TY - JOUR
T1 - Expanding the Spectrum of FOXC1 and PITX2 Mutations and Copy Number Changes in Patients with Anterior Segment Malformations
AU - D'haene, Barbara
AU - Meire, Francoise
AU - Claerhout, Ilse
AU - Kroes, Hester Y.
AU - Plomp, Astrid
AU - Arens, Yvonne H.
AU - de Ravel, Thomy
AU - Casteels, Ingele
AU - De Jaegere, Sarah
AU - Hooghe, Sally
AU - Wuyts, Wim
AU - van den Ende, Jenneke
AU - Roulez, Francoise
AU - Veenstra-Knol, Hermine E.
AU - Oldenburg, Rogier A.
AU - Giltay, Jacques
AU - Verheij, Johanna B. G. M.
AU - de Faber, Jan-Tjeerd
AU - Menten, Bjoern
AU - De Paepe, Anne
AU - Kestelyn, Philippe
AU - Leroy, Bart P.
AU - De Baere, Elfride
PY - 2011/1
Y1 - 2011/1
N2 - 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
AB - 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
U2 - 10.1167/iovs.10-5309
DO - 10.1167/iovs.10-5309
M3 - Article
C2 - 20881294
SN - 0146-0404
VL - 52
SP - 324
EP - 333
JO - Investigative Ophthalmology & Visual Science
JF - Investigative Ophthalmology & Visual Science
IS - 1
ER -