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Nanophthalmos and posterior microphthalmos are ocular abnormalities in which both eyes are abnormally small, and typically associated with extreme hyperopia. We recruited 40 individuals from 13 kindreds with nanophthalmos or posterior microphthalmos, with 12 probands subjected to exome sequencing. Nine probands (69.2%) were assigned a genetic diagnosis, with variants in MYRF, TMEM98, MFRP, and PRSS56. Two of four PRSS56 families harboured the previously described c.1066dupC variant implicated in over half of all reported PRSS56 kindreds, with different surrounding haplotypes in each family suggesting a mutational hotspot. Individuals with a genetic diagnosis had shorter mean axial lengths and higher hyperopia than those without, with recessive forms associated with the most extreme phenotypes. These findings detail the genetic architecture of nanophthalmos and posterior microphthalmos in a cohort of predominantly European ancestry, their relative clinical phenotypes, and highlight the shared genetic architecture of rare and common disorders of refractive error.

PurposeRefractive error is caused by a disparity between the axial length and focusing power of the eye. Nanophthalmos is a rare ocular abnormality in which both eyes are abnormally small, typically causing extreme hyperopic refractive error, and associated with an increased risk of angle-closure glaucoma.MethodsA cohort of 40 individuals from 13 unrelated nanophthalmos kindreds were recruited, with 11 probands subjected to exome sequencing.ResultsNine probands (69.2%) were assigned a genetic diagnosis, with variants in PRSS56 (4), MFRP (3), and previously reported variants in TMEM98 (1) and MYRF (1). Two of the four PRSS56 probands harboured the previously described c.1066dupC frameshift variant implicated in over half of all reported PRSS56 kindreds, with surrounding haplotypes distinct from each other, and from a previously reported Tunisian c.1066dupC haplotype. Individuals with a genetic diagnosis had shorter mean axial lengths (P=7.22×10−9) and more extreme hyperopia (P=0.0005) than those without a genetic diagnosis, with recessive forms associated with the shortest axial lengths and highest hyperopia. All individuals with an axial length below 18 mm in their smaller eye (17/17) were assigned a genetic diagnosis.ConclusionsThese findings detail the genetic architecture of nanophthalmos in an Australian cohort of predominantly European ancestry, their relative clinical phenotypes, and highlight the shared genetic architecture of rare and common disorders of refractive error.

Purpose: Thyroid-associated orbitopathy (TO) is an autoimmune-mediated orbital inflammation that can lead to disfigurement and blindness. Multiple genetic loci have been associated with Graves' disease, but the genetic basis for TO is largely unknown. This study aimed to identify loci associated with TO in individuals with Graves' disease, using a genome-wide association scan (GWAS) for the first time to our knowledge in TO. Methods: Genome-wide association scan was performed on pooled DNA from an Australian Caucasian discovery cohort of 265 participants with Graves' disease and TO (cases) and 147 patients with Graves' disease without TO (controls). Top-ranked single nucleotide polymorphisms (SNPs) then were genotyped in individual DNA samples from the discovery cohort, and two replication cohorts totaling 584 cases and 367 controls. Results: In the GWAS of pooled DNA samples, several SNPs showed suggestive association with TO at genome-wide P ≤ 10; rs953128 located on chr10q21.1, rs2867161 on chr7q11.22, rs13360861 on chr5q12.3, rs7636326 on chr3q26.2, rs10266576 on chr 7q11.22, rs60457622 on chr3q23, and rs6110809 on chr20p12.1. However, the only SNP consistently associated with TO on individual genotyping in the discovery and replication cohorts was rs6110809, located within MACROD2 on chromosome 20p12.1. On combined analysis of discovery and replication cohorts, the minor A allele of rs6110809 was more frequent in TO than in Graves' disease controls without TO (P = 4.35 × 10; odds ratio [OR] = 1.77; 95% confidence interval [CI], 1.35–2.32) after adjusting for age, sex, duration of Graves' disease, and smoking. Conclusions: In patients with Graves' disease, a common genetic variant inMACROD2 may increase susceptibility for thyroid-associated orbitopathy. This association now requires confirmation in additional independent cohorts.

Anterior segment dysgenesis describes a group of heterogeneous developmental disorders that affect the anterior chamber of the eye and are associated with an increased risk of glaucoma. Here, we report homozygous mutations in peroxidasin (PXDN) in two consanguineous Pakistani families with congenital cataract-microcornea with mild to moderate corneal opacity and in a consanguineous Cambodian family with developmental glaucoma and severe corneal opacification. These results highlight the diverse ocular phenotypes caused by PXDN mutations, which are likely due to differences in genetic background and environmental factors. Peroxidasin is an extracellular matrix-associated protein with peroxidase catalytic activity, and we confirmed localization of the protein to the cornea and lens epithelial layers. Our findings imply that peroxidasin is essential for normal development of the anterior chamber of the eye, where it may have a structural role in supporting cornea and lens architecture as well as an enzymatic role as an antioxidant enzyme in protecting the lens, trabecular meshwork, and cornea against oxidative damage.

OBJECTIVE Aldose reductase (ALR) is involved in diabetic microvascular damage via the polyol pathway. A recent meta-analysis found genetic variation in the ALR gene (AKR1B1) to be significantly associated with diabetic retinopathy (DR). We investigated the genetic association of AKR1B1 with DR. RESEARCH DESIGN AND METHODS The study enrolled 909 individuals with diabetes. Participants were genotyped for an AKR1B1 (CA)n microsatellite and 14 tag single nucleotide polymorphisms, and ophthalmological assessment was performed. RESULTS A total of 514 individuals were found to have DR. rs9640883 was significantly associated with DR (P = 0.0005). However, AKR1B1 variation was not independently associated with DR development after adjusting for relevant clinical parameters. rs9640883 was associated with duration of diabetes (P = 0.002). CONCLUSION Many previous reports have failed to account for known risk factors for DR. The commonly reported association of AKR1B1 with DR may be due to an association of the gene with younger age at onset of diabetes.

Congenital cataract is the most common cause of treatable visual impairment in children worldwide. Mutations in many different genes lead to congenital cataract. Recently, mutations in the receptor tyrosine kinase gene, EPHA2, have been found to cause congenital cataract in six different families. Although these findings have established EPHA2 as a causative gene, the total contribution of mutations in this gene to congenital cataract is unknown. In this study, for the first time, a population-based approach was used to investigate the frequency of disease causing mutations in the EPHA2 gene in inherited cataract cases in South-Eastern Australia. A cohort of 84 familial congenital or juvenile cataract index cases was screened for mutations in the EPHA2 gene by direct sequencing. Novel changes were assessed for segregation with the disease within the family and in unrelated controls. Microsatellite marker analysis was performed to establish any relationship between families carrying the same mutation. We report a novel congenital cataract causing mutation c.1751C>T in the EPHA2 gene and the previously reported splice mutation c.2826-9G>A in two new families. Additionally, we report a rare variant rs139787163 potentially associated with increased susceptibility to cataract. Thus mutations in EPHA2 account for 4.7% of inherited cataract cases in South-Eastern Australia. Interestingly, the identified rare variant provides a link between congenital and age-related cataract.

This article appeared in Human Mutation, published by Wiley-Blackwell. Under Wiley-Blackwell's copyright, mandated authors are not permitted to make work available in an institutional repository., Congenital cataract is a heterogeneous disorder causing severe visual impairment in affected children. We screened four South Australian families with autosomal dominant congenital cataract for mutations in 10 crystallin genes known to cause congenital cataract. We identified a novel segregating heterozygous mutation, c.62G>A (p.R21Q), in the CRYΑA gene in one family. Western blotting of proteins freshly extracted from cataractous lens material of the proband demonstrated a marked reduction in the amount of the high-molecular-weight oligomers seen in the lens material of an unaffected individual. We conclude that the p.R21Q mutation, which is located in the highly conserved and structurally significant N-terminal region of the protein, is responsible for the cataract phenotype observed in the family as this mutation likely reduces the formation of the functional oligomeric alpha-crystallin., Contract grant sponsors: National Health and Medical Research Council (NHMRC) of Australia (426753); Channel 7 Children's Research Foundation, South Australia.

Keratoconus is a corneal disorder with an incidence of approximately 1 in 2000 and a prevalence of 54.5 per 100,000.1 The disorder leads to severe refractive error and irregular astigmatism. It is typically bilateral and is characterized by progressive thinning of the cornea, leading to asymmetric bulging and, in advanced cases, formation of a conical cornea.1 Based on the results of twin studies, reports of familial aggregation, and formal segregation analysis (reviewed in Ref. 2), keratoconus appears to have a strong genetic component; however, to date, few if any genes have been reliably identified. Approximately 6% to 23% of individuals with keratoconus report a positive family history.2 Linkage to multiple loci has been reported through a combination of linkage studies in extended pedigrees (3p14-q133; 5q14-q214; 15q22-q245; 1p36 and 8q246; and 13q327), in collections of small families and sibling pairs (2p248; 16q22-q239; 9q34, 5q32-q33, and 5q21.210; and 14q11.211), and in an identity-by-descent approach (20q12).12 Although the causatives genes in these regions remain to be elucidated, several reports have been made of candidate genes associated with keratoconus. The best studied of these is VSX1, the visual system homeobox-1 gene, with mutations identified in a small number of keratoconus patients,13–17 although not all studies support these findings.18–21 A 7-bp deletion in intron 2 of the SOD1 gene was described in two families,22 but no mutations were reported in another study.23 Promoter variants in IL1B were also nominally associated with keratoconus in a small Korean cohort.24 Several coding polymorphisms in the COL4A3 and COL4A4 genes encoding the structural proteins collagens were also found to be associated with keratoconus.25 These results are awaiting further replication. In addition to the candidate gene approach, recent developments in genotyping technology have made feasible large-scale genetic studies with hundreds of thousands of dense markers, such as genome-wide association studies (GWASs). Understanding of genetic susceptibility to ophthalmic diseases, such as glaucoma, macular degeneration, and refractive error,26–28 and ocular quantitative traits, such as corneal thickness,29–31 has been greatly enhanced by recent GWASs. We present the results of two genome-wide association studies, both of which point to the HGF (hepatocyte growth factor) gene as a keratoconus susceptibility locus. Two SNPs located upstream of the HGF gene on chromosome 7 showed repeated association with keratoconus in independent cohorts of patients, thus providing initial evidence that they may be associated with the common form of keratoconus in Caucasian patients. We also present data indicating association of the same SNPs with the serum HGF level in normal participants.

© 2010 Hattersley et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited., Background A novel phenotype consisting of cataract, mental retardation, erythematous skin rash and facial dysmorphism was recently described in an extended pedigree of Australian Aboriginal descent. Large scale chromosomal re-arrangements had previously been ruled out. We have conducted a genome-wide scan to map the linkage region in this family. Methods Genome-wide linkage analysis using Single Nucleotide Polymorphism (SNP) markers on the Affymetrix 10K SNP array was conducted and analysed using MERLIN. Three positional candidate genes (ZBTB17, EPHA2 and EPHB2) were sequenced to screen for segregating mutations. Results Under a fully penetrant, dominant model, the locus for this unique phenotype was mapped to chromosome 1p35.3-p36.32 with a maximum LOD score of 2.41. The critical region spans 48.7 cM between markers rs966321 and rs1441834 and encompasses 527 transcripts from 364 annotated genes. No coding mutations were identified in three positional candidate genes EPHA2, EPHB2 or ZBTB17. The region overlaps with a previously reported region for Volkmann cataract and the phenotype has similarity to that reported for 1p36 monosomy. Conclusions The gene for this syndrome is located in a 25.6 Mb region on 1p35.3-p36.32. The known cataract gene in this region (EPHA2) does not harbour mutations in this family, suggesting that at least one additional gene for cataract is present in this region.

Purpose To identify the causative gene for autosomal dominant total congenital cataract in a six-generation Australian family displaying linkage to chromosome 1p36. Methods Eight candidate genes (HSPB7, FBXO42, EFHD2, ZBTB17, CAPZB, FBLIM1, ALDH4A1, and MFAP2) from within the previously defined linkage interval were selected based on expression in lens and their known or putative function. The coding exons were sequenced in multiple affected family members and compared to the reference sequence. Results No segregating mutations were identified in any of the eight genes. Thirty-one polymorphisms were detected, 20 of which were in the exons and 11 in the flanking introns. Conclusions Coding mutations in HSPB7, FBXO42, EFHD2, ZBTB17, CAPZB, FBLIM1, ALDH4A1, and MFAP2 do not account for congenital cataract in this family.

Keratoconus is a debilitating ocular disease characterised by progressive asymmetrical thinning of the cornea, the clear covering at the front of the eye. The resulting protrusion of the cornea results in severe refractive error, in the most severe cases requiring corneal grafting. It is a complex disease with a genetic component. Despite several reports of linked loci, major gene identification has been elusive. A genome-wide linkage scan in a large Australian pedigree with apparent autosomal dominant keratoconus was conducted using the Affymetrix 10K SNP chip and two regions of linkage identified. Functional candidate genes from within both linkage peaks were assessed for corneal expression and screened for mutations in affected family members. Equal evidence of linkage was detected to both 1p36.23-36.21 and 8q13.1-q21.11 with LOD scores of 1.9. Analysis of both loci concurrently suggests digenic linkage with two-locus LOD score of 3.4. All affected individuals carry identical haplotypes at both loci. Carriers of either linked haplotype without the other do not have keratoconus. No mutations were identified in the following candidate genes expressed in the cornea: ENO1, CTNNBIP1, PLOD1, UBIAD1, SPSB1 or TCEB1. Although the pedigree appears to demonstrate simple autosomal dominant inheritance, the disorder is actually genetically complex. This pedigree may provide a link between inherited forms of keratoconus and sporadic cases.

Background Graves’ disease is an autoimmune thyroid disease of complex inheritance. Multiple genetic susceptibility loci are thought to be involved in Graves’ disease and it is therefore likely that these can be identified by genome wide association studies. This study aimed to determine if a genome wide association study, using a pooling methodology, could detect genomic loci associated with Graves’ disease. Results Nineteen of the top ranking single nucleotide polymorphisms including HLA-DQA1 and C6orf10, were clustered within the Major Histo-compatibility Complex region on chromosome 6p21, with rs1613056 reaching genome wide significance (p = 5 × 10−8). Technical validation of top ranking non-Major Histo-compatablity complex single nucleotide polymorphisms with individual genotyping in the discovery cohort revealed four single nucleotide polymorphisms with p ≤ 10−4. Rs17676303 on chromosome 1q23.1, located upstream of FCRL3, showed evidence of association with Graves’ disease across the discovery, replication and combined cohorts. A second single nucleotide polymorphism rs9644119 downstream of DPYSL2 showed some evidence of association supported by finding in the replication cohort that warrants further study. Conclusions Pooled genome wide association study identified a genetic variant upstream of FCRL3 as a susceptibility locus for Graves’ disease in addition to those identified in the Major Histo-compatibility Complex. A second locus downstream of DPYSL2 is potentially a novel genetic variant in Graves’ disease that requires further confirmation. Electronic supplementary material The online version of this article (doi:10.1186/s12864-016-3276-z) contains supplementary material, which is available to authorized users.