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Retinal dystrophies (RD) constitute a group of blinding diseases that are characterized by clinical variability and pronounced genetic heterogeneity. The different nonsyndromic and syndromic forms of RD can be attributed to mutations in more than 200 genes. Consequently, next generation sequencing (NGS) technologies are among the most promising approaches to identify mutations in RD. We screened a large cohort of patients comprising 89 independent cases and families with various subforms of RD applying different NGS platforms. While mutation screening in 50 cases was performed using a RD gene capture panel, 47 cases were analyzed using whole exome sequencing. One family was analyzed using whole genome sequencing. A detection rate of 61% was achieved including mutations in 34 known and two novel RD genes. A total of 69 distinct mutations were identified, including 39 novel mutations. Notably, genetic findings in several families were not consistent with the initial clinical diagnosis. Clinical reassessment resulted in refinement of the clinical diagnosis in some of these families and confirmed the broad clinical spectrum associated with mutations in RD genes.

X-linked cone dysfunction disorders such as Blue Cone Monochromacy and X-linked Cone Dystrophy are characterized by complete loss (of) or reduced L- and M- cone function due to defects in the OPN1LW/OPN1MW gene cluster. Here we investigated 24 affected males from 16 families with either a structurally intact gene cluster or at least one intact single (hybrid) gene but harbouring rare combinations of common SNPs in exon 3 in single or multiple OPN1LW and OPN1MW gene copies. We assessed twelve different OPN1LW/MW exon 3 haplotypes by semi-quantitative minigene splicing assay. Nine haplotypes resulted in aberrant splicing of ≥20% of transcripts including the known pathogenic haplotypes (i.e. ‘LIAVA’, ‘LVAVA’) with absent or minute amounts of correctly spliced transcripts, respectively. De novo formation of the ‘LIAVA’ haplotype derived from an ancestral less deleterious ‘LIAVS’ haplotype was observed in one family with strikingly different phenotypes among affected family members. We could establish intrachromosomal gene conversion in the male germline as underlying mechanism. Gene conversion in the OPN1LW/OPN1MW genes has been postulated, however, we are first to demonstrate a de novo gene conversion within the lineage of a pedigree.

Background: The relationship between systemic inflammatory processes to total knee arthroplasty (TKA) outcomes remains unclear. This study investigates the relationship between serum high-sensitivity C-reactive protein (hs-CRP) and functional outcomes post-TKA. Methods: A total of 31 patients with osteoarthritis (OA) who underwent TKA were enrolled in the study; 15 with hs-CRP ≤1.0 mg/l (low hs-CRP group) and 16 subjects with hs-CRP ≥4.0 mg/l (high hs-CRP group). During surgery, synovium and bone sections were sequestered, formalin-fixed, and paraffin embedded for slide preparation. Tissue sections were stained with hematoxylin and eosin and analyzed using a light microscope. A total of 12 cytokines were measured in synovial fluid samples from the knee joint at time of surgery and analyzed using the Luminex Multi-Analyte Profiling System. Relationships between cytokines and hs-CRP were assessed using Spearman correlation coefficients. Student’s t-tests were used to compare Short Form health outcomes survey (SF-12) health outcomes between high and low hs-CRP, and presurgical and postsurgical visits. Results: Mean ± standard deviation (SD) baseline and 1-year hs-CRP values for the low hs-CRP group were 0.55 ± 0.23 mg/l and 1.22 ± 1.32 mg/l, respectively (n = 15; p = 0.051) and for the high hs-CRP group were 7.86 ± 5.98 mg/l and 14.11 ± 38.9 mg/l, respectively (n = 13; p = 0.54). Lymphocytes were present in 10 synovium and one bone sample (all but one from high hs-CRP group). Interleukin (IL)-5 and IL-10 were significantly correlated with hs-CRP (p = 0.0137 and p = 0.0029, respectively). The low hs-CRP group exhibited significant improvement in the physical component of SF-12 at 6 and 12 months compared with baseline, whereas the high hs-CRP group exhibited significant improvement only at 6 months. Body mass index (BMI) had a significant positive correlation with presurgical hs-CRP. Conclusions: The results of this study provide support for inflammatory mechanisms contributing to the OA progression, with hs-CRP being a possible predictive variable, combined with BMI and other comorbidities, of post-TKA function.

The Marfan syndrome (MFS) is a pleiotropic, autosomal dominant disorder of connective tissue with highly variable clinical manifestations including aortic dilatation and dissection, ectopia lentis, and a series of skeletal anomalies. Mutations in the gene for fibrillin‐1 (FBN1) cause MFS, and at least 337 mainly unique mutations have been published to date. FBN1 mutations have been found not only in MFS but also in a range of connective tissue disorders collectively termed fibrillinopathies ranging from mild phenotypes, such as isolated ectopia lentis, to severe disorders including neonatal MFS, which generally leads to death within the first two years of life. The present article intends to provide an overview of mutations found in MFS and related disorders and to discuss potential genotype–phenotype correlations in MFS. Hum Mutat 20:153–161, 2002. © 2002 Wiley‐Liss, Inc.

Background Investigation of the OPA1 mutation spectrum in autosomal dominant optic atrophy (ADOA) in Denmark. Methods Index patients from 93 unrelated ADOA families were assessed for a common Danish founder mutation (c.2826_2836delinsGGATGCTCCA) in OPA1 . If negative, direct DNA sequencing of the coding sequence and multiplex ligation-dependent probe amplification (MLPA) were performed. Results from MLPA analysis have been previously reported. Haplotype analysis was carried out analysing single nucleotide polymorphisms (SNP). Retrospective clinical data were retrieved from medical files. Results Probably causative mutations were identified in 84 out of 93 families (90%) including 15 novel mutations. Three mutations c.983A > G, c.2708_2711delTTAG and c.2826_2836delinsGGATGCTCCA, were responsible for ADOA in10, 11 and 28 families, respectively, corresponding to 11%, 12% and 30%. A common haplotype in nine of ten c.983A > G families suggests that they descend from a single founder. The c.2708_2711delTTAG mutation was present on at least two haplotypes and has been repeatedly reported in various ethnic groups,thus represents a mutational hotspot. Clinical examinations of index patients with the two latter mutations demonstrated large inter- and intra-familial variations apparently. Conclusions Genetic testing for OPA1 mutations assist in the diagnosis. We have identified mutations in OPA1 in 90% of families including 15 novel mutations. Both DNA sequencing and MLPA analysis are necessary to achieve a high detection rate. More than half of the affected families in Denmark are represented by three common mutations, at least two of which are due to a founder effect, which may account for the high prevalence of ADOA in Denmark.

Wolfram syndrome (WS) is a neuro-degenerative autosomal recessive (AR) disorder (OMIM #222300) caused by mutations in the WFS1 gene on 4p16.1. More than 120 mutations have been identified in WFS1 associated with AR WS, as well as autosomal dominant nonsyndromic low-frequency sensorineural hearing loss (LFSNHL). WFS1 variants were identified in eight subjects from seven families with WS, leading to the identification of four novel mutations, Q194X (nonsense), H313Y (missense), L313fsX360 (duplication frame shift) and F883fsX951 (deletion frame shift), and four previously reported mutations, A133T and L543R (missense), V415del (in frame triple deletion) and F883fsX950 (deletion frame shift). A mutation was found in 11/14 disease chromosomes, two subjects were homozygous for one mutation, one subject was compound heterozygous for two nucleotide substitutions (missense), one subject was compound heterozygous for a duplication and a deletion (frame shift), and in three families only one mutation was detected (Q194X and H313Y). All affected individuals shared clinically early-onset diabetes mellitus and progressive optic atrophy with onset in the first and second decades, respectively. In contrast, diabetes insipidus was present in two subjects only. Various degrees and types of hearing impairment were diagnosed in six individuals and cataract was observed in five subjects.

Inherited retinal diseases (IRDs) are a common cause of visual impairment. IRD covers a set of genetically highly heterogeneous disorders with more than 150 genes associated with one or more clinical forms of IRD. Molecular genetic diagnosis has become increasingly important especially due to expanding number of gene therapy strategies under development. Next generation sequencing (NGS) of gene panels has proven a valuable diagnostic tool in IRD. We present the molecular findings of 677 individuals, residing in Denmark, with IRD and report 806 variants of which 187 are novel. We found that deletions and duplications spanning one or more exons can explain 3% of the cases, and thus copy number variation (CNV) analysis is important in molecular genetic diagnostics of IRD. Seven percent of the individuals have variants classified as pathogenic or likely-pathogenic in more than one gene. Possible Danish founder variants in EYS and RP1 are reported. A significant number of variants were classified as variants with unknown significance; reporting of these will hopefully contribute to the elucidation of the actual clinical consequence making the classification less troublesome in the future. In conclusion, this study underlines the relevance of performing targeted sequencing of IRD including CNV analysis as well as the importance of interaction with clinical diagnoses.

Mutations in the gene for fibrillin-1 (FBN1) cause Marfan syndrome, an autosomal dominant disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular system. There is a remarkable degree of clinical variability both within and between families with Marfan syndrome as well as in individuals with related disorders of connective tissue caused by FBN1 mutations and collectively termed type-1 fibrillinopathies. The so-called neonatal region in FBN1 exons 24-32 comprises one of the few generally accepted genotype-phenotype correlations described to date. In this work, we report 12 FBN1 mutations identified by temperature-gradient gel electrophoresis screening of exons 24-40 in 127 individuals with Marfan syndrome or related disorders. The data reported here, together with other published reports, document a significant clustering of mutations in exons 24-32. Although all reported mutations associated with neonatal Marfan syndrome and the majority of point mutations associated with atypically severe presentations have been found in exons 24-32, mutations associated with classic Marfan syndrome occur in this region as well. It is not possible to predict whether a given mutation in exons 24-32 will be associated with classic, atypically severe, or neonatal Marfan syndrome.

Oculocutaneous albinism (OCA) is a genetically heterogeneous disorder. Six genes are associated with autosomal recessive OCA ( TYR , OCA2 , TYRP1 , SLC45A2 , SLC24A5 and LRMDA ), and one gene, GPR143 , is associated with X-linked ocular albinism (OA). Molecular genetic analysis provides a genetic diagnosis in approximately 60% of individuals with clinical OA/OCA. A considerably number of the remaining 40% are heterozygous for a causative sequence variation in TYR . To identify missing causative sequence variants in these, we used a NGS based approach, genotyping and segregation analysis. We report two putative pathogenic haplotypes which only differ by two extremely rare SNVs, indicating that the haplotypes have a common derivation. Both haplotypes segregate consistent with an autosomal recessive inheritance pattern and include the allele p.S192Y-p.R402Q. An explanation for the pathogenicity of the haplotypes could be the combination of p.S192Y and p.R402Q. Homozygosity for the pathogenic haplotypes causes a partial albinism phenotype. In our cohort, 15% of affected individuals had a molecular genetic diagnosis involving the pathogenic haplotype. Consequently, the prevalence of albinism seems to be substantially underestimated, and children with unexplained bilateral subnormal vision and/or nystagmus should be analysed clinically and molecularly for albinism.

Objectives To evaluate comorbidity before and after the diagnosis of branch retinal vein occlusion to determine whether it is a consequence of arterial thickening and therefore could serve as a diagnostic marker for other comorbidities and to evaluate the risk factors for the development of such occlusion.Design Case-control study with prospective follow-up data from Danish national registries.Setting Four secondary referral centres covering about 80% of the Danish population (4.4 million).Participants 1168 patients with photographically verified branch retinal vein occlusion and 116 800 controls alive and aged ≥40 when the occlusion was diagnosed in the corresponding case.Main outcome measures The risk of comorbidity 10 years and 1 year before the diagnosis of branch retinal vein occlusion and the incident comorbidity in a mean period of seven years after the diagnosis, with odds ratios and incidence rate ratios adjusted for age, sex, and year of diagnosis.Results Risk factors present 10 years and 1 year before the diagnosis of branch retinal vein occlusion included peripheral artery disease (odds ratio 1.83, 95% confidence interval 1.14 to 2.95), diabetes (1.74, 1.40 to 2.17) and arterial hypertension (2.16, 1.86 to 2.51). After the diagnosis, patients had an increased risk of developing arterial hypertension (incidence rate ratio 1.37, 95% confidence interval 1.15 to 1.57), diabetes (1.51, 1.17 to 2.04), congestive heart failure (1.41, 1.12 to 1.68), and cerebrovascular disease (1.49, 1.27 to 1.76).Conclusion Diabetes, hypertension, and peripheral artery disease are associated with an increased risk of developing branch retinal vein occlusion up to a decade later. Branch retinal vein occlusion was associated with an increased risk of subsequently developing hypertension, diabetes, congestive heart failure, and cerebrovascular disease, emphasising the importance of preventive initiatives. These results fit the assumption that branch retinal vein occlusion is a consequence of arterial thickening and that the arteriovenous crossing signs that precede it are hallmarks of arterial disease.