title: A Novel Homozygous Mutation in FOXC1 Causes Axenfeld Rieger Syndrome with Congenital Glaucoma.
abstract: BACKGROUND
  Anterior 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  Mutations 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Shazia
authors.initials: S
authors.lastname: Micheal
authors.affiliation: Department of Pediatric Ophthalmology, Al-Shifa Eye Trust Hospital, Jhelum Road, Rawalpindi, Pakistan.
authors.forename: Sorath Noorani
authors.initials: SN
authors.lastname: Siddiqui
authors.affiliation: Department of Pediatric Ophthalmology, Al-Shifa Eye Trust Hospital, Jhelum Road, Rawalpindi, Pakistan.
authors.forename: Saemah Nuzhat
authors.initials: SN
authors.lastname: Zafar
authors.affiliation: Genetics Department Asociación Para Evitar la Ceguera en México, Coyoacán, Mexico.
authors.forename: Cristina
authors.initials: C
authors.lastname: Villanueva-Mendoza
authors.affiliation: Genetics Department Asociación Para Evitar la Ceguera en México, Coyoacán, Mexico.
authors.forename: Vianney
authors.initials: V
authors.lastname: Cortés-González
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Muhammad Imran
authors.initials: MI
authors.lastname: Khan
authors.affiliation: Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
mesh_terms: D000293:Adolescent; D000328:Adult; D000869:Anterior Eye Segment / Q000002:abnormalities*; D002648:Child; D002675:Child, Preschool; D005124:Eye Abnormalities / Q000175:diagnosis / Q000235:genetics*; D015785:Eye Diseases, Hereditary; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005901:Glaucoma / Q000151:congenital / Q000175:diagnosis / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D000071841:PAX6 Transcription Factor / Q000235:genetics; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics; D000097577:Homeobox Protein PITX2
chemical_list: D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C112743:FOXC1 protein, human; C000605730:PAX6 protein, human