title: PITX2 and FOXC1 spectrum of mutations in ocular syndromes.
abstract: Anterior segment dysgenesis (ASD) encompasses a broad spectrum of developmental conditions affecting anterior ocular structures and associated with an increased risk for glaucoma. Various systemic anomalies are often observed in ASD conditions such as Axenfeld-Rieger syndrome (ARS) and De Hauwere syndrome. We report DNA sequencing and copy number analysis of PITX2 and FOXC1 in 76 patients with syndromic or isolated ASD and related conditions. PITX2 mutations and deletions were found in 24 patients with dental and/or umbilical anomalies seen in all. Seven PITX2-mutant alleles were novel including c.708_730del, the most C-terminal mutation reported to date. A second case of deletion of the distant upstream but not coding region of PITX2 was identified, highlighting the importance of this recently discovered mechanism for ARS. FOXC1 deletions were observed in four cases, three of which demonstrated hearing and/or heart defects, including a patient with De Hauwere syndrome; no nucleotide mutations in FOXC1 were identified. Review of the literature identified several other patients with 6p25 deletions and features of De Hauwere syndrome. The 1.3-Mb deletion of 6p25 presented here defines the critical region for this phenotype and includes the FOXC1, FOXF2, and FOXQ1 genes. In summary, PITX2 or FOXC1 disruptions explained 63% of ARS and 6% of other ASD in our cohort; all affected patients demonstrated additional systemic defects with PITX2 mutations showing a strong association with dental and/or umbilical anomalies and FOXC1 with heart and hearing defects. FOXC1 deletion was also found to be associated with De Hauwere syndrome.
authors.affiliation: Department of Pediatrics and Children's Research Institute, Milwaukee, WI, USA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Reis
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Tyler
authors.forename: Bethany A
authors.initials: BA
authors.lastname: Volkmann Kloss
authors.forename: Kala F
authors.initials: KF
authors.lastname: Schilter
authors.forename: Alex V
authors.initials: AV
authors.lastname: Levin
authors.forename: R Brian
authors.initials: RB
authors.lastname: Lowry
authors.forename: Petra J G
authors.initials: PJ
authors.lastname: Zwijnenburg
authors.forename: Eliza
authors.initials: E
authors.lastname: Stroh
authors.forename: Ulrich
authors.initials: U
authors.lastname: Broeckel
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.forename: Elena V
authors.initials: EV
authors.lastname: Semina
mesh_terms: D000483:Alleles; D000869:Anterior Eye Segment / Q000002:abnormalities; D001842:Bone and Bones / Q000002:abnormalities; D056915:DNA Copy Number Variations; D005124:Eye Abnormalities / Q000175:diagnosis / Q000235:genetics*; D015785:Eye Diseases, Hereditary; D019066:Facies; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D017353:Gene Deletion; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D006849:Hydrocephalus / Q000175:diagnosis / Q000235:genetics; D006972:Hypertelorism / Q000175:diagnosis / Q000235:genetics; D007593:Joint Instability / Q000175:diagnosis / Q000235:genetics; D008297:Male; D009123:Muscle Hypotonia / Q000175:diagnosis / Q000235:genetics; D009154:Mutation; D009801:Oculomotor Muscles / Q000002:abnormalities; D014157:Transcription Factors / Q000235:genetics*; D000097577:Homeobox Protein PITX2
chemical_list: D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C112743:FOXC1 protein, human