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 Paepe; Philippe Kestelyn; Bart P. Leroy; Elfride De Baere

doi:10.1167/iovs.10-5309

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 journal › Article › Academic › peer-review

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Abstract

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 language	English
Pages (from-to)	324-333
Number of pages	10
Journal	Investigative ophthalmology & visual science
Volume	52
Issue number	1
DOIs	https://doi.org/10.1167/iovs.10-5309
Publication status	Published - Jan-2011

Keywords

AXENFELD-RIEGER-SYNDROME
TRANSCRIPTION FACTOR GENE
CHROMOSOME 6P25
FKHL7 GENE
MICRODELETIONS
GLAUCOMA
PROTEIN
TARGET
DUPLICATIONS
DELETION

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D'haene, B., Meire, F., Claerhout, I., Kroes, H. Y., Plomp, A., Arens, Y. H., de Ravel, T., Casteels, I., De Jaegere, S., Hooghe, S., Wuyts, W., van den Ende, J., Roulez, F., Veenstra-Knol, H. E., Oldenburg, R. A., Giltay, J., Verheij, J. B. G. M., de Faber, J.-T., Menten, B., ... De Baere, E. (2011). Expanding the Spectrum of FOXC1 and PITX2 Mutations and Copy Number Changes in Patients with Anterior Segment Malformations. Investigative ophthalmology & visual science, 52(1), 324-333. https://doi.org/10.1167/iovs.10-5309

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

abstract = "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",

keywords = "AXENFELD-RIEGER-SYNDROME, TRANSCRIPTION FACTOR GENE, CHROMOSOME 6P25, FKHL7 GENE, MICRODELETIONS, GLAUCOMA, PROTEIN, TARGET, DUPLICATIONS, DELETION",

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

year = "2011",

month = jan,

doi = "10.1167/iovs.10-5309",

language = "English",

volume = "52",

pages = "324--333",

journal = "Investigative ophthalmology & visual science",

issn = "0146-0404",

publisher = "ASSOC RESEARCH VISION OPHTHALMOLOGY INC",

number = "1",

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D'haene, B, Meire, F, Claerhout, I, Kroes, HY, Plomp, A, Arens, YH, de Ravel, T, Casteels, I, De Jaegere, S, Hooghe, S, Wuyts, W, van den Ende, J, Roulez, F, Veenstra-Knol, HE, Oldenburg, RA, Giltay, J, Verheij, JBGM, de Faber, J-T, Menten, B, De Paepe, A, Kestelyn, P, Leroy, BP & De Baere, E 2011, 'Expanding the Spectrum of FOXC1 and PITX2 Mutations and Copy Number Changes in Patients with Anterior Segment Malformations', Investigative ophthalmology & visual science, vol. 52, no. 1, pp. 324-333. https://doi.org/10.1167/iovs.10-5309

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

KW - AXENFELD-RIEGER-SYNDROME

KW - TRANSCRIPTION FACTOR GENE

KW - CHROMOSOME 6P25

KW - FKHL7 GENE

KW - MICRODELETIONS

KW - GLAUCOMA

KW - PROTEIN

KW - TARGET

KW - DUPLICATIONS

KW - DELETION

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 -

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

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Keywords

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