A Genome-First Approach to Characterize <i>DICER1</i> Pathogenic Variant Prevalence, Penetrance, and Phenotype
Authors: Uyenlinh L. Mirshahi, Jung Kim, Ana F. Best, Zongming E. Chen, Ying Hu, Jeremy S. Haley, Alicia Golden, Richard Stahl, Kandamurugu Manickam, Ann G. Carr, Laura A. Harney, Amanda Field, Jessica Hatton, Kris Ann P. Schultz, Andrew J. Bauer, D. Ashley Hill, Philip S. Rosenberg, Michael F. Murray, David J. Carey, Douglas R. Stewart
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Genetic disorders are historically defined through phenotype-first approaches. However, risk estimates derived from phenotype-linked ascertainment may overestimate severity and penetrance. Pathogenic variants in<i>DICER1</i>are associated with increased risks of rare and common neoplasms and thyroid disease in adults and children. This study explored how effectively a genome-first approach could characterize the clinical traits associated with germline<i>DICER1</i>putative loss-of-function (pLOF) variants in an unselected clinical cohort. <h3>Objective</h3> To examine the prevalence, penetrance, and phenotypic characteristics of carriers of germline<i>DICER1</i>pLOF variants via genome-first ascertainment. <h3>Design, Setting, and Participants</h3> This cohort study classifies<i>DICER1</i>variants in germline exome sequence data from 92 296 participants of the Geisinger MyCode Community Health Initiative. Data for each MyCode participant were used from the start of the Geisinger electronic health record to February 1, 2018. <h3>Main Outcomes and Measures</h3> Prevalence of germline<i>DICER1</i>variation; penetrance of malignant tumors and thyroid disease in carriers of germline<i>DICER1</i>variation; structured, manual review of electronic health records; and<i>DICER1</i>sequencing of available tumors from an associated cancer registry. <h3>Results</h3> A total of 92 296 adults (mean [SD] age, 59 [18] years; 98% white; 60% female) participated in the study. Germline<i>DICER1</i>pLOF variants were observed in 1 in 3700 to 1 in 4600 participants, more than double the expected prevalence. Malignant tumors (primarily thyroid carcinoma) were observed in 4 of 25 participants (16%) with<i>DICER1</i>pLOF variants, which is comparable (by 50 years of age) to the frequency of neoplasms in the largest registry- and clinic-based (phenotype-first)<i>DICER1</i>studies published to date.<i>DICER1</i>pLOF variants were significantly associated with risks of thyroidectomy (odds ratio [OR], 6.0; 95% CI, 2.2-16.3;<i>P</i> = .007) and thyroid cancer (OR, 9.2; 95% CI, 2.1-34.7;<i>P</i> = .02) compared with controls, but there was not a significant increase in the risk of goiter (OR, 1.8; 95% CI, 0.7-4.9). A female patient in her 80s who was a carrier of a germline<i>DICER1</i>hotspot variant was apparently healthy on electronic health record review. The term<i>DICER1</i>did not appear in any of the medical records of the 25 participants with a pLOF<i>DICER1</i>variant, even in those affected with a known<i>DICER1</i>-associated tumor or thyroid phenotype. <h3>Conclusions and Relevance</h3> This cohort study was able to ascertain individuals with germline<i>DICER1</i>variants based on a genome-first approach rather than through a previously established<i>DICER1</i>-related phenotype. Use of the genome-first approach may complement more traditional approaches to syndrome delineation and may be an efficient approach for risk estimation.