PITX2 and FOXC1 spectrum of mutations in ocular syndromes. Eur J Hum Genet 2012 Dec;20(12):1224-33
Date
05/10/2012Pubmed ID
22569110Pubmed Central ID
PMC3499749DOI
10.1038/ejhg.2012.80Scopus ID
2-s2.0-84869223456 (requires institutional sign-in at Scopus site) 113 CitationsAbstract
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.
Author List
Reis LM, Tyler RC, Volkmann Kloss BA, Schilter KF, Levin AV, Lowry RB, Zwijnenburg PJ, Stroh E, Broeckel U, Murray JC, Semina EVAuthors
Ulrich Broeckel MD Chief, Center Associate Director, Professor in the Pediatrics department at Medical College of WisconsinKala Schilter in the CTSI department at Medical College of Wisconsin - CTSI
Elena V. Semina PhD Chief, Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AllelesAnterior Eye Segment
Bone and Bones
DNA Copy Number Variations
Eye Abnormalities
Eye Diseases, Hereditary
Facies
Female
Forkhead Transcription Factors
Gene Deletion
Hearing Loss, Sensorineural
Homeodomain Proteins
Humans
Hydrocephalus
Hypertelorism
Joint Instability
Male
Muscle Hypotonia
Mutation
Oculomotor Muscles
Transcription Factors
