Article
Biochemical Research Methods
Sina Abdollahi, Peng-Chan Lin, Meng-Ru Shen, Jung-Hsien Chiang
Summary: The study proposes algorithms to assign a significance to each gene for predicting uncertain significance scores, and successfully shows low error and high accuracy in prediction. By designing different models and evaluating the effectiveness of novel input features, it demonstrates high accuracy as the main impact comes from the features.
BRIEFINGS IN BIOINFORMATICS
(2021)
Article
Endocrinology & Metabolism
Paul J. Newey
Summary: Establishing a genetic diagnosis is beneficial, but accurate interpretation of test results is crucial. Uncertain VUS results pose challenges for clinicians and patients. This article provides a decision-making framework, emphasizing the importance of evaluating VUS results.
CLINICAL ENDOCRINOLOGY
(2022)
Editorial Material
Endocrinology & Metabolism
Stephan Kemp, Joseph J. Orsini, Merel S. Ebberink, Marc Engelen, Troy C. Lund
Summary: Advancements in population screening help identify disease-causing variants, but also lead to the identification of variants with uncertain significance. X-linked adrenoleukodystrophy (ALD), a complex disease, has 62% of missense variants identified through screening with uncertain pathogenicity. Continuous research and improvement of screening protocols are needed.
MOLECULAR GENETICS AND METABOLISM
(2023)
Review
Biochemistry & Molecular Biology
Jane H. Frederiksen, Sara B. Jensen, Zeynep Tumer, Thomas V. O. Hansen
Summary: Lynch syndrome is a common hereditary cancer predisposition syndrome caused by pathogenic variants in DNA mismatch repair genes, emphasizing the importance of clear genetic diagnosis for clinical management. Functional assays can provide insights into difficult-to-predict variants. Future perspectives include high-throughput functional analyses of MMR genes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Genetics & Heredity
Aren E. Marshall, Yijing Liang, Madeline Couse, Haley McConkey, Bekim Sadikovic, Kym M. Boycott, David A. Dyment, Kristin D. Kernohan
Summary: Partial duplications of genes can be an underreported cause of human disease. X-linked dominant variants in ATRX are associated with a clinically heterogeneous syndrome. This case report demonstrates the diagnostic utility of integrating multiple omics technologies in detecting and interpreting gene duplications.
JOURNAL OF HUMAN GENETICS
(2023)
Article
Medical Laboratory Technology
Ping Wang, Ying Qian, Chunyu Gu, Xiufang Zhi, Linjie Pu, Dandan Yan, Jianbo Shu, Ling Lv, Chunquan Cai
Summary: HSH is a rare genetic disease caused by compound heterozygous variants in the TRPM6 gene, leading to seizures and decreased levels of serum magnesium and calcium. The combination of whole exome sequencing and functional studies helps improve pathogenicity evidence, aiding in early diagnosis and treatment.
CLINICA CHIMICA ACTA
(2021)
Article
Oncology
Sukh Makhnoon, Brooke Levin, Megan Ensinger, Kristin Mattie, Robert J. Volk, Zhongming Zhao, Tito Mendoza, Sanjay Shete, Laila Samiian, Generosa Grana, Andrew Grainger, Banu Arun, Brian H. Shirts, Susan K. Peterson
Summary: This study found that reclassification of variants of uncertain significance (VUS) in oncology care settings has significant implications for clinical management and precision cancer prevention. There were significant variations in reclassification rates between different cancer care settings, as well as among racial/ethnic groups.
Article
Medicine, General & Internal
Benjamin J. McCormick, Razvan M. Chirila
Summary: ANKRD26-related thrombocytopenia is a rare inherited disorder associated with an increased risk of malignancy. This case report highlights the presence of ANKRD26-related thrombocytopenia in a patient with AML and emphasizes the importance of understanding the contribution of hereditary germline mutations in disease management.
CUREUS JOURNAL OF MEDICAL SCIENCE
(2023)
Article
Obstetrics & Gynecology
A. H. Mardy, A. P. Wiita, B. Wayman, K. Drexler, T. N. Sparks, M. E. Norton
Summary: The study aimed to categorize variants of uncertain significance found with prenatal chromosomal microarray and determine their association with well-known phenotypes. Results showed that 5.8% of prenatal microarrays contained variants of uncertain significance, with the majority having data available regarding the predicted phenotype.
BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY
(2021)
Article
Computer Science, Artificial Intelligence
Adam Stiff, Michael White, Eric Fosler-Lussier, Lifeng Jin, Evan Jaffe, Douglas Danforth
Summary: Randomized prospective study validates the benefits of combining rule-based and data-driven methods in a virtual patient dialogue system. The hybrid system improves over individual approaches and handles unseen classes with some success. However, there are deficits in the training data and modifications are needed to better handle out-of-scope questions.
NATURAL LANGUAGE ENGINEERING
(2022)
Article
Communication
Lingzi Zhong, Erin E. Donovan, Anita L. Vangelisti
Summary: Receiving variant of uncertain significance (VUS) results is common in genetic testing, but can be challenging for genetic counselors to communicate. This research found that specific message features and individuals' intolerance of uncertainty influenced the effectiveness of counselors' communication of VUS results. The study has theoretical and practical implications for communicating uncertainty in genetic counseling.
HEALTH COMMUNICATION
(2021)
Article
Clinical Neurology
Ana L. Manera, Mahsa Dadar, John Cornelis Van Swieten, Barbara Borroni, Raquel Sanchez-Valle, Fermin Moreno, Robert Laforce, Caroline Graff, Matthis Synofzik, Daniela Galimberti, James Benedict Rowe, Mario Masellis, Maria Carmela Tartaglia, Elizabeth Finger, Rik Vandenberghe, Alexandre de Mendonca, Fabrizio Tagliavini, Isabel Santana, Christopher R. Butler, Alex Gerhard, Adrian Danek, Johannes Levin, Markus Otto, Giovanni Frisoni, Roberta Ghidoni, Sandro Sorbi, Jonathan Daniel Rohrer, Simon Ducharme, D. Louis Collins
Summary: The combination of structural MRI and semantic fluency can accurately predict individual-level bvFTD, showing high accuracy and specificity. This demonstrates the effectiveness of the method in a completely independent validation cohort from a different and independent database.
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2021)
Article
Genetics & Heredity
Marcy E. Richardson, Chunling Hu, Kun Y. Lee, Holly LaDuca, Kelly Fulk, Kate M. Durda, Ashley M. Deckman, David E. Goldgar, Alvaro N. A. Monteiro, Rohan Gnanaolivu, Steven N. Hart, Eric C. Polley, Elizabeth Chao, Tina Pesaran, Fergus J. Couch
Summary: Assessing 252 missense VUSs from the BRCA2 gene, functional data plays a crucial role in reclassifying VUSs and improving clinical management.
AMERICAN JOURNAL OF HUMAN GENETICS
(2021)
Article
Pediatrics
Therese S. Woodring, Mohammed H. Mirza, Valeria Benavides, Katarzyna A. Ellsworth, Meredith S. Wright, M. Jawad Javed, Susan Ramiro
Summary: Congenital anomalies affect 3% to 5% of births and remain the leading cause of infant death in the United States. While VUS results have uncertainty, they may have potential clinical significance in individual patient cases.
Letter
Clinical Neurology
L. Vlahovic, C. B. Lock, M. H. Han, K. Van Haren, J. B. Sampson
Summary: SDHAF1 protein is crucial in the assembly of succinate dehydrogenase. Variants in the SDHAF1 gene have been linked to infantile leukoencephalopathy.
MULTIPLE SCLEROSIS AND RELATED DISORDERS
(2021)
Article
Public, Environmental & Occupational Health
Sukh Makhnoon, Deborah J. Bowen, Brian H. Shirts, Stephanie M. Fullerton, Hendrika W. Meischke, Eric B. Larson, James D. Ralston, Kathleen Leppig, David R. Crosslin, David Veenstra, Gail P. Jarvik
Summary: This study found that patients' genetic knowledge was associated with their future intended familial communication of genetic information, but not with current communication of colorectal cancer risk. Better family functioning was associated with more frequent current communication of CRC risk.
TRANSLATIONAL BEHAVIORAL MEDICINE
(2021)
Article
Public, Environmental & Occupational Health
Deborah J. Bowen, Sukh Makhnoon, Brian H. Shirts, Stephanie M. Fullerton, Eric Larson, James D. Ralston, Kathleen Leppig, David R. Crosslin, David Veenstra, Gail P. Jarvik
Summary: The study found infrequent communication of cancer risk among family members, with a low overall impact of communication within the family. Age and education were associated with the frequency of familial communication, but not with the cancer-related impact of familial communication.
PATIENT EDUCATION AND COUNSELING
(2021)
Article
Oncology
Sukh Makhnoon, Deborah J. Bowen, Brian H. Shirts, Stephanie M. Fullerton, Eric B. Larson, James D. Ralston, Kathleen A. Leppig, David R. Crosslin, David Veenstra, Gail P. Jarvik
Summary: Genetic information plays a role in family communication about colorectal cancer risk and screening, but the study found that tools like FamilyTalk did not significantly impact patient-reported outcomes in terms of privacy concerns, reactions to test results, and lifestyle changes. The limited sample size of participants with specific genetic results and the short follow-up period could have influenced the lack of significant findings.
CANCER CAUSES & CONTROL
(2021)
Article
Medicine, Research & Experimental
Deborah J. Bowen, Catharine Wang, Allison M. Cole, Barbara M. Norquist, Sarah Knerr, Beth Devine, Brian Shirts, Kevin Cain, Heather M. Harris, Helen G. Haile, Elizabeth M. Swisher
Summary: This study aims to compare and evaluate two population-wide engagement strategies for identifying members of a primary care clinic's population with a family or personal history of cancer and offering high-risk individuals genetic testing for cancer susceptibility mutations. The study will evaluate the effects of the two engagement strategies on patient, provider, and clinic leader outcomes, including perceptions of benefits, harms, and satisfaction with the engagement strategy and process of cancer risk assessment and genetic testing. Additionally, the study will assess the cost-effectiveness and budget impact of each engagement strategy.
CONTEMPORARY CLINICAL TRIALS
(2021)
Article
Genetics & Heredity
Stephen E. Lincoln, Tina Hambuch, Justin M. Zook, Sara L. Bristow, Kathryn Hatchell, Rebecca Truty, Michael Kennemer, Brian H. Shirts, Andrew Fellowes, Shimul Chowdhury, Eric W. Klee, Shazia Mahamdallie, Megan H. Cleveland, Peter M. Vallone, Yan Ding, Sheila Seal, Wasanthi DeSilva, Farol L. Tomson, Catherine Huang, Russell K. Garlick, Nazneen Rahman, Marc Salit, Stephen F. Kingsmore, Matthew J. Ferber, Swaroop Aradhya, Robert L. Nussbaum
Summary: The study evaluated the impact of technically challenging variants on clinical genetic tests, finding considerable variability in the analytic and clinical sensitivity of NGS workflows. Some challenging variants were not detected by all workflows, highlighting the importance of test design, validation, and selection for clinicians.
GENETICS IN MEDICINE
(2021)
Article
Allergy
Sarah K. Baxter, Tom Walsh, Silvia Casadei, Mary M. Eckert, Eric J. Allenspach, David Hagin, Gesmar Segundo, Ming K. Lee, Suleyman Gulsuner, Brian H. Shirts, Kathleen E. Sullivan, Michael D. Keller, Troy R. Torgerson, Mary-Claire King
Summary: This study identified damaging germline mutations in 27 genes in about 39% of patients with childhood-onset immune dysregulation, polyendocrinopathy, and enteropathy. Many of these genes had not been previously associated with the disease. Genetic diagnoses of these patients have clinical implications and can potentially alter therapeutic management, providing targeted treatments and recommendations for hematopoietic cell transplantation.
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
(2022)
Article
Genetics & Heredity
Shawn Fayer, Carrie Horton, Jennifer N. Dines, Alan F. Rubin, Marcy E. Richardson, Kelly McGoldrick, Felicia Hernandez, Tina Pesaran, Rachid Karam, Brian H. Shirts, Douglas M. Fowler, Lea M. Starita
Summary: The combination of multiplexed functional data with clinical data can effectively drive the reclassification of missense variants, reducing the number of variants of uncertain significance and having a major impact on clinical variant interpretation.
AMERICAN JOURNAL OF HUMAN GENETICS
(2021)
Article
Urology & Nephrology
Kara N. Maxwell, Heather H. Cheng, Jacquelyn Powers, Roman Gulati, Elisa M. Ledet, Casey Morrison, Anh Le, Ryan Hausler, Jill Stopfer, Sophie Hyman, Wendy Kohlmann, Anne Naumer, Jennie Vagher, Samantha E. Greenberg, Lorraine Naylor, Mercy Laurino, Eric Q. Konnick, Brian H. Shirts, Saud H. AlDubayan, Eliezer M. Van Allen, Bastien Nguyen, Joseph Vijai, Wassim Abida, Maria Carlo, Marianne Dubard-Gault, Daniel J. Lee, Luke D. Maese, Diana Mandelker, Bruce Montgomery, Michael J. Morris, Piper Nicolosi, Robert L. Nussbaum, Lauren E. Schwartz, Zsofia Stadler, Judy E. Garber, Kenneth Offit, Joshua D. Schiffman, Peter S. Nelson, Oliver Sartor, Michael F. Walsh, Colin C. Pritchard
Summary: Complementary analysis of prostate cancer incidence in LFS males and gTP53 prevalence in prostate cancer cohorts suggests that gTP53 predisposes to aggressive prostate cancer. Prostate cancer should be considered as part of LFS screening protocols and TP53 should be considered in germline prostate cancer susceptibility testing.
Article
Genetics & Heredity
Steven M. Harrison, Christina A. Austin-Tse, Serra Kim, Matthew Lebo, Annette Leon, David Murdock, Aparna Radhakrishnan, Brian H. Shirts, Marcie Steeves, Eric Venner, Richard A. Gibbs, Gail P. Jarvik, Heidi L. Rehm
Summary: The All of Us Research Program aims to accelerate research and improve healthcare by collecting data from one million people in the United States. Participants can choose to receive genome analysis results, including actionable findings for certain gene-disorder pairs. Four participating clinical laboratories conducted a prelaunch study to ensure consistent reporting of variant classifications, with 99.1% concordance and resolution of all reportability differences through reassessment and discussion. This approach will be maintained for continuous classification harmonization and consistent reporting within the program.
Article
Genetics & Heredity
Laura M. Amendola, Elizabeth Shuster, Michael C. Leo, Michael O. Dorschner, Bradley A. Rolf, Brian H. Shirts, Marian J. Gilmore, Sonia Okuyama, Jamilyn M. Zepp, Tia L. Kauffman, Kathleen F. Mittendorf, Cecilia Bellcross, Charisma L. Jenkins, Galen Joseph, Leslie Riddle, Sapna Syngal, Chinedu Ukaegbu, Katrina A. B. Goddard, Benjamin S. Wilfond, Gail P. Jarvik
Summary: This study aims to evaluate the laboratory-related outcomes of participants offered genomic testing based on cancer family history risk assessment tools. The study found that 5% of participants had a pathogenic/likely pathogenic cancer risk variant and 1% had a secondary finding. Participant personal history and PREMM5 score were associated with the category of findings.
GENETICS IN MEDICINE
(2022)
Article
Genetics & Heredity
Ronald W. Buie, John Michael O. Ranola, Annie T. Chen, Brian H. Shirts
Summary: This paper proposes an algorithm to evaluate the variant information gain in familial cosegregation analysis, and validates its performance by comparing actual recruitment strategies with optimized testing strategies. The results show that the testing strategy indicated by the algorithm can achieve maximal information gain more rapidly.
Article
Genetics & Heredity
Shangqing Jiang, Patrick C. Mathias, Nathaniel Hendrix, Brian H. Shirts, Peter Tarczy-Hornoch, David Veenstra, Daniel Malone, Beth Devine
Summary: A cost-effectiveness model was constructed to evaluate the clinical and economic value of a CDS alert program providing PGx testing results in ACS and AF. The program was found to significantly reduce major clinical events and deaths in ACS and AF, and was cost-effective with an incremental cost-effectiveness ratio of $39,477/QALY compared to no alert program, under a willingness-to-pay threshold of $100,000/QALY gained.
PHARMACOGENOMICS JOURNAL
(2022)
Article
Health Care Sciences & Services
E. J. Dusic, Deborah J. Bowen, Robin Bennett, Kevin C. Cain, Tesla Theoryn, Mariebeth Velasquez, Elizabeth Swisher, Jeannine M. Brant, Brian Shirts, Catharine Wang
Summary: This study found that socioeconomic status affects individuals' interest in pursuing hereditary cancer genetic testing, with factors such as education and household income being related to the level of interest.
Article
Medicine, Research & Experimental
Wei-Liang Chen, Emily Pao, James Owens, Ian Glass, Colin Pritchard, Brain H. Shirts, Christina Lockwood, Ghayda M. Mirzaa
Summary: The megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth disorder caused by mosaic gain-of-function variants in PIK3CA. This study reports the utility of cerebrospinal fluid (CSF)-derived cfDNA for the molecular diagnosis of MCAP syndrome and highlights the importance of minimally invasive approaches using cfDNA for accurate diagnosis and potential therapeutic implications for individuals with refractory epilepsy.
COLD SPRING HARBOR MOLECULAR CASE STUDIES
(2022)
Article
Oncology
Rachel Pearlman, Wendy L. Frankel, Benjamin J. Swanson, Dan Jones, Weiqiang Zhao, Ahmet Yilmaz, Kristin Miller, Jason Bacher, Christopher Bigley, Lori Nelsen, Paul J. Goodfellow, Richard M. Goldberg, Electra Paskett, Peter G. Shields, Jo L. Freudenheim, Peter P. Stanich, Ilene Lattimer, Mark Arnold, Thomas W. Prior, Mitchell Haut, Matthew F. Kalady, Brandie Heald, Ian Paquette, David J. Draper, Joanna M. Brell, Sameer Mahesh, Kisa Weeman, Shyamal Bastola, Jeffrey Zangmeister, Aruna Gowda, Filix Kencana, Albert Malcolm, Yinong Liu, Sharon Cole, Charles Bane, Chaoyang Li, Esther Rehmus, Colin C. Pritchard, Brian H. Shirts, Angela Jacobson, Shelly A. Cummings, Albert de la Chapelle, Heather Hampel
Summary: The study found that 7.1% of individuals with CRC have PGVs, and UTS alone is insufficient for identifying a large proportion of CRC patients with hereditary syndromes, including some with LS. Pan-cancer MGPT for all patients with CRC may be a better screening method.
JCO PRECISION ONCOLOGY
(2021)
Article
Genetics & Heredity
Katerina S. Kucera, Beth Lincoln Boyea, Brooke Migliore, Sarah Nelson Potter, Veronica R. Robles, Oksana Kutsa, Heidi Cope, Katherine C. Okoniewski, Anne Wheeler, Catherine W. Rehder, Edward C. Smith, Holly L. Peay
Summary: Screening for elevated CK-MM levels in dried blood spots is a feasible method to identify newborns with DMD. Including specific cutoffs, repeat testing, and genetic sequencing can improve the accuracy and sensitivity of screening.
GENETICS IN MEDICINE
(2024)
Article
Genetics & Heredity
Madeline Currey, Ilana Solomon, Sarah Mcgraw, Jenny Shen, Francisco Munoz, Ernesto Sosa, Vanessa Puello-Lozano, Sam Wing, Lisa Lopez, Michelle Afkhami, Janine Lobello, Szabolcs Szelinger, Stacy W. Gray
Summary: This study conducted qualitative interviews with cancer patients and providers to identify gaps in clinical care and propose care delivery solutions for the return of secondary germline findings. The responses of patients varied depending on the amount of pre-test counseling they received, and providers identified insufficient clinic time as a major barrier to pretest education. Online support tools and standardized pre-test education models were favored by providers. There were differing perspectives on how pre-test education should be integrated into clinical workflows, but agreement on the inclusion of differences between somatic and germline testing, likelihood of medically actionable findings, and the possibility of being referred to a genetics provider.
GENETICS IN MEDICINE
(2024)
Article
Genetics & Heredity
Kiely N. James, Shimul Chowdhury, Yan Ding, Sergey Batalov, Kelly Watkins, Yong Hyun Kwon, Lucitia Van Der Kraan, Katarzyna Ellsworth, Stephen F. Kingsmore, Lucia Guidugli
Summary: This study used genome sequencing to detect a wide range of copy-number variants (CNVs) and other non-single nucleotide variant/indel variant types. These genetic alterations accounted for 15.8% of reported variants, with deletions being the most common type. The study also found that additional genetic tests were ordered in some cases, but failed to report the variants detected by genome sequencing.
GENETICS IN MEDICINE
(2024)
Article
Genetics & Heredity
Asem Berkalieva, Nicole R. Kelly, Ashley Fisher, Samuel F. Hohmann, Monisha Sebastin, Miranda Di Biase, Katherine E. Bonini, Priya Marathe, Jacqueline A. Odgis, Sabrina A. Suckiel, Michelle A. Ramos, Rosamond Rhodes, Noura S. Abul-Husn, John M. Greally, Carol R. Horowitz, Melissa P. Wasserstein, Eimear E. Kenny, Bruce D. Gelb, Bart S. Ferket
Summary: The study aims to understand the effects of returning diagnostic sequencing results on clinical actions and economic outcomes for pediatric patients with suspected genetic disorders. The results showed that patients with positive findings were more likely to receive specialist consultation, but there were no significant increases in overall physician services and costs. More large-scale studies are needed to confirm these findings.
GENETICS IN MEDICINE
(2024)
Article
Genetics & Heredity
Kirstine Stochholm, Camilla Holmgard, Shanlee M. Davis, Claus H. Gravholt, Agnethe Berglund
Summary: This study assessed the incidence, prevalence, and age at diagnosis of individuals with 45,X/46,XY mosaicism and described the associated mortality pattern. The study found an increasing incidence of 45,X/46,XY mosaicism in males and a stable incidence in females. Males were diagnosed at an older age than females. Additionally, 45,X/46,XY mosaicism was associated with increased all-cause mortality.
GENETICS IN MEDICINE
(2024)
Article
Genetics & Heredity
Yunjia Chen, Ender Karaca, Nathaniel H. Robin, Dana Goodloe, Ali Al-Beshri, S. Joy Dean, Anna C. E. Hurst, Andrew J. Carroll, Fady M. Mikhail
Summary: This study confirms the association between DLG2 intragenic deletions and neurodevelopmental disorders, supports the haploinsufficiency of the DLG2 gene, and suggests a potential association between these deletions and congenital anomalies and dysmorphism.
GENETICS IN MEDICINE
(2024)