Standards and Guidelines for Genetic Variant Interpretation

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Spillmann, R. C., Tan, Q. K.-G., Reuter, C., Schoch, K., Kohler, J., Bonner, D., Zastrow, D., Alkelai, A., Baugh, E., Cope, H., Marwaha, S., Wheeler, M. T., Bernstein, J. A., Shashi, V., Acosta, M. T., Adam, M., Adams, D. R., Alvey, J., Amendola, L., … Zuchner, S. (2023). A concurrent dual analysis of genomic data augments diagnoses: Experiences of 2 clinical sites in the Undiagnosed Diseases Network. Genetics in Medicine, 25(4), 100353. https://doi.org/10.1016/j.gim.2022.12.001
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Columbia Affiliation
Sheppard, S. E., Bryant, L., Wickramasekara, R. N., Vaccaro, C., Robertson, B., Hallgren, J., Hulen, J., Watson, C. J., Faundes, V., Duffourd, Y., Lee, P., Simon, M. C., de la Cruz, X., Padilla, N., Flores-Mendez, M., Akizu, N., Smiler, J., Pellegrino Da Silva, R., Li, D., … Stessman, H. A. F. (2023). Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice. Science Advances, 9(10). https://doi.org/10.1126/sciadv.ade1463
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Iqbal, M. A., Broeckel, U., Levy, B., Skinner, S., Sahajpal, N. S., Rodriguez, V., Stence, A., Awayda, K., Scharer, G., Skinner, C., Stevenson, R., Bossler, A., Nagy, P. L., & Kolhe, R. (2023). Multisite Assessment of Optical Genome Mapping for Analysis of Structural Variants in Constitutional Postnatal Cases. The Journal of Molecular Diagnostics, 25(3), 175–188. https://doi.org/10.1016/j.jmoldx.2022.12.005
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Timmins, G. T., Wynn, J., Saami, A. M., Espinal, A., & Chung, W. K. (2022). Diverse Parental Perspectives of the Social and Educational Needs for Expanding Newborn Screening through Genomic Sequencing. Public Health Genomics, 25(5–6), 185–192. Portico. https://doi.org/10.1159/000526382
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Bain, J. M., Snyder, L. G., Helbig, K. L., Cooper, D. D., Chung, W. K., & Goodspeed, K. (2022). Consistency of parent-report SLC6A1 data in Simons Searchlight with Provider-Based Publications. Journal of Neurodevelopmental Disorders, 14(1). https://doi.org/10.1186/s11689-022-09449-7
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He, K. Y., Kelly, T. N., Wang, H., Liang, J., Zhu, L., Cade, B. E., Assimes, T. L., Becker, L. C., Beitelshees, A. L., Bielak, L. F., Bress, A. P., Brody, J. A., Chang, Y.-P. C., Chang, Y.-C., de Vries, P. S., Duggirala, R., Fox, E. R., Franceschini, N., Furniss, A. L., … Zhu, X. (2022). Rare coding variants in RCN3 are associated with blood pressure. BMC Genomics, 23(1). https://doi.org/10.1186/s12864-022-08356-4
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Feng, Y.-C. A., Stanaway, I. B., Connolly, J. J., Denny, J. C., Luo, Y., Weng, C., Wei, W.-Q., Weiss, S. T., Karlson, E. W., & Smoller, J. W. (2022). Psychiatric manifestations of rare variation in medically actionable genes: a PheWAS approach. BMC Genomics, 23(1). https://doi.org/10.1186/s12864-022-08600-x
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Barua, S., Pereira, E. M., Jobanputra, V., Anyane-Yeboa, K., Levy, B., & Liao, J. (2022). 3q27.1 microdeletion causes prenatal and postnatal growth restriction and neurodevelopmental abnormalities. Molecular Cytogenetics, 15(1). https://doi.org/10.1186/s13039-022-00587-0
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Ganapathi, M., Thomas-Wilson, A., Buchovecky, C., Dharmadhikari, A., Barua, S., Lee, W., Ruan, M. Z. C., Soucy, M., Ragi, S., Tanaka, J., Clark, L. N., Naini, A. B., Liao, J., Mansukhani, M., Tsang, S., & Jobanputra, V. (2022). Clinical exome sequencing for inherited retinal degenerations at a tertiary care center. Scientific Reports, 12(1). https://doi.org/10.1038/s41598-022-13026-2
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Hussain, S., Nawaz, S., Khan, H., Acharya, A., Schrauwen, I., Ahmad, W., & Leal, S. M. (2022). A splice site variant in TCTN3 underlies an atypical form of orofaciodigital syndrome IV. Annals of Human Genetics, 86(6), 291–296. Portico. https://doi.org/10.1111/ahg.12462
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Kayumi, S., Pérez-Jurado, L. A., Palomares, M., Rangu, S., Sheppard, S. E., Chung, W. K., Kruer, M. C., Kharbanda, M., Amor, D. J., McGillivray, G., Cohen, J. S., García-Miñaúr, S., van Eyk, C. L., Harper, K., Jolly, L. A., Webber, D. L., Barnett, C. P., Santos-Simarro, F., Pacio-Míguez, M., … Corbett, M. A. (2022). Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants. Genetics in Medicine, 24(11), 2351–2366. https://doi.org/10.1016/j.gim.2022.08.006
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Motelow, J. E., Lippa, N. C., Hostyk, J., Feldman, E., Nelligan, M., Ren, Z., Alkelai, A., Milner, J. D., Gharavi, A. G., Tang, Y., Goldstein, D. B., & Kernie, S. G. (2022). Risk Variants in the Exomes of Children With Critical Illness. JAMA Network Open, 5(10), e2239122. https://doi.org/10.1001/jamanetworkopen.2022.39122
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Wu, C.-H. W., Lim, T. Y., Wang, C., Seltzsam, S., Zheng, B., Schierbaum, L., Schneider, S., Mann, N., Connaughton, D. M., Nakayama, M., van der Ven, A. T., Dai, R., Kolvenbach, C. M., Kause, F., Ottlewski, I., Stajic, N., Soliman, N. A., Kari, J. A., El Desoky, S., … Hildebrandt, F. (2022). Copy Number Variation Analysis Facilitates Identification of Genetic Causation in Patients with Congenital Anomalies of the Kidney and Urinary Tract. European Urology Open Science, 44, 106–112. https://doi.org/10.1016/j.euros.2022.08.004
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Flerlage, J. E., Birz, S., Castellino, S. M., Appel, B., Furner, B., Graglia, L., Henderson, T. O., Hodgson, D., Hoppe, B. S., Kahn, J., Keller, F. G., Kessel, S., Li, C., Li, M., Lucas, J., Mccarten, K., Metzger, M., Milgrom, S., Parsons, S. K., … Kelly, K. M. (2022). P086: Advancing Pediatric Hodgkin Lymphoma Research Through NODAL. HemaSphere, 6, 39–40. https://doi.org/10.1097/01.hs9.0000890912.56229.80
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Jain, N. G., Ahram, D. F., Marasa, M., Rehman, A. U., May, H. J., Zacharoulis, S., Revah-Politi, A., Florido, M. E., Whittemore, G. B., Aggarwal, V. S., Hargus, G., Anyane-Yeboa, K., D’Agati, V. D., Lin, F., Jobanputra, V., & Sanna-Cherchi, S. (2022). Clinical Real-Time Genome Sequencing to Solve the Complex and Confounded Presentation of a Child With Focal Segmental Glomerulosclerosis and Multiple Malignancies. Kidney International Reports, 7(10), 2312–2316. https://doi.org/10.1016/j.ekir.2022.07.174
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Zhou, X., Feliciano, P., Shu, C., Wang, T., Astrovskaya, I., Hall, J. B., Obiajulu, J. U., Wright, J. R., Murali, S. C., Xu, S. X., Brueggeman, L., Thomas, T. R., Marchenko, O., Fleisch, C., Barns, S. D., Snyder, L. G., Han, B., Chang, T. S., Turner, T. N., … Chung, W. K. (2022). Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes. Nature Genetics, 54(9), 1305–1319. https://doi.org/10.1038/s41588-022-01148-2
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Küry, S., Zhang, J., Besnard, T., Caro-Llopis, A., Zeng, X., Robert, S. M., Josiah, S. S., Kiziltug, E., Denommé-Pichon, A.-S., Cogné, B., Kundishora, A. J., Hao, L. T., Li, H., Stevenson, R. E., Louie, R. J., Deb, W., Torti, E., Vignard, V., McWalter, K., … Isidor, B. (2022). Rare pathogenic variants in WNK3 cause X-linked intellectual disability. Genetics in Medicine, 24(9), 1941–1951. https://doi.org/10.1016/j.gim.2022.05.009
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Liu, C., Ta, C. N., Havrilla, J. M., Nestor, J. G., Spotnitz, M. E., Geneslaw, A. S., Hu, Y., Chung, W. K., Wang, K., & Weng, C. (2022). OARD: Open annotations for rare diseases and their phenotypes based on real-world data. The American Journal of Human Genetics, 109(9), 1591–1604. https://doi.org/10.1016/j.ajhg.2022.08.002
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Berger, S. M., Appelbaum, P. S., Siegel, K., Wynn, J., Saami, A. M., Brokamp, E., O’Connor, B. C., Hamid, R., Martin, D. M., & Chung, W. K. (2022). Challenges of variant reinterpretation: Opinions of stakeholders and need for guidelines. Genetics in Medicine, 24(9), 1878–1887. https://doi.org/10.1016/j.gim.2022.06.002
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Lai, D., Gade, M., Yang, E., Koh, H. Y., Lu, J., Walley, N. M., Buckley, A. F., Sands, T. T., Akman, C. I., Mikati, M. A., McKhann, G. M., Goldman, J. E., Canoll, P., Alexander, A. L., Park, K. L., Von Allmen, G. K., Rodziyevska, O., Bhattacharjee, M. B., Lidov, H. G. W., … Heinzen, E. L. (2022). Somatic variants in diverse genes leads to a spectrum of focal cortical malformations. Brain, 145(8), 2704–2720. https://doi.org/10.1093/brain/awac117
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Dhombres, F., Morgan, P., Chaudhari, B. P., Filges, I., Sparks, T. N., Lapunzina, P., Roscioli, T., Agarwal, U., Aggarwal, S., Beneteau, C., Cacheiro, P., Carmody, L. C., Collardeau‐Frachon, S., Dempsey, E. A., Dufke, A., Duyzend, M. H., el Ghosh, M., Giordano, J. L., Glad, R., … Robinson, P. N. (2022). Prenatal phenotyping: A community effort to enhance the Human Phenotype Ontology. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 190(2), 231–242. Portico. https://doi.org/10.1002/ajmg.c.31989
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Appelbaum, P. S., Burke, W., Parens, E., Zeevi, D. A., Arbour, L., Garrison, N. A., Bonham, V. L., & Chung, W. K. (2022). Is there a way to reduce the inequity in variant interpretation on the basis of ancestry? The American Journal of Human Genetics, 109(6), 981–988. https://doi.org/10.1016/j.ajhg.2022.04.012
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Hayeck, T. J., Stong, N., Baugh, E., Dhindsa, R., Turner, T. N., Malakar, A., Mosbruger, T. L., Shaw, G. T.-W., Duan, Y., Ionita-Laza, I., Goldstein, D., & Allen, A. S. (2022). Ancestry adjustment improves genome-wide estimates of regional intolerance. Genetics. https://doi.org/10.1093/genetics/iyac050
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Cornejo-Sanchez, D. M., Acharya, A., Bharadwaj, T., Marin-Gomez, L., Pereira-Gomez, P., Nouel-Saied, L. M., Nickerson, D. A., Bamshad, M. J., Mefford, H. C., Schrauwen, I., Carrizosa-Moog, J., Cornejo-Ochoa, W., Pineda-Trujillo, N., & Leal, S. M. (2022). SCN1A Variants as the Underlying Cause of Genetic Epilepsy with Febrile Seizures Plus in Two Multi-Generational Colombian Families. Genes, 13(5), 754. https://doi.org/10.3390/genes13050754
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López-Gómez, C., Cámara, Y., Hirano, M., & Martí, R. (2022). 232nd ENMC international workshop: Recommendations for treatment of mitochondrial DNA maintenance disorders. 16 – 18 June 2017, Heemskerk, The Netherlands. Neuromuscular Disorders, 32(7), 609–620. https://doi.org/10.1016/j.nmd.2022.05.008
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Willcox, J. A. L., Geiger, J. T., Morton, S. U., McKean, D., Quiat, D., Gorham, J. M., Tai, A. C., DePalma, S., Bernstein, D., Brueckner, M., Chung, W. K., Giardini, A., Goldmuntz, E., Kaltman, J. R., Kim, R., Newburger, J. W., Shen, Y., Srivastava, D., Tristani-Firouzi, M., … Seidman, C. E. (2022). Neither cardiac mitochondrial DNA variation nor copy number contribute to congenital heart disease risk. The American Journal of Human Genetics, 109(5), 961–966. https://doi.org/10.1016/j.ajhg.2022.03.011
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Aguiar, T., Teixeira, A., Scliar, M. O., Sobral de Barros, J., Lemes, R. B., Souza, S., Tolezano, G., Santos, F., Tojal, I., Cypriano, M., Caminada de Toledo, S. R., Valadares, E., Borges Pinto, R., Pinto Artigalas, O. A., Caetano de Aguirre Neto, J., Novak, E., Cristofani, L. M., Miura Sugayama, S. M., Odone, V., … Krepischi, A. (2022). Unraveling the Genetic Architecture of Hepatoblastoma Risk: Birth Defects and Increased Burden of Germline Damaging Variants in Gastrointestinal/Renal Cancer Predisposition and DNA Repair Genes. Frontiers in Genetics, 13. https://doi.org/10.3389/fgene.2022.858396
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Wright, J., Barns, S., Goler, A., Hall, J., Han, B., Astrovskaya, I., Marchenko, O., Ganesan, S., Volfovsky, N., Feliciano, P., & Chung, W. (2022). eP287: Return of individual genetic results in the largest recontactable cohort of individuals with autism. Genetics in Medicine, 24(3), S181–S182. https://doi.org/10.1016/j.gim.2022.01.322
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Sahajpal, N., Rodriguez, V., Kanyo, L., Stence, A., Skinner, S., Iqbal, A., Awayda, K., Levy, B., Broeckel, U., Scharer, G., Hackman, J., Mondal, A., Bossler, A., Nagy, P., & Kolhe, R. (2022). eP391: Optical genome mapping for constitutional postnatal SV, CNV, and repeat array sizing: A multi-site clinical study. Genetics in Medicine, 24(3), S246–S247. https://doi.org/10.1016/j.gim.2022.01.426
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Nagy, D., Verheyen, S., Wigby, K. M., Borovikov, A., Sharkov, A., Slegesky, V., Larson, A., Fagerberg, C., Brasch-Andersen, C., Kibæk, M., Bader, I., Hernan, R., High, F. A., Chung, W. K., Schieving, J. H., Behunova, J., Smogavec, M., Laccone, F., Witsch-Baumgartner, M., … Weis, D. (2022). Genotype-Phenotype Comparison in POGZ-Related Neurodevelopmental Disorders by Using Clinical Scoring. Genes, 13(1), 154. https://doi.org/10.3390/genes13010154
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Zoghbi, A. W., Dhindsa, R. S., Goldberg, T. E., Mehralizade, A., Motelow, J. E., Wang, X., Alkelai, A., Harms, M. B., Lieberman, J. A., Markx, S., & Goldstein, D. B. (2021). High-impact rare genetic variants in severe schizophrenia. Proceedings of the National Academy of Sciences, 118(51). https://doi.org/10.1073/pnas.2112560118
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Wang, Z., Fan, X., Shen, Y., Pagadala, M. S., Signer, R., Cygan, K. J., Fairbrother, W. G., Carter, H., Chung, W. K., & Huang, K. (2021). Non-cancer-related pathogenic germline variants and expression consequences in ten-thousand cancer genomes. Genome Medicine, 13(1). https://doi.org/10.1186/s13073-021-00964-1
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Nudelman, K. N. H., Oblak, A. L., Faber, K. M., Reyes‐Dumeyer, D., Issen, H., Lacy, K., Wilmes, K., Marshall, J. D., Case, K. R., Mitchell, C. M., Hobbick, C. C., Mayeux, R., & Foroud, T. M. (2021). NCRAD Family Study and NIA‐LOAD brain tissue: A NCRAD resource. Alzheimer’s & Dementia, 17(S3). Portico. https://doi.org/10.1002/alz.056284
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Bajorek, L. P., Kiekhofer, R., Hall, M., Taylor, J., Lucente, D. E., Brushaber, D., Appleby, B., Coppolla, G., Bordelon, Y. M., Botha, H., Dickerson, B. C., Dickson, D. W., Domoto‐Reilly, K., Fagan, A. M., Fields, J. A., Fong, J. C., Foroud, T. M., Forsberg, L. K., … Galasko, D. R. (2021). Demographic and psychosocial factors associated with the decision to learn mutation status in familial frontotemporal dementia and the impact of disclosure on mood. Alzheimer’s & Dementia, 17(S7). Portico. https://doi.org/10.1002/alz.050692
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Weerts, M. J. A., Lanko, K., Guzmán-Vega, F. J., Jackson, A., Ramakrishnan, R., Cardona-Londoño, K. J., Peña-Guerra, K. A., van Bever, Y., van Paassen, B. W., Kievit, A., van Slegtenhorst, M., Allen, N. M., Kehoe, C. M., Robinson, H. K., Pang, L., Banu, S. H., Zaman, M., Efthymiou, S., Houlden, H., … Barakat, T. S. (2021). Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome. Genetics in Medicine, 23(11), 2122–2137. https://doi.org/10.1038/s41436-021-01246-2
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