Congenital aniridia beyond black eyes: From phenotype and novel genetic mechanisms to innovative therapeutic approaches.

Congenital PAX6-aniridia, initially characterized by the absence of the iris, has progressively been shown to be associated with other developmental ocular abnormalities and systemic features making congenital aniridia a complex syndromic disorder rather than a simple isolated disease of the iris. Moreover, foveal hypoplasia is now recognized as a more frequent feature than complete iris hypoplasia and a major visual prognosis determinant, reversing the classical clinical picture of this disease. Conversely, iris malformation is also a feature of various anterior segment dysgenesis disorders caused by PAX6-related developmental genes, adding a level of genetic complexity for accurate molecular diagnosis of aniridia.

Comprehensive phenotypic and functional analysis of dominant and recessive FOXE3 alleles in ocular developmental disorders.

The forkhead transcription factor FOXE3 is critical for vertebrate eye development. Recessive and dominant variants cause human ocular disease but the full range of phenotypes and mechanisms of action for the two classes of variants are unknown. We identified FOXE3 variants in individuals with congenital eye malformations and carried out in vitro functional analysis on selected alleles.

Functional characterization of zebrafish orthologs of the human Beta 3-Glucosyltransferase B3GLCT gene mutated in Peters Plus Syndrome.

Peters Plus Syndrome (PPS) is a rare autosomal recessive disease characterized by ocular defects, short stature, brachydactyly, characteristic facial features, developmental delay and other highly variable systemic defects. Classic PPS is caused by loss-of-function mutations in the B3GLCT gene encoding for a β3-glucosyltransferase that catalyzes the attachment of glucose via a β1-3 glycosidic linkage to O-linked fucose on thrombospondin type 1 repeats (TSRs). B3GLCT was shown to participate in a non-canonical ER quality control mechanism; however, the exact molecular processes affected in PPS are not well understood.

Analysis of in pediatric and adult glaucoma and other ocular phenotypes.

Purpose: The gene encodes an enzyme that is a member of the cytochrome P450 superfamily. Mutations in have been mainly reported in recessive pediatric ocular phenotypes, such as primary congenital glaucoma (PCG) and congenital glaucoma with anterior segment dysgenesis (CG with ASD), with some likely pathogenic variants also identified in families affected with adult-onset primary open angle glaucoma (POAG).

Methods: We examined in 158 pediatric patients affected with PCG (eight), CG with ASD (22), CG with other developmental ocular disorders (11), juvenile glaucoma with or without additional ocular anomalies (26), and ASD or other developmental ocular conditions without glaucoma (91); in addition, a large cohort of adult patients with POAG (193) and POAG-negative controls (288) was examined.

EFTUD2 deficiency in vertebrates: Identification of a novel human mutation and generation of a zebrafish model.

Background: Congenital microphthalmia and coloboma are severe developmental defects that are frequently associated with additional systemic anomalies and display a high level of genetic heterogeneity.

Methods: To identify the pathogenic variant in a patient with microphthalmia, coloboma, retinal dystrophy, microcephaly, and other features, whole exome sequencing analysis of the patient and parental samples was undertaken. To further explore the identified variant/gene, expression and functional studies in zebrafish were performed.

Mutations in MAB21L2 result in ocular Coloboma, microcornea and cataracts.

Ocular coloboma results from abnormal embryonic development and is often associated with additional ocular and systemic features. Coloboma is a highly heterogeneous disorder with many cases remaining unexplained. Whole exome sequencing from two cousins affected with dominant coloboma with microcornea, cataracts, and skeletal dysplasia identified a novel heterozygous allele in MAB21L2, c.

A case of 22q11.2 deletion syndrome with Peters anomaly, congenital glaucoma, and heterozygous mutation in CYP1B1.

We read with interest the recent publication by Tarlan and colleagues 1 describing a patient with 22q11.2 deletion syndrome and ocular features of right microphthalmia and left anterior segment dysgenesis. While anterior segment dysgenesis disorders are occasionally reported with 22q11.

VSX2 mutations in autosomal recessive microphthalmia.

Purpose: To further explore the spectrum of mutations in the Visual System Homeobox 2 (VSX2/CHX10) gene previously found to be associated with autosomal recessive microphthalmia.

Methods: We screened 95 probands with syndromic or isolated developmental ocular conditions (including 55 with anophthalmia/microphthalmia) for mutations in VSX2.

Results: Homozygous mutations in VSX2 were identified in two out of five consanguineous families with isolated microphthalmia.

Genetics of anterior segment dysgenesis disorders.

Purpose Of Review: Anterior segment dysgenesis (ASD) disorders encompass a spectrum of developmental conditions affecting the cornea, iris, and lens and are generally associated with an approximate 50% risk for glaucoma. These conditions are characterized by both autosomal dominant and recessive patterns of inheritance often with incomplete penetrance/variable expressivity. This article summarizes what is known about the genetics of ASD disorders and reviews recent developments.

Examination of SOX2 in variable ocular conditions identifies a recurrent deletion in microphthalmia and lack of mutations in other phenotypes.

Purpose: The role of SRY-Box 2 (SOX2) in anophthalmia/microphthalmia (A/M) is well known, with 10%-20% of A/M explained by mutations in SOX2. SOX2 plays roles in the development of both the posterior and anterior segment structures of the eye and relies on interactions with tissue-specific partner proteins to execute its function, raising the possibility that SOX2 mutations may result in varying ocular phenotypes. Recent data has identified a missense mutation in SOX2 in an extended pedigree with phenotypes as varied as A/M, isolated iris hypoplasia, iris and chorioretinal coloboma, pupil defects, and hypermetropia, suggesting a broader phenotypic spectrum associated with SOX2 mutations.

FOXE3 plays a significant role in autosomal recessive microphthalmia.

FOXE3 forkhead transcription factor is essential to lens development in vertebrates. The eyes of Foxe3/foxe3-deficient mice and zebrafish fail to develop normally. In humans, autosomal dominant and recessive mutations in FOXE3 have been associated with variable phenotypes including anterior segment anomalies, cataract, and microphthalmia.

Mutation analysis of B3GALTL in Peters Plus syndrome.

Peters Plus syndrome comprises ocular anterior segment dysgenesis (most commonly Peters anomaly), short stature, hand anomalies, distinctive facial features, and often other additional defects and is inherited in an autosomal-recessive pattern. Mutations in the beta1,3-glucosyltransferase gene (B3GALTL) were recently reported in 20 out of 20 patients with Peters Plus syndrome. In our study, B3GALTL was examined in four patients with typical Peters Plus syndrome and four patients that demonstrated a phenotypic overlap with this condition.