Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia

Abstract

Anophthalmia and microphthalmia (AM) are the most severe malformations of the eye, corresponding respectively to reduced size or absent ocular globe. Wide genetic heterogeneity has been reported and different genes have been demonstrated to be causative of syndromic and non-syndromic forms of AM. We screened seven AM genes [GDF6 (growth differentiation factor 6), FOXE3 (forkhead box E3), OTX2 (orthodenticle protein homolog 2), PAX6 (paired box 6), RAX (retina and anterior neural fold homeobox), SOX2 (SRY sex determining region Y-box 2), and VSX2 (visual system homeobox 2 gene)] in a cohort of 150 patients with isolated or syndromic AM. The causative genetic defect was identified in 21% of the patients (32/150). Point mutations were identified by direct sequencing of these genes in 25 patients (13 in SOX2, 4 in RAX, 3 in OTX2, 2 in FOXE3, 1 in VSX2, 1 in PAX6, and 1 in GDF6). In addition eight gene deletions (five SOX2, two OTX2 and one RAX) were identified using a semi-quantitative multiplex polymerase chain reaction (PCR) [quantitative multiplex PCR amplification of short fluorescent fragments (QMPSF)]. The causative genetic defect was identified in 21% of the patients. This result contributes to our knowledge of the molecular basis of AM, and will facilitate accurate genetic counselling.

Clinical utility gene card for: Non-Syndromic Microphthalmia Including Next-Generation Sequencing-Based Approaches

“…However, deletion of exon 3 has also been described. [8][9][10] Autosomal-recessive variants in RAX (MCOP3) [10][11][12] and ALDH1A3 (MCOP8) can be missense, nonsense or frameshift, with some splice donor variants. A RAX gene deletion has also been described in one patient with bilateral anophthalmia, with no other ocular or systemic abnormalities reported.…”

“…A RAX gene deletion has also been described in one patient with bilateral anophthalmia, with no other ocular or systemic abnormalities reported. 10 RAX mutations account for~2% of inherited anophthalmia/microphthalmia cases. 11 Only missense variants have been found in GDF6 (MCOP4) 10,13 and GDF3 (MCOP7), 14 and are inherited in an autosomal-dominant manner.…”

“…10 RAX mutations account for~2% of inherited anophthalmia/microphthalmia cases. 11 Only missense variants have been found in GDF6 (MCOP4) 10,13 and GDF3 (MCOP7), 14 and are inherited in an autosomal-dominant manner. Homozygous or compound heterozygous variants in MFRP (MCOP5) [15][16][17][18][19] or PRSS56 (MCOP6) [20][21][22][23] are associated with autosomal-recessive posterior microphthalmia, which defines a rare distinct phenotype restricted primarily to the posterior segment of the eye.…”

“…The majority of SOX2 sequence variants are de novo; nonsense, missense, frameshift and whole-gene deletions have been reported. 10,45,46 Like SOX2, the majority of OTX2 variants are inherited nonsense and frameshift variants leading to haploinsufficiency, with some reports of whole-gene deletions. 10,47 Patients often present with additional brain abnormalities.…”

“…10,45,46 Like SOX2, the majority of OTX2 variants are inherited nonsense and frameshift variants leading to haploinsufficiency, with some reports of whole-gene deletions. 10,47 Patients often present with additional brain abnormalities. In view that variants in the genes listed in Table 2 cause a wide range of ocular phenotypes with different expressivity, their molecular screening must be recommended.…”