Expanding the Spectrum of FOXC1 and PITX2 Mutations and Copy Number Changes in Patients with Anterior Segment Malformations

Barbara D'haene, Francoise Meire, Ilse Claerhout, Hester Y. Kroes, Astrid Plomp, Yvonne H. Arens, Thomy de Ravel, Ingele Casteels, Sarah De Jaegere, Sally Hooghe, Wim Wuyts, Jenneke van den Ende, Francoise Roulez, Hermine E. Veenstra-Knol, Rogier A. Oldenburg, Jacques Giltay, Johanna B. G. M. Verheij, Jan-Tjeerd de Faber, Bjoern Menten, Anne De PaepePhilippe Kestelyn, Bart P. Leroy, Elfride De Baere*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


PURPOSE. Anterior segment dysgenesis (ASD) comprises a heterogeneous group of developmental abnormalities that affect several structures of the anterior segment of the eye. The main purpose of this study was to assess the proportion of FOXC1 and PITX2 mutations and copy number changes in 80 probands with ASD. METHODS. The patients were examined for FOXC1 and PITX2 copy number changes and mutations using MLPA (multiplex ligation-dependent probe amplification) and direct sequencing. Subsequently, the identified copy number changes were fine-mapped using high-resolution microarrays. In the remaining mutation-negative patients, sequencing of the FOXC1 and-PITX2 3' untranslated regions (UTRs) and three other candidate genes (P32, PDP2, and FOXC2) was performed. RESULTS. Thirteen FOXC1 and eight PITX2 mutations were identified, accounting for 26% (21/80) of the cases. In addition, six FOXC1 and five PITX2 deletions were found, explaining 14% (11/80) of the cases. The smallest FOXC1 and PITX2 deletions were 5.4 and 1.6 kb in size, respectively. Six patients carrying FOXC1 deletions presented with variable extraocular phenotypic features such as hearing defects (in 4/6) and mental retardation (in 2/6). No further genetic defects were found in the remaining mutation-negative patients. CONCLUSIONS. FOXC1 and PITX2 genetic defects explain 40% of our large ASD cohort. The current spectrum of intragenic FOXC1 and PITX2 mutations was extended considerably, the identified copy number changes were fine mapped, the smallest FOXC1 and PITX2 deletions reported so far were identified, and the need for dedicated copy number screening of the FOXC1 and PITX2 genomic landscape was emphasized. This study is unique in that sequence and copy number changes were screened simultaneously in both genes. (Invest Ophthalmol Vis Sci. 2011;52:324-333) DOI:10.1167/iovs.10-5309
Original languageEnglish
Pages (from-to)324-333
JournalInvestigative Ophthalmology & Visual Science
Issue number1
Publication statusPublished - Jan 2011

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