De Novo Mutations Contributes Approximately 7% of Pathogenicity in Inherited Eye Diseases.

Purpose: The purpose of this study was to describe genotype-phenotype associations and novel insights into genetic characteristics in a trio-based cohort of inherited eye diseases (IEDs). Methods: To determine the etiological role of de novo mutations (DNMs) and genetic profile in IEDs, we retrospectively reviewed a large cohort of proband-parent trios of Chinese origin. The patients underwent a detailed examination and was clinically diagnosed by an ophthalmologist. Panel-based targeted exome sequencing was performed on DNA extracted from blood samples, containing coding regions of 792 IED-causative genes and their flanking exons. All participants underwent genetic testing. Results: All proband-parent trios were divided into 22 subgroups, the overall diagnostic yield was 48.67% (605/1243), ranging from 4% to 94.44% for each of the subgroups. A total of 108 IED-causative genes were identified, with the top 24 genes explaining 67% of the 605 genetically solved trios. The genetic etiology of 6.76% (84/1243) of the trio was attributed to disease-causative DNMs, and the top 3 subgroups with the highest incidence of DNM were aniridia (n = 40%), Marfan syndrome/ectopia lentis (n = 38.78%), and retinoblastoma (n = 37.04%). The top 10 genes have a diagnostic yield of DNM greater than 3.5% in their subgroups, including PAX6 (40.00%), FBN1 (38.78%), RB1 (37.04%), CRX (10.34%), CHM (9.09%), WFS1 (8.00%), RP1L1 (5.88%), RS1 (5.26%), PCDH15 (4.00%), and ABCA4 (3.51%). Additionally, the incidence of DNM in offspring showed a trend of correlation with paternal age at reproduction, but not statistically significant with paternal (P = 0.154) and maternal (P = 0.959) age at reproduction. Conclusions: Trios-based genetic analysis has high accuracy and validity. Our study helps to quantify the burden of the full spectrum IED caused by each gene, offers novel potential for elucidating etiology, and plays a crucial role in genetic counseling and patient management.

Genetic Characteristics and Variation Spectrum of USH2A-Related Retinitis Pigmentosa and Usher Syndrome.

Purposes: We aimed to characterize the USH2A genotypic spectrum in a Chinese cohort and provide a detailed genetic profile for Chinese patients with USH2A-IRD. Methods: We designed a retrospective study wherein a total of 1,334 patients diagnosed with IRD were included as a study cohort, namely 1,278 RP and 56 USH patients, as well as other types of IEDs patients and healthy family members as a control cohort. The genotype-phenotype correlation of all participants with USH2A variant was evaluated. Results: Etiological mutations in USH2A, the most common cause of RP and USH, were found in 16.34% (n = 218) genetically solved IRD patients, with prevalences of 14.87% (190/1,278) and 50% (28/56). After bioinformatics and QC processing, 768 distinct USH2A variants were detected in all participants, including 136 disease-causing mutations present in 665 alleles, distributed in 5.81% of all participants. Of these 136 mutations, 43 were novel, nine were founder mutations, and two hot spot mutations with allele count ≥10. Furthermore, 38.5% (84/218) of genetically solved USH2A-IRD patients were caused by at least one of both c.2802T>G and c.8559-2 A>G mutations, and 36.9% and 69.6% of the alleles in the RP and USH groups were truncating, respectively. Conclusion: USH2A-related East Asian-specific founder and hot spot mutations were the major causes for Chinese RP and USH patients. Our study systematically delineated the genotype spectrum of USH2A-IRD, enabled accurate genetic diagnosis, and provided East Asian and other ethnicities with baseline data of a Chinese origin, which would better serve genetic counseling and therapeutic targets selection.

Mutation spectrum in a cohort with familial exudative vitreoretinopathy.

PURPOSE: To expand the mutation spectrum of patients with familial exudative vitreoretinopathy (FEVR) disease. PARTICIPANTS: 74 probands (53 families and 21 sporadic probands) with familial exudative vitreoretinopathy (FEVR) disease and their available family members (n = 188) were recruited for sequencing. METHODS: Panel-based targeted screening was performed on all subjects. Before sanger sequencing, variants of LRP5, NDP, FZD4, TSPAN12, ZNF408, KIF11, RCBTB1, JAG1, and CTNNA1 genes were verified by a series of bioinformatics tools and genotype-phenotype co-segregation analysis. RESULTS: 40.54% (30/74) of the probands were sighted to possess at least one etiological mutation of the nine FEVR-causative genes. The etiological mutation detection rate was 37.74% (20/53) in family-attainable probands while 47.62% (10/21) in sporadic cases. The diagnosis rate of patients in the early-onset subgroup (≤5 years old, 45.4%) is higher than that of the children or adolescence-onset subgroup (6-16 years old, 42.1%) and the late-onset subgroup (≥17 years old, 39.4%). A total of 36 etiological mutations were identified in this study, comprising 26 novel mutations and 10 reported mutations. LRP5 was the most prevalent mutant gene among the 36 mutation types with a percentage of 41.67% (15/36). Followed by FZD4 (10/36, 27.78%), TSPAN12 (5/36, 13.89%), NDP (4/36, 11.11%), KIF11 (1/36, 2.78%), and RCBTB1 (1/36, 2.78%). Among these mutations, 63.89% (23/36) were missense mutations, 25.00% (9/36) were frameshift mutations, 5.56% (2/36) were splicing mutations, 5.56% (2/36) were nonsense mutations. Moreover, the clinical pathogenicity of these variants was defined according to American College of Medical Genetics (ACMG) and genomics guidelines: 41.67% (15/36) were likely pathogenic variants, 27.78% (10/36) pathogenic variants, 30.55% (11/36) variants of uncertain significance. No etiological mutations discovered in the ZNF408, JAG1, and CTNNA1 genes in this FEVR cohort. CONCLUSIONS: We systematically screened nine FEVR disease-associated genes in a cohort of 74 Chinese probands with FEVR disease. With a detection rate of 40.54%, 36 etiological mutations of six genes were authenticated in 30 probands, including 26 novel mutations and 10 reported mutations. The most prevalent mutated gene is LRP5, followed by FZD4, TSPAN12, NDP, KIF11, and RCBTB1. In total, a de novo mutation was confirmed. Our study significantly clarified the mutation spectrum of variants bounded up to FEVR disease.

Evaluation of the Genetic Variation Spectrum Related to Corneal Dystrophy in a Large Cohort.

AIMS: To characterize the genetic landscape and mutation spectrum of patients with corneal dystrophies (CDs) in a large Han ethnic Chinese Cohort with inherited eye diseases (IEDs). METHODS: Retrospective study. A large IED cohort was recruited in this study, including 69 clinically diagnosed CD patients, as well as other types of eye diseases patients and healthy family members as controls. The 792 genes on the Target_Eye_792_V2 chip were used to screen all common IEDs in our studies, including 22 CD-related genes. RESULTS: We identified 2334 distinct high-quality variants on 22 CD-related genes in a large IEDs cohort. A total of 21 distinct pathogenic or likely pathogenic mutations were identified, and the remaining 2313 variants in our IED cohort had no evidence of CD-related pathogenicity. Overall, 81.16% (n = 56/69) of CD patients received definite molecular diagnoses, and transforming growth factor-beta-induced protein (TGFBI), CHTS6, and SLC4A11 genes covered 91.07, 7.14, and 1.79% of the diagnosed cases, respectively. Twelve distinct disease-associated mutations in the TGFBI gene were identified, 11 of which were previously reported and one is novel. Four of these TGFBI mutations (p.D123H, p.M502V, p.P501T, and p.P501A) were redefined as likely benign in our Han ethnic Chinese IED cohort after performing clinical variant interpretation. These four TGFBI mutations were detected in asymptomatic individuals but not in CD patients, especially the previously reported disease-causing mutation p.P501T. Among 56 CD patients with positive detected mutations, the recurrent TGFBI mutations were p.R124H, p.R555W, p.R124C, p.R555Q, and p.R124L, and the proportions were 32.14, 19.64, 14.29, 10.71, and 3.57%, respectively. Twelve distinct pathogenic or likely pathogenic mutations of CHTS6 were detected in 28 individuals. The recurrent mutations were p.Y358H, p.R140X, and p.R205W, and the proportions were 25.00, 21.43, and 14.29%, respectively. All individuals associated with TGFBI were missense mutations; 74.19% associated with CHTS6 mutations were missense mutations, and 25.81% were non-sense mutations. Hot regions were located in exons 4 and 12 of TGFBI individuals and located in exon 3 of CHTS6 individuals. No de novo mutations were identified. CONCLUSION: For the first time, our large cohort study systematically described the variation spectrum of 22 CD-related genes and evaluated the frequency and pathogenicity of all 2334 distinct high-quality variants in our IED cohort. Our research will provide East Asia and other populations with baseline data from a Han ethnic population-specific level.

Comparative Study of Amide Proton Transfer-Weighted Imaging and Intravoxel Incoherent Motion Imaging in Breast Cancer Diagnosis and Evaluation.

BACKGROUND: Amide proton transfer-weighted imaging (APTWI) and intravoxel incoherent motion imaging (IVIM) are valuable MRI techniques applied to cancer. PURPOSE: To compare APTWI and IVIM in the diagnosis of benign and malignant breast lesions and to evaluate the correlations between different parameters (MTRasym [3.5 ppm], D, D*, and f) and prognostic factors for breast cancer. STUDY TYPE: Retrospective. POPULATION: In all, 123 breast lesions were studied before treatment, including 58 benign lesions and 65 malignant lesions. FIELD STRENGTH/SEQUENCE: Conventional MRI (T1 WI, T2 WI, and diffusion-weighted imaging [DWI]), APTWI, and IVIM MRI at 3T. ASSESSMENT: The magnetization transfer ratio asymmetry at 3.5 ppm (MTRasym [3.5 ppm]), diffusion coefficient (D), pseudo diffusion coefficient (D*), and perfusion fraction (f) values were compared between the benign and malignant groups and between groups with different expression levels of prognostic factors. STATISTICAL TESTS: Individual sample t-test, χ2 test, Spearman correlation, logistic regression, and the Delong test. RESULTS: The D and MTRasym (3.5 ppm) values of the malignant group were lower than those of the benign group; however, D* and f values were higher than those of the benign group (all P < 0.05). The areas under the curve (AUCs) of D, MTRasym (3.5 ppm), D*, and f were 0.809, 0.778, 0.670, and 0.766, respectively; however, only the difference between AUC (D) and AUC (D*) was significant (Z = 2.374, P < 0.05). The D value showed a low correlation with the pathological grade and Ki-67 expression (| r | = 0.294, 0.367); the f value showed a low correlation with estrogen receptor (ER) expression (| r | = 0.382); and the MTRasym (3.5 ppm) value showed a low correlation with pathological grade (| r | = 0.371). DATA CONCLUSION: This analysis revealed that both IVIM and APTWI could be used for the differential diagnosis of benign and malignant breast lesions, and APTWI-derived MTRasym (3.5 ppm), IVIM-derived D, D*, and f values showed correlations with some prognostic factors for breast cancer. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2 J. Magn. Reson. Imaging 2020;52:1175-1186.

CT-pathologic correlation in lung adenocarcinoma and squamous cell carcinoma.

Distinguishing lung adenocarcinoma from squamous cell carcinoma (SCC) is clinically important. Computed tomography (CT) scan is an economical, effective, noninvasive, commonly available, and quick diagnostic way for lung cancer. In this study, we aim to compare the CT characteristics in adenocarcinoma and SCC.Data from 275 cases (259 adenocarcinoma and 16 SCC) were retrospectively compared. CT characteristics, including lesion size and shape, single/multifocal lesions, location of the tumor, the margin of lobes, whether the lesion had deep lobulated margin, bronchial cut-off sign, signs of dilated bronchial arteries, signs of vascular bundle thickening, signs of short burrs, spinous processes, and pleural indentation, were compared in 148 cases (137 adenocarcinoma and 11 SCC).Patients with adenocarcinoma were more likely to be female (44.2% vs 25.0%, P = .017). Compared with SCC, adenocarcinomas were more likely to have deep lobulated margin (81.0% vs 54.5%, P = .038), less likely to have smooth lobes margin (2.7% vs 83.3%, P < .001), more likely to have vascular bundle thickening (37.2% vs 0, P = .016) and pleural indentation (59.9% vs 18.2%, P = .01), and marginally less likely to have dilated bronchial arteries (17.5% vs 45.5%, P = .064). No significant difference was observed regarding to characteristics, including tumor size, location of the tumor, signs of bronchial cut-off, dilated bronchial arteries, short burrs, or spinous processes.CT scan has the potential to help to distinguish lung adenocarcinoma and SCC in a fast and commonly available way. CT could be a rough but fast way to diagnosis, and may thus shorten the waiting time to treatment and allow more time for clinicians, patients, and their families to prepare for future treatment.

A promising randomized trial of a new therapy for obsessive-compulsive disorder.

Pharmacotherapy and cognitive-behavioral therapy (CBT) are currently the most effective interventions for treating obsessive-compulsive disorder (OCD). These treatments, however, are time consuming and in some cases the patients do not show significant improvement. In all, 30%-60% of OCD patients do not respond adequately to pharmacotherapy and 20%-40% of OCD patients who complete CBT do not improve significantly, suggesting a more efficacious approach is needed. The objectives of this study are to demonstrate an efficacious pharmacotherapy plus psychotherapy, named cognitive-coping therapy (CCT), for OCD and to investigate the efficacy of this approach in a larger sample size. Therefore, a total of 108 patients with OCD were randomly allocated into three groups: pharmacotherapy (N = 38), pharmacotherapy plus CBT (PCBT, N = 34), and pharmacotherapy plus CCT (PCCT, N = 36). The severity of symptoms and the patients' functioning were assessed pretreatment and after 7, 14, 21 days, and 1-, 3-, 6-, and 12-month treatment using the Yale-Brown Obsessive Compulsive Scale and Global Assessment of Functioning (GAF). Compared with the pharmacotherapy and PCBT groups, the severity of OCD symptoms was significantly reduced (P < 0.001), the rates of response (100%) and remission (85.0%) were significantly higher (P < 0.001), and relapse rate was lower (P = 0.017) in PCCT group during the 1-year follow-up. In addition, the GAF score was significantly higher in the PCCT group than in the other two groups (P < 0.001). Our preliminary data suggest that PCCT is a more efficacious psychotherapy for OCD patients than pharmacotherapy or PCBT.