Mutation Detection in Patients with Retinal Dystrophies Using Targeted Next Generation Sequencing

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

Sickle Cell Maculopathy: Microstructural Analysis Using OCTA and Identification of Genetic, Systemic, and Biological Risk Factors

International audienceTo identify genetic, systemic, and biological factors associated with the occurrence of sickle cell maculopathy (SCM). To evaluate microvascular macular alterations using optical coherence tomography angiography (OCTA) in sickle cell disease (SCD). DESIGN: Cross-sectional study. METHODS: One hundred fifty-one eyes of 78 adult SCD patients (43 HbSS, 30 HbSC, 4 S/b D , and 1 HbS Lepore) and 40 eyes of 20 healthy controls underwent spectral-domain optical coherence tomography (SDOCT) and OCTA using Spectralis HRADOCT (Heidelberg Engineering, Heidelberg, Germany). We analyzed the occurrence of SCM, the foveal avascular zone (FAZ) area, and the severity of macular ischemia and studied their relationships with genetic, systemic, and biological parameters using multivariate logistic regression analysis. RESULTS: Maculopathy occurred in 66 eyes (44%), and more frequently in HbSS patients (71%, P [ .004). Multivariate analysis identified HbSS genotype and lower prothrombin ratio (PR) as independently associated with SCM (P [ .01). Proliferative sickle cell retinopathy was also associated with SCM (P [ .02). FAZ enlargement was associated with higher lactate dehydrogenase level (P [ .02). Macular ischemia was more severe in patients with lower hemoglobin level (P [ .004) and lower PR (P [ .01). No flow areas were identified with OCTA even in eyes with no macular thinnin

Sickle Cell Maculopathy: Microstructural Analysis Using OCTA and Identification of Genetic, Systemic, and Biological Risk Factors

International audienceTo identify genetic, systemic, and biological factors associated with the occurrence of sickle cell maculopathy (SCM). To evaluate microvascular macular alterations using optical coherence tomography angiography (OCTA) in sickle cell disease (SCD). DESIGN: Cross-sectional study. METHODS: One hundred fifty-one eyes of 78 adult SCD patients (43 HbSS, 30 HbSC, 4 S/b D , and 1 HbS Lepore) and 40 eyes of 20 healthy controls underwent spectral-domain optical coherence tomography (SDOCT) and OCTA using Spectralis HRADOCT (Heidelberg Engineering, Heidelberg, Germany). We analyzed the occurrence of SCM, the foveal avascular zone (FAZ) area, and the severity of macular ischemia and studied their relationships with genetic, systemic, and biological parameters using multivariate logistic regression analysis. RESULTS: Maculopathy occurred in 66 eyes (44%), and more frequently in HbSS patients (71%, P [ .004). Multivariate analysis identified HbSS genotype and lower prothrombin ratio (PR) as independently associated with SCM (P [ .01). Proliferative sickle cell retinopathy was also associated with SCM (P [ .02). FAZ enlargement was associated with higher lactate dehydrogenase level (P [ .02). Macular ischemia was more severe in patients with lower hemoglobin level (P [ .004) and lower PR (P [ .01). No flow areas were identified with OCTA even in eyes with no macular thinnin

Sickle Cell Maculopathy: Microstructural Analysis Using OCTA and Identification of Genetic, Systemic, and Biological Risk Factors

International audienceTo identify genetic, systemic, and biological factors associated with the occurrence of sickle cell maculopathy (SCM). To evaluate microvascular macular alterations using optical coherence tomography angiography (OCTA) in sickle cell disease (SCD). DESIGN: Cross-sectional study. METHODS: One hundred fifty-one eyes of 78 adult SCD patients (43 HbSS, 30 HbSC, 4 S/b D , and 1 HbS Lepore) and 40 eyes of 20 healthy controls underwent spectral-domain optical coherence tomography (SDOCT) and OCTA using Spectralis HRADOCT (Heidelberg Engineering, Heidelberg, Germany). We analyzed the occurrence of SCM, the foveal avascular zone (FAZ) area, and the severity of macular ischemia and studied their relationships with genetic, systemic, and biological parameters using multivariate logistic regression analysis. RESULTS: Maculopathy occurred in 66 eyes (44%), and more frequently in HbSS patients (71%, P [ .004). Multivariate analysis identified HbSS genotype and lower prothrombin ratio (PR) as independently associated with SCM (P [ .01). Proliferative sickle cell retinopathy was also associated with SCM (P [ .02). FAZ enlargement was associated with higher lactate dehydrogenase level (P [ .02). Macular ischemia was more severe in patients with lower hemoglobin level (P [ .004) and lower PR (P [ .01). No flow areas were identified with OCTA even in eyes with no macular thinnin

MERTK mutation update in inherited retinal diseases

International audienceMER tyrosine kinase (MERTK) encodes a surface receptor localized at the apical membrane of the retinal pigment epithelium. It plays a critical role in photoreceptor outer segment internalization prior to phagocytosis. Mutations in MERTK have been associated with severe autosomal recessive retinal dystrophies in the RCS rat and in humans. We present here a comprehensive review of all reported MERTK disease causing variants with the associated phenotype. In addition, we provide further data and insights of a large cohort of 1,195 inherited retinal dystrophies (IRD) index cases applying state-of-the-art genotyping techniques and summarize current knowledge. A total of 79 variants have now been identified underlying rod-cone dystrophy and cone-rod dystrophy including 11 novel variants reported here. The mutation spectrum in MERTK includes 33 missense, 12 nonsense, 12 splice defects, 12 small deletions, two small insertion-deletions, three small duplications, and two exonic and three gross deletions. Altogether, mutations in MERTK account for ∼2% of IRD cases with a severe retinal phenotype. These data are important for current and future therapeutic trials including gene replacement therapy or cell-based therapy