Journal Article

PITX2 and FOXC1 spectrum of mutations in ocular syndromes

Broeckel, Ulrich, Volkmann Kloss, Bethany A, Zwijnenburg, Petra J G, Schilter, Kala F, Murray, Jeffrey C, Lowry, R Brian, Semina, Elena V, Tyler, Rebecca C, Stroh, Eliza, Reis, Linda M, Levin, Alex V

2012

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Alleles / Anterior Eye Segment - abnormalities / Biological and medical sciences / Bone and Bones - abnormalities / Clonal deletion / Congenital diseases / Copy number / Defects / Deoxyribonucleic acid / DNA / DNA Copy Number Variations / DNA sequencing / Eye Abnormalities - diagnosis / Eye Abnormalities - genetics / Eye Diseases, Hereditary / Facies / Female / Forkhead Transcription Factors - genetics / Fundamental and applied biological sciences. Psychology / Gene Deletion / Gene expression / Genetics / Genetics of eukaryotes. Biological and molecular evolution / Glaucoma / Hearing / Hearing loss / Hearing Loss, Sensorineural - diagnosis / Hearing Loss, Sensorineural - genetics / Heart / Homeobox Protein PITX2 / Homeodomain Proteins - genetics / Humans / Hydrocephalus - diagnosis / Hydrocephalus - genetics / Hypertelorism - diagnosis / Hypertelorism - genetics / Joint Instability - diagnosis / Joint Instability - genetics / Literature reviews / Male / Malformations of the eye / Medical genetics / Medical sciences / Molecular and cellular biology / Muscle Hypotonia - diagnosis / Muscle Hypotonia - genetics / Mutation / Neurosciences / Oculomotor Muscles - abnormalities / Ophthalmology / Patients / Pediatrics / Phenotypes / Transcription factors / Transcription Factors - genetics