The quality of online information on Legg-Calvé-Perthes disease: can we do better?

INTRODUCTION: As patients increasingly utilize the Internet to obtain health-related information, the accuracy and usability of information prove critical, especially for patients and parents seeking care for relatively common orthopedic childhood disorders such as Legg-Calvé-Perthes (LCP) disease. Therefore, the purpose of this study is to evaluate available online health information regarding LCP disease. The study specifically seeks to (1) examine the accessibility, usability, reliability, and readability of online information, (2) compare the quality of sites from different sources, and (3) determine whether Health on the Net Foundation Code (HON-code) certification guarantees higher quality of information. MATERIALS AND METHODS: Websites from a query of both Google and Bing were compiled and scored using the Minervalidation tool (LIDA), an appraisal tool quantifying website quality, along with the Flesch-Kinkaid (FK) analysis, a metric assessing readability of content. All sites were organized based on source category [academic, private physician/physician group, governmental/non-profit organization (NPO), commercial, and unspecified] and HON-code certification. RESULTS: Physician-based and governmental/NPO sites had the highest accessibility, the unspecified site group were the most reliable and usable, and the physician-based group was found to require the least education to comprehend. Unspecified sites had a significantly higher rating of reliability than physician sites (p = 0.0164) and academic sites (p < 0.0001). HON-code-certified sites were found to have greater scores across quality domains along with being easier to read compared to sites without certification, with significantly higher reliability scoring (p < 0.0001). CONCLUSIONS: As a whole, information on the Internet regarding LCP disease is of poor quality. However, our findings also encourage patients to utilize HON-code-certified websites due to their significantly higher reliability. Future studies should analyze methods of improving this publicly available information. Additionally, future analyses should examine methods for patients to better identify reliable websites, as well as the best mediums for optimized patient access and comprehension.

Genome sequencing increases diagnostic yield in clinically diagnosed Alagille syndrome patients with previously negative test results.

PURPOSE: Detection of all major classes of genomic variants in a single test would decrease cost and increase the efficiency of genomic diagnostics. Genome sequencing (GS) has the potential to provide this level of comprehensive detection. We sought to demonstrate the utility of GS in the molecular diagnosis of 18 patients with clinically defined Alagille syndrome (ALGS), who had a negative or inconclusive result by standard-of-care testing. METHODS: We performed GS on 16 pathogenic variant-negative probands and two probands with inconclusive results (of 406 ALGS probands) and analyzed the data for sequence, copy-number, and structural variants in JAG1 and NOTCH2. RESULTS: GS identified four novel pathogenic alterations including a copy-neutral inversion, a partial deletion, and a promoter variant in JAG1, and a partial NOTCH2 deletion, for an additional diagnostic yield of 0.9%. Furthermore, GS resolved two complex rearrangements, resulting in identification of a pathogenic variant in 97.5% (n = 396/406) of patients after GS. CONCLUSION: GS provided an increased diagnostic yield for individuals with clinically defined ALGS who had prior negative or incomplete genetic testing by other methods. Our results show that GS can detect all major classes of variants and has potential to become a single first-tier diagnostic test for Mendelian disorders.

Alagille syndrome mutation update: Comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification.

Alagille syndrome is an autosomal dominant disease with a known molecular etiology of dysfunctional Notch signaling caused primarily by pathogenic variants in JAGGED1 (JAG1), but also by variants in NOTCH2. The majority of JAG1 variants result in loss of function, however disease has also been attributed to lesser understood missense variants. Conversely, the majority of NOTCH2 variants are missense, though fewer of these variants have been described. In addition, there is a small group of patients with a clear clinical phenotype in the absence of a pathogenic variant. Here, we catalog our single-center study, which includes 401 probands and 111 affected family members amassed over a 27-year period, to provide updated mutation frequencies in JAG1 and NOTCH2 as well as functional validation of nine missense variants. Combining our cohort of 86 novel JAG1 and three novel NOTCH2 variants with previously published data (totaling 713 variants), we present the most comprehensive pathogenic variant overview for Alagille syndrome. Using this data set, we developed new guidance to help with the classification of JAG1 missense variants. Finally, we report clinically consistent cases for which a molecular etiology has not been identified and discuss the potential for next generation sequencing methodologies in novel variant discovery.