Genetics in Medicine

Journal Information
ISSN / EISSN : 10983600 / 15300366
Current Publisher: Springer Science and Business Media LLC (10.1038)
Former Publisher: Ovid Technologies (Wolters Kluwer Health) (10.1097)
Total articles ≅ 3,987
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Rosie O’Shea, Nicole M. Rankin, Maira Kentwell, Margaret Gleeson, Lucinda Salmon, Katherine M. Tucker, Sarah Lewis, Natalie Taylor
Genetics in Medicine pp 1-10; doi:10.1038/s41436-020-0838-x

The publisher has not yet granted permission to display this abstract.
Francisco Del Caño-Ochoa, Bobby G. Ng, Malak Abedalthagafi, Mohammed Almannai, Ronald D. Cohn, Gregory Costain, Orly Elpeleg, Henry Houlden, Ehsan Ghayoor Karimiani, Pengfei Liu, et al.
Genetics in Medicine pp 1-8; doi:10.1038/s41436-020-0833-2

PurposePathogenic autosomal recessive variants in CAD, encoding the multienzymatic protein initiating pyrimidine de novo biosynthesis, cause a severe inborn metabolic disorder treatable with a dietary supplement of uridine. This condition is difficult to diagnose given the large size of CAD with over 1000 missense variants and the nonspecific clinical presentation. We aimed to develop a reliable and discerning assay to assess the pathogenicity of CAD variants and to select affected individuals that might benefit from uridine therapy.MethodsUsing CRISPR/Cas9, we generated a human CAD-knockout cell line that requires uridine supplements for survival. Transient transfection of the knockout cells with recombinant CAD restores growth in absence of uridine. This system determines missense variants that inactivate CAD and do not rescue the growth phenotype.ResultsWe identified 25 individuals with biallelic variants in CAD and a phenotype consistent with a CAD deficit. We used the CAD-knockout complementation assay to test a total of 34 variants, identifying 16 as deleterious for CAD activity. Combination of these pathogenic variants confirmed 11 subjects with a CAD deficit, for whom we describe the clinical phenotype.ConclusionsWe designed a cell-based assay to test the pathogenicity of CAD variants, identifying 11 CAD-deficient individuals who could benefit from uridine therapy.
Barbara Ogórek, EPISTOP Consortium members, Lana Hamieh, Hanna M. Hulshof, Kathryn Lasseter, Katarzyna Klonowska, Hugo Kuijf, Romina Moavero, Christoph Hertzberg, Bernhard Weschke, et al.
Genetics in Medicine pp 1-9; doi:10.1038/s41436-020-0823-4

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Matthias Pergande, Susanne Motameny, Özkan Özdemir, Mona Kreutzer, Haicui Wang, Hülya-Sevcan Daimagüler, Kerstin Becker, Mert Karakaya, Harald Ehrhardt, Nursel Elcioglu, et al.
Genetics in Medicine pp 1-2; doi:10.1038/s41436-020-0839-9

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Mary Pritzlaff, Yuan Tian, Patrick Reineke, A. J. Stuenkel, Kyle Allen, Stephanie Gutierrez, Michelle Jackson, Jill S. Dolinsky, Holly LaDuca, Jianfeng Xu, et al.
Genetics in Medicine pp 1-7; doi:10.1038/s41436-020-0830-5

PurposeWe describe the pathogenic variant spectrum and identify predictors of positive results among men referred for clinical genetic testing for prostate cancer.MethodsOne thousand eight hundred twelve men with prostate cancer underwent clinical multigene panel testing between April 2012 and September 2017. Stepwise logistic regression determined the most reliable predictors of positive results among clinical variables reported on test requisition forms.ResultsA yield of 9.4–12.1% was observed among men with no prior genetic testing. In this group, the positive rate of BRCA1 and BRCA2 was 4.6%; the positive rate for the mismatch repair genes was 2.8%. Increasing Gleason score (odds ratio [OR] 1.19; 95% confidence interval [CI] 0.97–1.45); personal history of breast or pancreatic cancer (OR 3.62; 95% CI 1.37–9.46); family history of breast, ovarian, or pancreatic cancer (OR 2.32 95% CI 1.48–3.65); and family history of Lynch syndrome–associated cancers (OR 1.97; 95% CI 1.23–3.15) were predictors of positive results.ConclusionThese results support multigene panel testing as the primary genetic testing approach for hereditary prostate cancer and are supportive of recommendations for consideration of germline testing in men with prostate cancer. Expanding the criteria for genetic testing should be considered as many pathogenic variants are actionable for treatment of advanced prostate cancer.
Joseph T. Alaimo, Kevin E. Glinton, Ning Liu, Jing Xiao, Yaping Yang, V. Reid Sutton, Sarah H. Elsea
Genetics in Medicine pp 1-7; doi:10.1038/s41436-020-0827-0

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Nicci Bartley, Christine Napier, Megan Best, Phyllis Butow
Genetics in Medicine pp 1-11; doi:10.1038/s41436-020-0829-y

While genomics provides new clinical opportunities, its complexity generates uncertainties. This systematic review aimed to summarize what is currently known about the experience of uncertainty for adult patients undergoing cancer genomic testing. A search of five databases (2001 to 2018) yielded 6508 records. After removing duplicates, abstract/title screening, and assessment of full articles, ten studies were included for quality appraisal and data extraction. Qualitative studies were subjected to thematic analysis, and quantitative data were summarized using descriptive statistics. Cancer genomic results reduced uncertainty for patients regarding treatment decisions but did not reduce uncertainty in the risk context. Qualitative and quantitative data synthesis revealed four themes: (1) coexisting uncertainties, (2) factors influencing uncertainty, (3) outcomes of uncertainty, and (4) coping with uncertainty. Uncertainty can motivate, or be a barrier to, pursuing cancer genomic testing. Appraisal of uncertainty influences the patient experience of uncertainty, the outcome of uncertainty for patients, as well as the coping strategies utilized. While this systematic review found that appraisal of uncertainty is important to the patients’ experience of uncertainty in the cancer genomic context, more mixed methods longitudinal research is needed to address the complexities that contribute to patient uncertainty across the process.
Li Xin Zhang, Gabrielle Lemire, Claudia Gonzaga-Jauregui, Sirinart Molidperee, Carolina Galaz-Montoya, David S. Liu, Alain Verloes, Amelle G. Shillington, Kosuke Izumi, Alyssa L. Ritter, et al.
Genetics in Medicine pp 1-10; doi:10.1038/s41436-020-0811-8

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Nadim Hamzaoui, Flora Alarcon, Nicolas Leulliot, Rosine Guimbaud, Bruno Buecher, Chrystelle Colas, Carole Corsini, Gregory Nuel, Benoît Terris, Pierre Laurent-Puig, et al.
Genetics in Medicine pp 1-9; doi:10.1038/s41436-020-0828-z

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Denise M. Kay, Colleen F. Stevens, April Parker, Carlos A. Saavedra-Matiz, Virginia Sack, Wendy K. Chung, Claudia A. Chiriboga, Kristin Engelstad, Emma Laureta, Osman Farooq, et al.
Genetics in Medicine pp 1-7; doi:10.1038/s41436-020-0824-3

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