Background. Germline mutations in telomerase and other telomere maintenance genes manifest in the premature aging short telomere syndromes. Myelodysplastic syndromes and acute myeloid leukemia (MDS/AML) account for 75% of associated malignancies, but how these cancers overcome the inherited telomere defect is unknown.Methods. We used ultra-deep targeted sequencing to detect somatic reversion mutations in 17 candidate telomere lengthening genes among controls and short telomere syndrome patients with and without MDS/AML and we tested the functional significance of these mutations.Results. While no controls carried somatic mutations in telomere maintenance genes, 29% (16 of 56) of adults with germline telomere maintenance defects carried at least one (P<0.001) and 13% (7 of 56) had 2 or more. In addition to TERT promoter mutations which were present in 19%, we identified POT1 and TERF2IP mutations in 13%. POT1 mutations impaired telomere binding in vitro and some mutations were identical to ones seen in familial melanoma associated with longer telomere length. Exclusively in patients with germline defects in telomerase RNA (TR), we identified somatic mutations in nuclear RNA exosome genes, RBM7, SKIV2L2, and DIS3, where loss-of-function upregulates mature TR levels. Somatic reversion events in six telomererelated genes were more prevalent in patients who were MDS/AML-free (P = 0.02, RR 4.4, 95% CI 1.2-16.7), and no MDS/AML patient had more than one reversion mutation. Conclusion.Our data identify diverse adaptive somatic mechanisms in the short telomere syndrome; they raise the possibility that their presence alleviates the telomere crisis that promotes transformation to MDS/AML.

Background In response to the cancellation of clinical clerkships due to COVID-19, the Johns Hopkins (JH) Neurology Education Team developed a virtual elective to enhance medical students’ clinical telemedicine skills and foster community between academic institutions. Methods This two-week clinical elective, entitled “Virtual Patient Rounds in Neurology,” was administered once in April 2020 and once in May 2020. The curriculum included attending/fellow-led Virtual Rounds, Student Presentations, and Asynchronous Educational Activities. We also developed a new lecture series entitled JHNeuroChats, which consisted of live synchronous lectures presented by JH faculty and Virtual Visiting Professors. Trainees and faculty from outside institutions were invited to participate in the JHNeuroChats. Students and faculty completed pre- and post-elective surveys to assess the educational impact of the elective. Student’s t-tests were used to compare scores between pre- and post-elective surveys. Results Seven JH medical students enrolled in each iteration of the elective, and an additional 337 trainees and faculty, representing 14 different countries, registered for the JHNeuroChats. We hosted 48 unique JHNeuroChats, 32 (66.7%) of which were led by invited Virtual Visiting Professors. At the end of the elective, students reported increased confidence in virtually obtaining a history (P < 0.0001) and performing a telehealth neurological physical exam (P < 0.0001), compared to the start of the course. In addition, faculty members reported increased confidence in teaching clinical medicine virtually, although these findings were not statistically significant (P = 0.15). Conclusions Despite the constraints imposed by COVID-19, this virtual Neurology elective increased medical students’ confidence in certain telemedicine skills and successfully broadened our learning community to encompass learners from around the world. As virtual medical education becomes more prevalent, it is important that we are intentional in creating opportunities for shared learning across institutions. We believe that this elective can serve as a model for these future educational collaborations.

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