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Background: Anophthalmia, microphthalmia and coloboma are a genetically heterogenous spectrum of developmental eye disorders. Recently, variants in the Wnt-pathway gene Frizzled Class Receptor 5 (FZD5) have been identified in individuals with coloboma and rarely microphthalmia, sometimes with additional phenotypes and variable penetrance., Materials and Methods: We identified variants in FZD5 in individuals with developmental eye disorders from the UK (including the DDD Study [www.ddduk.org/access.html]), France and Spain using whole genome/exome sequencing or customized NGS panels of ocular development genes., Results: We report eight new families with FZD5 variants and ocular coloboma. Three individuals presented with additional syndromic features, two explicable by additional variants in other genes ( SLC12A2 and DDX3X ). In two families initially showing incomplete penetrance, re-examination of apparently unaffected carrier individuals revealed subtle ocular colobomatous phenotypes. Finally, we report two families with microphthalmia in addition to coloboma, representing the second and third reported cases of this phenotype in conjunction with FZD5 variants., Conclusions: Our findings indicate FZD5 variants are typically associated with isolated ocular coloboma, occasionally microphthalmia, and that extraocular phenotypes are likely to be explained by other gene alterations.

Background: Congenital cataract displays large phenotypic (syndromic and isolated cataracts) and genetic heterogeneity. Mutations in several transcription factors involved in eye development, like PITX3, have been associated with congenital cataracts and anterior segment mesenchymal disorders., Materials and Methods: Targeted sequencing of 187 genes involved in ocular development was performed in 96 patients with mainly anophthalmia and microphthalmia. Additionally, Sanger sequencing analysis of PITX3 was performed on a second cohort of 32 index cases with congenital cataract and Peters anomaly and/or sclereocornea., Results: We described five families with four different PITX3 mutations, two of which were novel. In Family 1, the heterozygous recurrent c.640_656dup (p.Gly220Profs*95) mutation cosegregated with eye anomalies ranging from congenital cataract to Peters anomaly. In Family 2, the novel c.669del [p.(Leu225Trpfs*84)] mutation cosegregated with dominantly inherited eye anomalies ranging from posterior embryotoxon to congenital cataract in heterozygous carriers and congenital sclereocornea and cataract in a patient homozygous for this mutation. In Family 3, we identified the recurrent heterozygous c.640_656dup (p.Gly220Profs*95) mutation segregating with congenital cataract. In Family 4, the de novo c.582del [p.(Ile194Metfs*115)] mutation was identified in a patient with congenital cataract, microphthalmia, developmental delay and autism. In Family 5, the c.38G>A (p.Ser13Asn) mutation segregated dominantly in a family with Peters anomaly, which is a novel phenotype associated with the c.38G>A variant compared with the previously reported isolated congenital cataract., Conclusions: Our study unveils different phenotypes associated with known and novel mutations in PITX3, which will improve the genetic counselling of patients and their families.

The Usher syndrome (USH) is an autosomal recessive hereditary disorder characterized by the association of sensorineural hearing loss, retinitis pigmentosa (RP) and, in some cases, vestibular dysfunction. The USH1G gene, encoding SANS, has been found to cause both Usher syndrome type I and atypical Usher syndrome. 109 Spanish unrelated patients suffering from Usher syndrome type I, type II, type III and unclassified Usher syndrome were screened for mutations in this gene, but only eight different changes without a clear pathogenic effect have been detected. Based on these results as well as previous studies in other populations where mutational analysis of this gene has been carried out, one can conclude that USH1G has a minor involvement in Usher syndrome pathogenesis.

The intracellular distribution of proteins, compartments, substrates, and products is an active process called intracellular traffic. Control of intracellular traffic is established by small GTP-binding proteins (Rab proteins). Rab proteins are modified by geranyl-geranyl moieties necessary for membrane association and target-protein recognition. Geranyl-geranyl groups are transferred to Rab proteins by geranyl-geranyl transferase 2 (GGTase2). GGTase2 requires Rab escort protein 1 (REP1) to bind Rab proteins. REP1 null mutations underlie an X-linked retinal degeneration called choroideremia (CHM). This review summarizes the current biochemical and clinical knowledge on REP1 and CHM.

Defects in retinal vitamin A metabolism or in genes expressed in the retinal pigment epithelium (RPE) are related to nonsyndromic retinitis pigmentosa (RP). The RLBP1 gene encodes the cellular retinaldehyde-binding protein which, in the RPE and Müller cells of the retina, is thought to play a role in retinoid metabolism and visual pigment regeneration. We describe a study of the involvement of the RLBP1 gene in 50 autosomal recessive retinitis pigmentosa (ARRP) and four retinitis punctata albescens Spanish families. Cosegregation and homozygosity studies using an intragenic polymorphism and three close markers (D15S116, D15S127, and D15S130) ruled out RLBP1 as the cause of ARRP in 26 pedigrees. In the remaining families, SSCP analysis of the coding region and sequencing of the abnormal migrating bands did not detect any disease-causing mutation. These results indicate that mutations in the RLBP1 gene are not responsible for the ARRP or retinitis punctata albescens in this set of Spanish families. We did, however, identify two frequent polymorphisms (3'UTR + 167 G > T, T: 0.23 and G: 0.77; IVS6 + 20 T > C, T: 0.36 and C: 0.64), a silent substitution (S218S), and a rare variant (5'UTR-101 G > A).

A Spanish family affected with autosomal dominant retinitis pigmentosa (ADRP) with a diffuse phenotype showed a mutation in the rhodopsin gene. The mutation was the transition T-->C in codon 186, which has been reported once before in an American patient (Dryja et al., Proc Natl Acad Sci USA 1991;88:9370-9374). This change replaces a serine by a proline in the second intradiscal loop of the protein, generating a molecule that is probably folding- and transport-defective.

We present clinical and cytogenetic studies of a female patient affected with choroideremia, mild sensorineural deafness, and primary amenorrhea showing a balanced translocation between chromosomes X and 4. The breakpoint was precisely defined applying FISH techniques: 46,X,t(X;4)(q21.2;p16.3).ish t(X;4)(D4S96+, D4F26+; wcpX+). The X-chromosomal breakpoint was located within a region where both the choroideremia locus and a deafness locus (DFN3/POU3F4) have been mapped. The presence of X-linked disorders in this balanced carrier of X-autosomal translocations (XAT) can be explained either by the disruption of the structural coding or regulatory sequences of the gene(s) or by the submicroscopic deletion of this region leading to a contiguous gene deletion syndrome. The primary ovarian failure (POF) found in the present case has been already observed in XAT when the breakpoint is within a previously defined critical region (Xq13-26). A position effect is postulated as a possible explanation.

Autosomal dominant retinitis pigmentosa (adRP) may be caused by point mutations in the rhodopsin gene in up to 20% of Spanish families. Most of the rhodopsin mutations causing adRP have been reported in the heterozygous state. We describe a patient with adRP who is homozygous for a missense mutation at codon 188 in the second intradiscal domain of rhodopsin. All her sons are heterozygous for the mutation and show an RP phenotype suggesting complete penetrance for this mutation. The homozygous carrier of the mutation Gly-188-Arg in the rhodopsin gene showed a later subjective onset of symptoms than the heterozygotes, suggesting that the photoreceptor degeneration induced by the mutation is not dramatically influenced by mutant allele dosage.

The Usher syndrome (USH) is a group of autosomal recessive diseases characterized by congenital sensorineural hearing loss and retinitis pigmentosa. Three clinically distinct forms of Usher syndrome have so far been recognized and can be distinguished from one another by assessing auditory and vestibular function. Usher syndrome type II (USH2) patients have congenital moderate-to-severe nonprogressive hearing loss, retinitis pigmentosa, and normal vestibular function. Genetic linkage studies have revealed genetic heterogeneity among the three types of USH, with the majority of USH2 families showing linkage to the USH2A locus in 1q41. The USH2A gene (MIM 276901) has been identified: three mutations, 2314delG, 2913delG, and 4353-54delC, were initially reported in USH2A patients, the most frequent of which is the 2314delG mutation. It has been reported that this mutation can give rise to typical and atypical USH2 phenotypes. USH2 cases represent 62% of all USH cases in the Spanish population, and 95% of these cases have provided evidence of linkage to the USH2A locus. In the present study, the three reported mutations were analyzed in 59 Spanish families with a diagnosis of USH type II. The 2314delG was the only mutation identified in our population: it was detected in 25% of families and 16% of USH2 chromosomes analyzed. This study attempts to estimate the prevalence of this common mutation in a homogeneous Spanish population.

We present two siblings with retinitis pigmentosa, mental retardation, markedly short stature, and brachydactyly. This association of clinical findings appears to be distinct from previously described syndromes and seems to represent the pleiotropic effects of a single autosomal recessive gene.

A large family affected with autosomal dominant retinitis pigmentosa (ADRP) with a sectorial phenotype showed a previously described (G to A) mutation in the rhodopsin gene resulting in the substitution of a glycine residue by an arginine in codon 106 of rhodopsin. This mutation shows some unusual characteristics, such as initial pathology of the inferior retina, superior visual field with normal disc and retinal vessels, and ERG findings that show a modest reduction in both cone and rod amplitudes with normal implicit times. The Gly 106 Arg mutation has been previously reported in American and British patients. Its presence in a Spanish ADRP family confirms that it and its homogeneous associated phenotype are geographically widespread.