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Beyond the Exome: What’s Next in Diagnostic Testing for Mendelian Conditions

Monica H. Wojcik,Chloe M. Reuter,Shruti Marwaha,Medhat Mahmoud,Michael H. Duyzend,Hayk Barseghyan,Bo Yuan,Philip M. Boone,Emily Groopman,Emmanuèle C. Délot,Deepti Jain,Alba Sanchis‐Juan,Lea M. Starita,Michael E. Talkowski,Stephen B. Montgomery,Michael J. Bamshad,Jessica X. Chong,Matthew T. Wheeler,Seth Berger,Anne O'Donnell‐Luria,Fritz J. Sedlazeck,Danny E. Miller, Siwaar Abouhala,Jessica Albert,Miguel Almalvez, Rafael González-Álvarez,Mutaz Amin, Peter Anderson,Swaroop Aradhya,Euan A. Ashley,Themistocles L. Assimes, Light Auriga,Christina Austin‐Tse,Mike Bamshad,Samantha Baxter,Sairam Behera, Shaghayegh Beheshti,Gill Bejerano,Jon Bernstein, Sonja M. Best, Benjamin Blankenmeister,Elizabeth Blue,Eric Boerwinkle,Emily Bonkowski,Devon Bonner,Philip Boone, Miriam Bornhorst, Tugce Bozkurt-Yozgatli,Harrison Brand,Kati J. Buckingham,Daniel G. Calame,Silvia Casadei,Lisa H. Chadwick, Clarisa Chavez,Ziwei Chen,Iván K. Chinn,Zeynep Coban–Akdemir,Andrea J. Cohen, Sarah J. Conner,Matthew P. Conomos,Karen J. Coveler, Yanfeng Cui, Sara Currin,Robert Daber,Zain Dardas, Colleen Davis,Moez Dawood, Ivan De Dios,Celine de Esch, Meghan Delaney,Stephanie DiTroia,Harsha Doddapaneni,Haowei Du,Ruizhi Duan,Shannon Dugan‐Perez,Nhat Duong,Evan E. Eichler, Sara Emami,Jawid M. Fatih,Jamie L. Fraser,Vincent A. Fusaro,Miranda Galey,Vijay Ganesh,Kiran Garimella,Richard A. Gibbs, Casey A. Gifford,Amy Ginsburg, P Goddard,Stephanie M. Gogarten, Nikhita Gogate, William Gordon,John E. Gorzynski,William J. Greenleaf,Christopher M. Grochowski, Rodrigo Guarischi Sousa,Sanna Gudmundsson, Ashima Gulati, Dong Guo,Walker Hale, Stacey J. Hall,William T. Harvey,Megan H. Hawley,Ben Heavner,Isabella Herman,Martha Horike‐Pyne,Jianhong Hu,Yongqing Huang, James C. M. Hwang,Gail P. Jarvik,Tanner Jensen,Shalini N. Jhangiani,David Jimenez‐Morales,Christopher Jin,Ahmed K. Saad,Amanda Kahn-Kirby,Jessica Kain, Parneet Kaur,Laura Keehan, Susan M. Knoblach,Arthur Ko,Jennefer N. Kohler,Anshul Kundaje, S. Kundu,Samuel M. Lancaster, Katie Larsson,Gabrielle Lemire,Richard A. Lewis, Wei Li, Yidan Li, Pengfei Liu,Jonathan LoTempio,James R. Lupski, Jialan Ma,Daniel G. MacArthur, Manal Hamed Mahmoud,Nirav Malani,Brian E. Mangilog,Dana Marafi,Sofia Marmolejos, Daniel Marten, Eva Martı́nez,Colby T. Marvin,Francesco Mastrorosa,Dena R. Matalon, Susanne May,Sean McGee, Lauren Meador,Heather C. Mefford, H. Méndez, Alexander Miller,Tadahiro Mitani, Hajer Moussa, Mariana Moyses,Chloe Munderloh,Donna M. Muzny,Sarah C. Nelson, Matthew B. Neu, Jonathan V. Nguyen, Trung Viet Nguyen,Robert L. Nussbaum,Keith Nykamp, William B. O’Callaghan,Emily O’Heir,Melanie O’Leary, Jeffrey B. Olsen,Ikeoluwa Osei‐Owusu, Evin M. Padhi,Lynn Pais, Mingyang Pan, Paresh Panchal,Karynne Patterson,Stewart J. Payne,Davut Pehli̇van, Paul Petrowski, Alex Pham,Georgia Pitsava, A. Podesta, Santiago Ponce, Jennifer E. Posey, J.S. Prosser,Thomas Quertermous, Archana Rai,Arun Ramani,Heidi L. Rehm,Jason Reuter, M Richardson, Andres Rivera-Munoz, Oriane Rubio,Aniko Sabo,Monica Salani,Kaitlin E. Samocha,Sarah Savage,Stuart A. Scott, Elaine P. Scott, Gulalai Shah, Ali Shojaie, Mugdha Singh, Josh Smith, Kevin S. Smith,Hana Snow, M Snyder, Kayla M. Socarras, Batia Stark,Sarah L. Stenton,Andrew B. Stergachis,Adrienne M. Stilp,Laksshman Sundaram, V. Reid Sutton, Jingxie Tai,Christina G. Tise,Catherine Tong,Philip S. Tsao,Rachel Ungar,Grace E. VanNoy,Éric Vilain, Isabella Voutos, Kim Walker,Ben Weisburd, Joan Weiss, Cheryl L. Wellington, Ziming Weng, Emily Westheimer,Marsha M. Wheeler,Laurens Wiel, Michael W. Wilson,Quenna Wong, Ian Chi Kei Wong,Changrui Xiao,Rachita Yadav, Qing Yi, Jianhua Zhao,Jimmy Zhen, Harry Zhou

American journal of human genetics(2023)

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摘要
Despite advances in clinical genetic testing, including the introduction of exome sequencing (ES), more than 50% of individuals with a suspected Mendelian condition lack a precise molecular diagnosis. Clinical evaluation is increasingly undertaken by specialists outside of clinical genetics, often occurring in a tiered fashion and typically ending after ES. The current diagnostic rate reflects multiple factors, including technical limitations, incomplete understanding of variant pathogenicity, missing genotype-phenotype associations, complex gene-environment interactions, and reporting differences between clinical labs. Maintaining a clear understanding of the rapidly evolving landscape of diagnostic tests beyond ES, and their limitations, presents a challenge for non-genetics professionals. Newer tests, such as short-read genome or RNA sequencing, can be challenging to order and emerging technologies, such as optical genome mapping and long-read DNA or RNA sequencing, are not available clinically. Furthermore, there is no clear guidance on the next best steps after inconclusive evaluation. Here, we review why a clinical genetic evaluation may be negative, discuss questions to be asked in this setting, and provide a framework for further investigation, including the advantages and disadvantages of new approaches that are nascent in the clinical sphere. We present a guide for the next best steps after inconclusive molecular testing based upon phenotype and prior evaluation, including when to consider referral to a consortium such as GREGoR, which is focused on elucidating the underlying cause of rare unsolved genetic disorders.
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