Articles

Distinct patterns of complex rearrangements and a mutational signature of microhomeology are frequently observed in PLP1 copy number gain structural variants

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

Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants

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

Text-mining clinically relevant cancer biomarkers for curation into the CIViC database

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

Comparative analysis of functional assay evidence use by ClinGen Variant Curation Expert Panels

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

Standard operating procedure for curation and clinical interpretation of variants in cancer

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…

Genomic screening and genomic diagnostic testing—two very different kettles of fish

Authors: Leslie G. Biesecker

Low coverage whole genome sequencing enables accurate assessment of common variants and calculation of genome-wide polygenic scores

Inherited susceptibility to common, complex diseases may be caused by rare, pathogenic variants (“monogenic”) or by the cumulative effect of numerous common variants (“polygenic”). Comprehensive genome interpr...

Authors: Julian R. Homburger, Cynthia L. Neben, Gilad Mishne, Alicia Y. Zhou, Sekar Kathiresan and Amit V. Khera

Immune receptor repertoires in pediatric and adult acute myeloid leukemia

Acute myeloid leukemia (AML), caused by the abnormal proliferation of immature myeloid cells in the blood or bone marrow, is one of the most common hematologic malignancies. Currently, the interactions between...

Authors: Jian Zhang, Xihao Hu, Jin Wang, Avinash Das Sahu, David Cohen, Li Song, Zhangyi Ouyang, Jingyu Fan, Binbin Wang, Jingxin Fu, Shengqing Gu, Moshe Sade-Feldman, Nir Hacohen, Wuju Li, Xiaomin Ying, Bo Li…

Is ‘likely pathogenic’ really 90% likely? Reclassification data in ClinVar

In 2015, professional guidelines defined the term ‘likely pathogenic’ to mean with a 90% chance of pathogenicity. To determine whether current practice reflects this definition, ClinVar classifications were tr...

Authors: Steven M. Harrison and Heidi L. Rehm

Neoantigens and genome instability: impact on immunogenomic phenotypes and immunotherapy response

The resurgence of immune therapies in cancer medicine has elicited a corresponding interest in understanding the basis of patient response or resistance to these treatments. One aspect of patient response clea...

Authors: Elaine R. Mardis

Artificial intelligence in clinical and genomic diagnostics

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

Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension

Group 1 pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. Pathogenic remodeling of pulmonary arterioles leads to increased pulmonary pressures, ri...

Authors: Na Zhu, Michael W. Pauciulo, Carrie L. Welch, Katie A. Lutz, Anna W. Coleman, Claudia Gonzaga-Jauregui, Jiayao Wang, Joseph M. Grimes, Lisa J. Martin, Hua He, Yufeng Shen, Wendy K. Chung and William C. Nichols

From cytogenetics to cytogenomics: whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability

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…

pTuneos: prioritizing tumor neoantigens from next-generation sequencing data

Cancer neoantigens are expressed only in cancer cells and presented on the tumor cell surface in complex with major histocompatibility complex (MHC) class I proteins for recognition by cytotoxic T cells. Accur...

Authors: Chi Zhou, Zhiting Wei, Zhanbing Zhang, Biyu Zhang, Chenyu Zhu, Ke Chen, Guohui Chuai, Sheng Qu, Lu Xie, Yong Gao and Qi Liu

Inflammatory cytokines and organ dysfunction associate with the aberrant DNA methylome of monocytes in sepsis

Sepsis, a life-threatening organ dysfunction caused by a dysregulated systemic immune response to infection, associates with reduced responsiveness to subsequent infections. How such tolerance is acquired is n...

Authors: Clara Lorente-Sorolla, Antonio Garcia-Gomez, Francesc Català-Moll, Víctor Toledano, Laura Ciudad, José Avendaño-Ortiz, Charbel Maroun-Eid, Alejandro Martín-Quirós, Mónica Martínez-Gallo, Adolfo Ruiz-Sanmartín, Álvaro García del Campo, Ricard Ferrer-Roca, Juan Carlos Ruiz-Rodriguez, Damiana Álvarez-Errico, Eduardo López-Collazo and Esteban Ballestar

Dissecting the genetic basis of comorbid epilepsy phenotypes in neurodevelopmental disorders

Neurodevelopmental disorders (NDDs) such as autism spectrum disorder, intellectual disability, developmental disability, and epilepsy are characterized by abnormal brain development that may affect cognition, ...

Authors: Julie Chow, Matthew Jensen, Hajar Amini, Farhad Hormozdiari, Osnat Penn, Sagiv Shifman, Santhosh Girirajan and Fereydoun Hormozdiari

NARD: whole-genome reference panel of 1779 Northeast Asians improves imputation accuracy of rare and low-frequency variants

Here, we present the Northeast Asian Reference Database (NARD), including whole-genome sequencing data of 1779 individuals from Korea, Mongolia, Japan, China, and Hong Kong. NARD provides the genetic diversity...

Authors: Seong-Keun Yoo, Chang-Uk Kim, Hie Lim Kim, Sungjae Kim, Jong-Yeon Shin, Namcheol Kim, Joshua Sung Woo Yang, Kwok-Wai Lo, Belong Cho, Fumihiko Matsuda, Stephan C. Schuster, Changhoon Kim, Jong-Il Kim and Jeong-Sun Seo

Advances in omics-based methods to identify novel targets for malaria and other parasitic protozoan infections

A major advance in antimalarial drug discovery has been the shift towards cell-based phenotypic screening, with notable progress in the screening of compounds against the asexual blood stage, liver stage, and ...

Authors: Annie N. Cowell and Elizabeth A. Winzeler

Mapping genetic interactions in cancer: a road to rational combination therapies

The discovery of synthetic lethal interactions between poly (ADP-ribose) polymerase (PARP) inhibitors and BRCA genes, which are involved in homologous recombination, led to the approval of PARP inhibition as a...

Authors: Beril Tutuncuoglu and Nevan J. Krogan

Long non-coding RNAs identify a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis

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…

Relating the gut metagenome and metatranscriptome to immunotherapy responses in melanoma patients

Recent evidence suggests that immunotherapy efficacy in melanoma is modulated by gut microbiota. Few studies have examined this phenomenon in humans, and none have incorporated metatranscriptomics, important f...

Authors: Brandilyn A. Peters, Melissa Wilson, Una Moran, Anna Pavlick, Allison Izsak, Todd Wechter, Jeffrey S. Weber, Iman Osman and Jiyoung Ahn

Identifying Crohn’s disease signal from variome analysis

After years of concentrated research efforts, the exact cause of Crohn’s disease (CD) remains unknown. Its accurate diagnosis, however, helps in management and preventing the onset of disease. Genome-wide asso...

Authors: Yanran Wang, Maximilian Miller, Yuri Astrakhan, Britt-Sabina Petersen, Stefan Schreiber, Andre Franke and Yana Bromberg

Genetic underpinnings of recovery after stroke: an opportunity for gene discovery, risk stratification, and precision medicine

As the number of stroke survivors continues to increase, identification of therapeutic targets for stroke recovery has become a priority in stroke genomics research. The introduction of high-throughput genotyp...

Authors: Julián N. Acosta, Stacy C. Brown and Guido J. Falcone

The relationship between insomnia and complex diseases—insights from genetic data

Insomnia is a common condition whose pathophysiology is poorly understood. Large genetic studies have provided insights into the etiology of insomnia, highlighting biological pathways that are shared with othe...

Authors: Enda M. Byrne

Best practices for bioinformatic characterization of neoantigens for clinical utility

Neoantigens are newly formed peptides created from somatic mutations that are capable of inducing tumor-specific T cell recognition. Recently, researchers and clinicians have leveraged next generation sequenci...

Authors: Megan M. Richters, Huiming Xia, Katie M. Campbell, William E. Gillanders, Obi L. Griffith and Malachi Griffith

Comprehensive characterization of circular RNAs in ~ 1000 human cancer cell lines

Human cancer cell lines are fundamental models for cancer research and therapeutic strategy development. However, there is no characterization of circular RNAs (circRNAs) in a large number of cancer cell lines.

Authors: Hang Ruan, Yu Xiang, Junsuk Ko, Shengli Li, Ying Jing, Xiaoyu Zhu, Youqiong Ye, Zhao Zhang, Tingting Mills, Jing Feng, Chun-Jie Liu, Ji Jing, Jin Cao, Bingying Zhou, Li Wang, Yubin Zhou…

Improved precision of epigenetic clock estimates across tissues and its implication for biological ageing

DNA methylation changes with age. Chronological age predictors built from DNA methylation are termed ‘epigenetic clocks’. The deviation of predicted age from the actual age (‘age acceleration residual’, AAR) h...

Authors: Qian Zhang, Costanza L. Vallerga, Rosie M. Walker, Tian Lin, Anjali K. Henders, Grant W. Montgomery, Ji He, Dongsheng Fan, Javed Fowdar, Martin Kennedy, Toni Pitcher, John Pearson, Glenda Halliday, John B. Kwok, Ian Hickie, Simon Lewis…

Variant Interpretation for Cancer (VIC): a computational tool for assessing clinical impacts of somatic variants

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

Identifying chemogenetic interactions from CRISPR screens with drugZ

Chemogenetic profiling enables the identification of gene mutations that enhance or suppress the activity of chemical compounds. This knowledge provides insights into drug mechanism of action, genetic vulnerab...

Authors: Medina Colic, Gang Wang, Michal Zimmermann, Keith Mascall, Megan McLaughlin, Lori Bertolet, W. Frank Lenoir, Jason Moffat, Stephane Angers, Daniel Durocher and Traver Hart

A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases

Genomic medicine has paved the way for identifying biomarkers and therapeutically actionable targets for complex diseases, but is complicated by the involvement of thousands of variably expressed genes across ...

Authors: Danuta R. Gawel, Jordi Serra-Musach, Sandra Lilja, Jesper Aagesen, Alex Arenas, Bengt Asking, Malin Bengnér, Janne Björkander, Sophie Biggs, Jan Ernerudh, Henrik Hjortswang, Jan-Erik Karlsson, Mattias Köpsen, Eun Jung Lee, Antonio Lentini, Xinxiu Li…

Advancing cancer immunotherapy: a vision for the field

Authors: Noel F. C. C. de Miranda and Zlatko Trajanoski

Correction to: Molecular and pharmacological modulators of the tumor immune contexture revealed by deconvolution of RNA-seq data

It was highlighted that the original article [1] contained a typesetting mistake in the name of Noel Filipe da Cunha Carvalho de Miranda. This was incorrectly captured as Noel Filipe da Cunha Carvahlo de Miran...

Authors: Francesca Finotello, Clemens Mayer, Christina Plattner, Gerhard Laschober, Dietmar Rieder, Hubert Hackl, Anne Krogsdam, Zuzana Loncova, Wilfried Posch, Doris Wilflingseder, Sieghart Sopper, Marieke Ijsselsteijn, Thomas P. Brouwer, Douglas Johnson, Yaomin Xu, Yu Wang…

Hidden Markov models lead to higher resolution maps of mutation signature activity in cancer

Knowing the activity of the mutational processes shaping a cancer genome may provide insight into tumorigenesis and personalized therapy. It is thus important to characterize the signatures of active mutationa...

Authors: Damian Wojtowicz, Itay Sason, Xiaoqing Huang, Yoo-Ah Kim, Mark D. M. Leiserson, Teresa M. Przytycka and Roded Sharan

A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing

Although mosaic variation has been known to cause disease for decades, high-throughput sequencing technologies with the analytical sensitivity to consistently detect variants at reduced allelic fractions have ...

Authors: Ye Cao, Mari J. Tokita, Edward S. Chen, Rajarshi Ghosh, Tiansheng Chen, Yanming Feng, Elizabeth Gorman, Federica Gibellini, Patricia A. Ward, Alicia Braxton, Xia Wang, Linyan Meng, Rui Xiao, Weimin Bi, Fan Xia, Christine M. Eng…

Implementation of a genomic medicine multi-disciplinary team approach for rare disease in the clinical setting: a prospective exome sequencing case series

A multi-disciplinary approach to promote engagement, inform decision-making and support clinicians and patients is increasingly advocated to realise the potential of genome-scale sequencing in the clinic for p...

Authors: John Taylor, Jude Craft, Edward Blair, Sarah Wordsworth, David Beeson, Saleel Chandratre, Judith Cossins, Tracy Lester, Andrea H. Németh, Elizabeth Ormondroyd, Smita Y. Patel, Alistair T. Pagnamenta, Jenny C. Taylor, Kate L. Thomson, Hugh Watkins, Andrew O. M. Wilkie…

Deciphering drug resistance in Mycobacterium tuberculosis using whole-genome sequencing: progress, promise, and challenges

Tuberculosis (TB) is a global infectious threat that is intensified by an increasing incidence of highly drug-resistant disease. Whole-genome sequencing (WGS) studies of Mycobacterium tuberculosis, the causative ...

Authors: Keira A. Cohen, Abigail L. Manson, Christopher A. Desjardins, Thomas Abeel and Ashlee M. Earl

Identification of intermediate-sized deletions and inference of their impact on gene expression in a human population

Next-generation sequencing has allowed for the identification of different genetic variations, which are known to contribute to diseases. Of these, insertions and deletions are the second most abundant type of...

Authors: Jing Hao Wong, Daichi Shigemizu, Yukiko Yoshii, Shintaro Akiyama, Azusa Tanaka, Hidewaki Nakagawa, Shu Narumiya and Akihiro Fujimoto

The good, the bad, and the ugly: hyperprogression in cancer patients following immune checkpoint therapy

Immune checkpoint blockade therapy can elicit robust and durable responses in a variety of cancer types. While many patients do not respond, recent reports highlight a distinct group of patients whose tumors u...

Authors: Erich Sabio and Timothy A. Chan

Evolving neoantigen profiles in colorectal cancers with DNA repair defects

Neoantigens that arise as a consequence of tumor-specific mutations can be recognized by T lymphocytes leading to effective immune surveillance. In colorectal cancer (CRC) and other tumor types, a high number ...

Authors: Giuseppe Rospo, Annalisa Lorenzato, Nabil Amirouchene-Angelozzi, Alessandro Magrì, Carlotta Cancelliere, Giorgio Corti, Carola Negrino, Vito Amodio, Monica Montone, Alice Bartolini, Ludovic Barault, Luca Novara, Claudio Isella, Enzo Medico, Andrea Bertotti, Livio Trusolino…

Integrating informatics tools and portable sequencing technology for rapid detection of resistance to anti-tuberculous drugs

Mycobacterium tuberculosis resistance to anti-tuberculosis drugs is a major threat to global public health. Whole genome sequencing (WGS) is rapidly gaining traction as a diagnostic tool for clinical tuberculosis...

Authors: Jody E. Phelan, Denise M. O’Sullivan, Diana Machado, Jorge Ramos, Yaa E. A. Oppong, Susana Campino, Justin O’Grady, Ruth McNerney, Martin L. Hibberd, Miguel Viveiros, Jim F. Huggett and Taane G. Clark

Radiation therapy and anti-tumor immunity: exposing immunogenic mutations to the immune system

The expression of antigens that are recognized by self-reactive T cells is essential for immune-mediated tumor rejection by immune checkpoint blockade (ICB) therapy. Growing evidence suggests that mutation-ass...

Authors: Claire Lhuillier, Nils-Petter Rudqvist, Olivier Elemento, Silvia C. Formenti and Sandra Demaria

Mechanisms of immune-related adverse events associated with immune checkpoint blockade: using germline genetics to develop a personalized approach

Personalized care of cancer patients undergoing treatment with immune checkpoint inhibitors will require approaches that can predict their susceptibility to immune-related adverse events. Understanding the rol...

Authors: Zia Khan, Christian Hammer, Ellie Guardino, G. Scott Chandler and Matthew L. Albert

Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Diagnosis of primary immunodeficiencies (PIDs) is complex and cumbersome yet important for the clinical management of the disease. Exome sequencing may provide a genetic diagnosis in a significant number of pa...

Authors: Peer Arts, Annet Simons, Mofareh S. AlZahrani, Elanur Yilmaz, Eman AlIdrissi, Koen J. van Aerde, Njood Alenezi, Hamza A. AlGhamdi, Hadeel A. AlJubab, Abdulrahman A. Al-Hussaini, Fahad AlManjomi, Alaa B. Alsaad, Badr Alsaleem, Abdulrahman A. Andijani, Ali Asery, Walid Ballourah…

Associating somatic mutations to clinical outcomes: a pan-cancer study of survival time

We developed subclone multiplicity allocation and somatic heterogeneity (SMASH), a new statistical method for intra-tumor heterogeneity (ITH) inference. SMASH is tailored to the purpose of large-scale associat...

Authors: Paul Little, Dan-Yu Lin and Wei Sun

Prognostic value of B cells in cutaneous melanoma

Measures of the adaptive immune response have prognostic and predictive associations in melanoma and other cancer types. Specifically, intratumoral T cell density and function have considerable prognostic and ...

Authors: Sara R. Selitsky, Lisle E. Mose, Christof C. Smith, Shengjie Chai, Katherine A. Hoadley, Dirk P. Dittmer, Stergios J. Moschos, Joel S. Parker and Benjamin G. Vincent

Somatic mutation and clonal expansions in human tissues

Recent sequencing studies on healthy skin and esophagus have found that, as we age, these tissues become colonized by mutant clones of cells carrying driver mutations in traditional cancer genes. This comment ...

Authors: Inigo Martincorena

Clinical utility of custom-designed NGS panel testing in pediatric tumors

Somatic genetic testing is rapidly becoming the standard of care in many adult and pediatric cancers. Previously, the standard approach was single-gene or focused multigene testing, but many centers have moved...

Authors: Lea F. Surrey, Suzanne P. MacFarland, Fengqi Chang, Kajia Cao, Komal S. Rathi, Gozde T. Akgumus, Daniel Gallo, Fumin Lin, Adam Gleason, Pichai Raman, Richard Aplenc, Rochelle Bagatell, Jane Minturn, Yael Mosse, Mariarita Santi, Sarah K. Tasian…

Molecular and pharmacological modulators of the tumor immune contexture revealed by deconvolution of RNA-seq data

We introduce quanTIseq, a method to quantify the fractions of ten immune cell types from bulk RNA-sequencing data. quanTIseq was extensively validated in blood and tumor samples using simulated, flow cytometry...

Authors: Francesca Finotello, Clemens Mayer, Christina Plattner, Gerhard Laschober, Dietmar Rieder, Hubert Hackl, Anne Krogsdam, Zuzana Loncova, Wilfried Posch, Doris Wilflingseder, Sieghart Sopper, Marieke Ijsselsteijn, Thomas P. Brouwer, Douglas Johnson, Yaomin Xu, Yu Wang…

Dissecting lung development and fibrosis at single-cell resolution

Single-cell transcriptome profiling has enabled high-resolution analysis of cellular populations in tissues during development, health, and disease. Recent studies make innovative use of single-cell RNA sequen...

Authors: Donna L. Farber and Peter A. Sims

Points-to-consider on the return of results in epigenetic research

As epigenetic studies become more common and lead to new insights into health and disease, the return of individual epigenetic results to research participants, in particular in large-scale epigenomic studies,...

Authors: Stephanie O. M. Dyke, Katie M. Saulnier, Charles Dupras, Amy P. Webster, Karen Maschke, Mark Rothstein, Reiner Siebert, Jörn Walter, Stephan Beck, Tomi Pastinen and Yann Joly