In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD ...has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education.
Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers.
Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results.
Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.
Hepatitis B virus (HBV) persists with global and virus-specific T-cell dysfunction, without T-cell based correlates of outcomes. To determine if gammadeltaT-cells are altered in HBV infection ...relative to clinical status, we examined the frequency, phenotype and function of peripheral blood Vdelta1.sup.+ and Vdelta2.sup.+ gammadeltaT-cells by multi-parameter cytometry in a clinically diverse North American cohort of chronic hepatitis B (CHB), acute hepatitis B (AHB) and uninfected control subjects. We show that circulating gammadeltaT-cells were comprised predominantly of CD3.sup.hi CD4.sup.- Vdelta2.sup.+ gammadeltaT-cells with frequencies that were 2-3 fold higher among Asian than non-Asian Americans and inversely correlated with age, but without differences between CHB, AHB and control subjects. However, compared to control subjects, CHB was associated with increased Tbet.sup.hi Eomes.sup.dim phenotype in Vdelta2.sup.+ gammadeltaT-cells whereas AHB was associated with increased Tbet.sup.hi Eomes.sup.dim phenotype in Vdelta1.sup.+ gammadeltaT-cells, with significant correlations between Tbet/Eomes expression in gammadeltaT-cells with their expression of NK and T-cell activation and regulatory markers. As for effector functions, IFNgamma/TNF responses to phosphoantigens or PMA/Ionomycin in Vdelta2.sup.+ gammadeltaT-cells were weaker in AHB but preserved in CHB, without significant differences for Vdelta1.sup.+ gammadeltaT-cells. Furthermore, early IFNgamma/TNF responses in Vdelta2.sup.+ gammadeltaT-cells to brief PMA/Ionomycin stimulation correlated inversely with serum ALT but not HBV DNA. Accordingly, IFNgamma/TNF responses in Vdelta2.sup.+ gammadeltaT-cells were weaker in patients with CHB with hepatitis flare compared to those without hepatitis flares, and this functional deficit persisted beyond clinical resolution of CHB flare. We conclude that circulating gammadeltaT-cells show distinct activation and differentiatiation in acute and chronic HBV infection as part of lymphoid stress surveillance with potential role in clinical outcomes.
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