1 , PAX6 , FOXE3 , NDP , SLC4A11 , HCCS , PITX2 , PITX3 , LMX1B, and PXDN [4,5,6,7,8], several of which can modulate tyrosinase activity, postulated as an important modulator of iridocorneal angle malformations [6]. Importantly, diseases with multisystemic manifestations can also present with ASD, e.g., syndromes resulting from mutations in genes encoding collagen type IV: COL4A1 and COL4A2 [2,9,10], often manifest with neurological disorders, what may hinder finding the relevant genetic cause of the disease.…”