Novel heterozygousOTX2mutations and whole gene deletions in anophthalmia, microphthalmia and coloboma

Abstract

Severe ocular malformations, including anophthalmia-microphthalmia (AM), are responsible for around 25% of severe visual impairment in childhood. Recurrent interstitial deletions of 14q22-23 are associated with AM and a wide range of extra-ocular phenotypes including brain anomalies. The homeobox gene OTX2 is located at 14q22.3 and has recently been identified as mutated in AM patients. Eight human OTX2 mutations have been reported in subjects with severe eye malformations, including AM, and variable developmental delay. We screened a novel AM cohort for mutations and deletions in OTX2, and identified four new mutations in six individuals and two cases of whole gene deletions. Our data suggest that OTX2 mutations and deletions account for 2-3% of AM cases.

Otx2 Induction of the Gonadotropin-releasing Hormone Promoter Is Modulated by Direct Interactions with Grg Co-repressors

“…The varying degree of penetrance observed in these mice suggests that correct dosage of Otx2 is critical for normal development to occur, and this hypothesis is supported by data from human patients where a heterozygous loss-of-function mutation can have highly pleiotropic effects within an affected family. Furthermore, both duplication and deletion of the OTX2-containing region of human chromosome 14q22 lead to developmental abnormalities (69,70), whereas specific mutations can cause a number of deficiencies including hypopituitarism, which includes low gonadotropins (71,72). Ongoing studies are utilizing a GnRH-neuron-specific conditional Otx2 knockout approach to determine the role of Otx2 in GnRH neuronal development and regulation of GnRH transcription in the adult.…”

Midbrain-Hindbrain Involvement in Septo-Optic Dysplasia

“…12 However, no careful description of MH structures has been provided so far in these patients. We reviewed the available brain MR midline sagittal images including the posterior cranial fossa of previously reported patients with Otx2 mutations [35][36][37][38] or chromosome 14 deletions including Otx2, [39][40][41][42][43] and we recognized a similar midbrain hypoplasia with a long pons and large superior vermis in 5 patients. 35,36,40,41,43 We therefore suggest that MH abnormalities may have been underestimated in patients with Otx2 mutations or deletion; further studies on larger series are awaited to address this hypothesis.…”

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

“…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.…”