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Clinical interpretation of genome variation

Guest Editors: Heidi Rehm and Douglas Fowler

New Content Item Genome Medicine is pleased to present a special issue entitled ‘Clinical interpretation of genome variation’, guest edited by Dr Heidi Rehm from the Broad Institute and MGH and Dr Douglas Fowler from the University of Washington. As next-generation sequencing enters the clinic, research and clinical communities still face major challenges in characterizing genome variation including accurate variant classification, interpretation of variants of uncertain significance, understanding non-coding variants, assessing causality for diagnosis as well as addressing incidental findings. This special issue aims to capture the advances made in understanding genome variation in the clinical context covering the breadth of human disease including Mendelian and complex diseases and rare and common diseases, highlighting novel approaches for accurate variant classification, genome-guided diagnostics and prognostics as well as insights into disease mechanisms.

This collection of articles has not been sponsored and articles will undergo the journal’s standard peer-review process. The Guest Editors declare that they have no competing interests. Guest Editors serve an advisory role to guide the scope of the special issue and commissioned content; final editorial decisions lie with the Editor.

  1. Congenital heart disease (CHD) affects ~ 1% of live births and is the most common birth defect. Although the genetic contribution to the CHD has been long suspected, it has only been well established recently....

    Authors: Cigdem Sevim Bayrak, Peng Zhang, Martin Tristani-Firouzi, Bruce D. Gelb and Yuval Itan

    Citation: Genome Medicine 2020 12:9

    Content type: Research

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  2. The number of druggable tumor-specific molecular aberrations has grown substantially in the past decade, with a significant survival benefit obtained from biomarker matching therapies in several cancer types. ...

    Authors: Eoghan R. Malone, Marc Oliva, Peter J. B. Sabatini, Tracy L. Stockley and Lillian L. Siu

    Citation: Genome Medicine 2020 12:8

    Content type: Review

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  3. The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) clinical variant interpretation guidelines established criteria for different types of evidence. This incl...

    Authors: Sarah E. Brnich, Ahmad N. Abou Tayoun, Fergus J. Couch, Garry R. Cutting, Marc S. Greenblatt, Christopher D. Heinen, Dona M. Kanavy, Xi Luo, Shannon M. McNulty, Lea M. Starita, Sean V. Tavtigian, Matt W. Wright, Steven M. Harrison, Leslie G. Biesecker and Jonathan S. Berg

    Citation: Genome Medicine 2019 12:3

    Content type: Guideline

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  4. Pathogenic variants in BRCA1 and BRCA2 (BRCA1/2) lead to increased risk of breast, ovarian, and other cancers, but most variant-positive individuals in the general population are unaware of their risk, and little...

    Authors: Noura S. Abul-Husn, Emily R. Soper, Jacqueline A. Odgis, Sinead Cullina, Dean Bobo, Arden Moscati, Jessica E. Rodriguez, Ruth J. F. Loos, Judy H. Cho, Gillian M. Belbin, Sabrina A. Suckiel and Eimear E. Kenny

    Citation: Genome Medicine 2019 12:2

    Content type: Research

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  5. Variants of uncertain significance represent a massive challenge to medical genetics. Multiplexed functional assays, in which the functional effects of thousands of genomic variants are assessed simultaneously...

    Authors: Hannah Gelman, Jennifer N. Dines, Jonathan Berg, Alice H. Berger, Sarah Brnich, Fuki M. Hisama, Richard G. James, Alan F. Rubin, Jay Shendure, Brian Shirts, Douglas M. Fowler and Lea M. Starita

    Citation: Genome Medicine 2019 11:85

    Content type: Opinion

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  6. Whole-exome sequencing (WES) has become an efficient diagnostic test for patients with likely monogenic conditions such as rare idiopathic diseases or sudden unexplained death. Yet, many cases remain undiagnos...

    Authors: Elias L. Salfati, Emily G. Spencer, Sarah E. Topol, Evan D. Muse, Manuel Rueda, Jonathan R. Lucas, Glenn N. Wagner, Steven Campman, Eric J. Topol and Ali Torkamani

    Citation: Genome Medicine 2019 11:83

    Content type: Research

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  7. We investigated the features of the genomic rearrangements in a cohort of 50 male individuals with proteolipid protein 1 (PLP1) copy number gain events who were ascertained with Pelizaeus-Merzbacher disease (PMD;...

    Authors: Vahid Bahrambeigi, Xiaofei Song, Karen Sperle, Christine R. Beck, Hadia Hijazi, Christopher M. Grochowski, Shen Gu, Pavel Seeman, Karen J. Woodward, Claudia M. B. Carvalho, Grace M. Hobson and James R. Lupski

    Citation: Genome Medicine 2019 11:80

    Content type: Research

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  8. Genomic structural variants (SVs) can affect many genes and regulatory elements. Therefore, the molecular mechanisms driving the phenotypes of patients carrying de novo SVs are frequently unknown.

    Authors: Sjors Middelkamp, Judith M. Vlaar, Jacques Giltay, Jerome Korzelius, Nicolle Besselink, Sander Boymans, Roel Janssen, Lisanne de la Fonteijne, Ellen van Binsbergen, Markus J. van Roosmalen, Ron Hochstenbach, Daniela Giachino, Michael E. Talkowski, Wigard P. Kloosterman and Edwin Cuppen

    Citation: Genome Medicine 2019 11:79

    Content type: Research

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  9. Precision oncology involves analysis of individual cancer samples to understand the genes and pathways involved in the development and progression of a cancer. To improve patient care, knowledge of diagnostic,...

    Authors: Jake Lever, Martin R. Jones, Arpad M. Danos, Kilannin Krysiak, Melika Bonakdar, Jasleen K. Grewal, Luka Culibrk, Obi L. Griffith, Malachi Griffith and Steven J. M. Jones

    Citation: Genome Medicine 2019 11:78

    Content type: Research

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  10. The 2015 American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines for clinical sequence variant interpretation state that “well-established” functio...

    Authors: Dona M. Kanavy, Shannon M. McNulty, Meera K. Jairath, Sarah E. Brnich, Chris Bizon, Bradford C. Powell and Jonathan S. Berg

    Citation: Genome Medicine 2019 11:77

    Content type: Research

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  11. Manually curated variant knowledgebases and their associated knowledge models are serving an increasingly important role in distributing and interpreting variants in cancer. These knowledgebases vary in their ...

    Authors: Arpad M. Danos, Kilannin Krysiak, Erica K. Barnell, Adam C. Coffman, Joshua F. McMichael, Susanna Kiwala, Nicholas C. Spies, Lana M. Sheta, Shahil P. Pema, Lynzey Kujan, Kaitlin A. Clark, Amber Z. Wollam, Shruti Rao, Deborah I. Ritter, Dmitriy Sonkin, Gordana Raca…

    Citation: Genome Medicine 2019 11:76

    Content type: Correspondence

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  12. Artificial intelligence (AI) is the development of computer systems that are able to perform tasks that normally require human intelligence. Advances in AI software and hardware, especially deep learning algor...

    Authors: Raquel Dias and Ali Torkamani

    Citation: Genome Medicine 2019 11:70

    Content type: Review

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  13. Since different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements, underlie intellectual disability, we evaluated the use of whole-genome sequencing (WGS) ra...

    Authors: Anna Lindstrand, Jesper Eisfeldt, Maria Pettersson, Claudia M. B. Carvalho, Malin Kvarnung, Giedre Grigelioniene, Britt-Marie Anderlid, Olof Bjerin, Peter Gustavsson, Anna Hammarsjö, Patrik Georgii-Hemming, Erik Iwarsson, Maria Johansson-Soller, Kristina Lagerstedt-Robinson, Agne Lieden, Måns Magnusson…

    Citation: Genome Medicine 2019 11:68

    Content type: Research

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  14. Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease, and gene expression profiling has identified several molecular subtypes with distinct biological and clinicopathological characteristics. While...

    Authors: Joep J. de Jong, Yang Liu, A. Gordon Robertson, Roland Seiler, Clarice S. Groeneveld, Michiel S. van der Heijden, Jonathan L. Wright, James Douglas, Marc Dall’Era, Simon J. Crabb, Bas W. G. van Rhijn, Kim E. M. van Kessel, Elai Davicioni, Mauro A. A. Castro, Yair Lotan, Ellen C. Zwarthoff…

    Citation: Genome Medicine 2019 11:60

    Content type: Research

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  15. Clinical laboratories implement a variety of measures to classify somatic sequence variants and identify clinically significant variants to facilitate the implementation of precision medicine. To standardize t...

    Authors: Max M. He, Quan Li, Muqing Yan, Hui Cao, Yue Hu, Karen Y. He, Kajia Cao, Marilyn M. Li and Kai Wang

    Citation: Genome Medicine 2019 11:53

    Content type: Software

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