Genetic Analysis in a Swiss Cohort of Bilateral Congenital Cataract.

IMPORTANCE: Identification of geographic population-based differences in genotype and phenotype heterogeneity are important for targeted and patient-specific diagnosis and treatment, counseling, and screening strategies. OBJECTIVE: To report disease-causing variants and their detailed phenotype in patients with bilateral congenital cataract from a single center in Switzerland and thereby draw a genetic map and perform a genotype-phenotype comparison of this cohort. DESIGN, SETTING, AND PARTICIPANTS: This clinical and molecular-genetic cohort study took place through the collaboration of the Department of Ophthalmology at the University Hospital Zurich and the Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland. Thirty-seven patients from 25 families with different types of bilateral congenital cataract were included. All participating family members received a comprehensive eye examination. Whole exome sequencing was performed in the index patients, followed by a filtering process to detect possible disease-associated variants in genes previously described in association with congenital cataract. Probable disease-causing variants were confirmed by Sanger sequencing in available family members. All data were collected from January 2018 to June 2020, and the molecular-genetic analyses were performed from January 2019 to July 2020. MAIN OUTCOMES AND MEASURES: Identification of the underlying genetic causes of bilateral congenital cataract, including novel disease-causing variants and phenotype correlation. RESULTS: Among the 37 patients (18 [49%] male and 19 [51%] female; mean [SD] age, 17.3 [15.9] years) from 25 families, pathogenic variants were detected in 20 families (80% detection rate), which included 13 novel variants in the following genes: BCOR, COL4A1, CRYBA2, CRYBB2, CRYGC, CRYGS, GJA3, MAF, NHS, and WFS1. Putative disease-causing variants were identified in 14 of 20 families (70%) as isolated cases and in 6 of 20 families (30%) with syndromic cases. A recessive variant in the CRYBB2 gene in a consanguineous family with 2 affected siblings showing a nuclear and sutural cataract was reported in contrast to previously published reports. In addition, the effect on splicing in a minigene assay of a novel splice site variant in the NHS gene (c.[719-2A>G]) supported the pathogenicity of this variant. CONCLUSIONS AND RELEVANCE: This study emphasizes the importance of genetic testing of congenital cataracts. Known dominant genes need to be considered for recessive inheritance patterns. Syndromic types of cataract may be underdiagnosed in patients with mild systemic features.

Quantitative MRI of visually intact rotator cuff muscles by multiecho Dixon-based fat quantification and diffusion tensor imaging.

BACKGROUND: Quantitative MRI allows assessment of shoulder rotator cuff (RC) muscles by Dixon MR sequences with calculation of fractional fat content (FF%) maps and diffusion tensor imaging (DTI) including tractography. PURPOSE: To compare FF% and DTI derived parameters among visually intact RC muscles, to compare 2D with 3D DTI measurements and to establish normative values. STUDY TYPE: Prospective. SUBJECTS: Forty patients aged >18 years undergoing shoulder MR arthrography were included. FIELD STRENGTH/SEQUENCE: MR arthrography of the shoulder including 3D multiecho Dixon and 3D echo-planar DTI sequences (15 gradient encoding directions, b-value 600 s/mm2 ) was performed at 3.0T. ASSESSMENT: Muscles affected by RC tears or fatty infiltration of Goutallier grade ≥1 were excluded. Two independent radiologists measured FF%, apparent diffusion coefficient (ADC), and fractional anisotropy (FA) by region-of-interest (ROI) placements at the Y-position of the scapula and 3D tractography of each muscle with qualitative evaluation was performed. STATISTICAL TESTS: Intraclass correlation coefficients (ICCs) and Cohen's kappa were used for interreader agreement and Pearson correlation coefficient to correlate quantitative measures with each other and age, independent-samples t-test, one-way analysis of variance (ANOVA), and Kruskal-Wallis test were performed to investigate differences between genders and muscles. RESULTS: Qualitative and quantitative measurements showed moderate (κ = 0.41-0.56) to almost perfect (ICC = 0.75-0.99) agreement. There were weak but significant positive correlations of FF% with age (r = 0.273, P < 0.05) and FA-2D (r = 0.319-0.383, P < 0.05). Significant differences were found among RC muscles for ADC, radial diffusivity (RD), and tract homogeneity (all P < 0.05) but not between genders (all P ≥ 0.05). High correlations of 2D with 3D measurements for ADC (r = 0.639, P < 0.001) and FA (r = 0.628, P < 0.001) were seen. DATA CONCLUSION: Quantitative MRI with estimation of FF% and DTI parameters shows significant age-associated changes and differences among visually intact RC muscles. High reproducibility and correlations of 2D with 3D DTI measurements can be expected. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:109-117.