Importance
Variants of uncertain significance (VUSs) are rampant in clinical genetic testing, frustrating clinicians, patients, and laboratories because the uncertainty hinders diagnoses and clinical ...management. A comprehensive assessment of VUSs across many disease genes is needed to guide efforts to reduce uncertainty.
Objective
To describe the sources, gene distribution, and population-level attributes of VUSs and to evaluate the impact of the different types of evidence used to reclassify them.
Design, Setting, and Participants
This cohort study used germline DNA variant data from individuals referred by clinicians for diagnostic genetic testing for hereditary disorders. Participants included individuals for whom gene panel testing was conducted between September 9, 2014, and September 7, 2022. Data were analyzed from September 1, 2022, to April 1, 2023.
Main Outcomes and Measures
The outcomes of interest were VUS rates (stratified by age; clinician-reported race, ethnicity, and ancestry groups; types of gene panels; and variant attributes), percentage of VUSs reclassified as benign or likely benign vs pathogenic or likely pathogenic, and enrichment of evidence types used for reclassifying VUSs.
Results
The study cohort included 1 689 845 individuals ranging in age from 0 to 89 years at time of testing (median age, 50 years), with 1 203 210 (71.2%) female individuals. There were 39 150 Ashkenazi Jewish individuals (2.3%), 64 730 Asian individuals (3.8%), 126 739 Black individuals (7.5%), 5539 French Canadian individuals (0.3%), 169 714 Hispanic individuals (10.0%), 5058 Native American individuals (0.3%), 2696 Pacific Islander individuals (0.2%), 4842 Sephardic Jewish individuals (0.3%), and 974 383 White individuals (57.7%). Among all individuals tested, 692 227 (41.0%) had at least 1 VUS and 535 385 (31.7%) had only VUS results. The number of VUSs per individual increased as more genes were tested, and most VUSs were missense changes (86.6%). More VUSs were observed per sequenced gene in individuals who were not from a European White population, in middle-aged and older adults, and in individuals who underwent testing for disorders with incomplete penetrance. Of 37 699 unique VUSs that were reclassified, 30 239 (80.2%) were ultimately categorized as benign or likely benign. A mean (SD) of 30.7 (20.0) months elapsed for VUSs to be reclassified to benign or likely benign, and a mean (SD) of 22.4 (18.9) months elapsed for VUSs to be reclassified to pathogenic or likely pathogenic. Clinical evidence contributed most to reclassification.
Conclusions and Relevance
This cohort study of approximately 1.6 million individuals highlighted the need for better methods for interpreting missense variants, increased availability of clinical and experimental evidence for variant classification, and more diverse representation of race, ethnicity, and ancestry groups in genomic databases. Data from this study could provide a sound basis for understanding the sources and resolution of VUSs and navigating appropriate next steps in patient care.
Recent developments in vasectomy Aradhya, Kerry Wright; Best, Kim; Sokal, David C
BMJ,
02/2005, Letnik:
330, Številka:
7486
Journal Article, Book Review
Recenzirano
Odprti dostop
Surgical techniques used for vasectomy vary widely throughout the world. The two main components of vasectomy are isolation of the vas deferens from the scrotum and subsequent vas occlusion. However, ...more than 30 different combinations of vas occlusion techniques probably exist, and poor quality studies, heterogeneous study designs, and conflicting results have made it difficult to determine which are the most effective.
Purpose of Review
RNA analysis is beginning to be integrated into clinical laboratory genomics, and a review of its current uses and limitations is warranted. Here, we summarize the scope and utility ...of RNA analysis in the context of clinical genetic testing, including considerations for genetic counseling.
Recent Findings
RNA analysis is a powerful approach for interpreting some variants of uncertain significance, for analyzing splicing alterations, for providing additional functional evidence for sequence and structural variants, and for discovering novel variants. However, a review of RNA sequencing methods has noted variability in both laboratory processes and findings. Genetic counseling related to RNA analysis has to take into account nonstandardized laboratory processes, sample-type limitations, and differences in variant-interpretation outcomes.
Summary
RNA analysis is an important complement to DNA testing, although limitations still exist. Maximizing the utility of RNA analysis will require appropriate patient referrals and standardization of laboratory processes as the practice continues to expand the ability to identify and resolve molecular diagnoses.
Black men who have sex with men (MSM) have disproportionate HIV disease burden in the United States. Black MSM have been underrepresented in biomedical research, including HIV clinical trials, due to ...a myriad of socio-structural, socio-cultural, and psychosocial factors. The HIV Prevention Trials Network (HPTN) 061, a feasibility study of a multi-component HIV prevention intervention for Black MSM in six US cities, incorporated the development and implementation of a Black Caucus as a culturally grounded model for the integration of Black MSM in clinical trials and research in HPTN. Based on a qualitative methodological approach, we describe the formation and implementation of the Black Caucus from the perspective of Black MSM key community stakeholders. Three major themes emerged from the qualitative narratives: (1) the role of the Black Caucus in shaping the HPTN, (2) how the Black Caucus addresses the needs of Black MSM communities pertaining to the influence of race and sexual identity, and (3) socio-cultural needs of Black MSM. These findings have implications for the provision of culturally congruent expertise, community engagement, cultural mistrust, recruitment and retention of Black MSM in HIV clinical trials, culturally-relevant study design and implementation, and the role of developing Black MSM prevention researchers.
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