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Christina Gerth-Kahlert, Kathy Williamson, Volker Hingst, Rudolf Guthoff, David R. FitzPatrick, Veronica van Heyningen; Mutational Analysis In A Large Number Of Patients With Uni- Or Bilateral Anophthalmia. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1568.
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To investigate the frequency and phenotype variability of SOX2, OTX2 and PAX6 mutations associated with unilateral or bilateral anophthalmia.
Whole genome amplified (WGA) gDNA templates were PCR amplified for SOX2 (two amplicons), OTX2 (four amplicons) and PAX6 paired domain (three amplicons), followed by direct sequencing (ABI). Sequence data were analysed by Mutation Surveyor (Version 2.61, SoftGenetics). Point mutations were confirmed by 2nd PCR using non-WGA gDNA templates: the products were subjected to enzyme mismatch cleavage (EMC) analysis using Surveyor Nuclease S (Transgenomic) and/or re-sequenced. Genomic DNA samples from family members were analyzed in parallel to the 2nd PCRs. Patients and available family members received a comprehensive eye exam including dilated fundus examination. Extraocular anomalies and developmental data were extracted from medical reports and parent interview. Cerebral MRIs were reassessed if available.
32 patients with unilateral (23/32) or bilateral (9/32) clinical anophthalmia were included in the study. No mutations in PAX6, SOX2 and OTX2 were found in 22 patients (2A: 4/22; 1A: 18/22). Heterozygous SOX2 mutations were found in 7 patients (2A: 4/7, 1A: 3/7) and 2 affected mothers (1A or bilateral iris/ chorioretinal coloboma). Heterozygous OTX2 mutations were identified in 3 patients (2A: 2/3, 1A: 1/3) and one unaffected mother of a child with unilateral anophthalmia. No PAX6 mutations were identified in this patient group.The second eye in patients with unilateral anophthamia showed severe malformation in 2/3 (SOX2) and 1/2 (OTX2) cases. Extraocular malformations were seen in 1/7 and 2/3 patients with SOX2 or OTX2 mutation, respectively. Intracerebral abnormalities were evident in 2/5 and 1/3 examined patients with OTX2 or SOX2 mutations, respectively.
Heterozygous loss of function mutations in SOX2 and OTX2 were identified in 31% of patients with uni- or bilateral anophthalmia, which is more than previously reported. Patients in either group show severe eye malformation resulting in complete blindness in most of them. Extraocular or intracerebral malformation or abnormalities are seen in only a small number in this patient group. The 2 affected mothers with SOX2 mutations might be due to mosaicism. The unaffected mother with OTX2 mutation might be a sign of non-penetrance.
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