Medical genomics

  • Article
    | Open Access

    Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

    • Shimin Shuai
    • , Federico Abascal
    • , Samirkumar B. Amin
    • , Gary D. Bader
    • , Pratiti Bandopadhayay
    • , Jonathan Barenboim
    • , Rameen Beroukhim
    • , Johanna Bertl
    • , Keith A. Boroevich
    • , Søren Brunak
    • , Peter J. Campbell
    • , Joana Carlevaro-Fita
    • , Dimple Chakravarty
    • , Calvin Wing Yiu Chan
    • , Ken Chen
    • , Jung Kyoon Choi
    • , Jordi Deu-Pons
    • , Priyanka Dhingra
    • , Klev Diamanti
    • , Lars Feuerbach
    • , J. Lynn Fink
    • , Nuno A. Fonseca
    • , Joan Frigola
    • , Carlo Gambacorti-Passerini
    • , Dale W. Garsed
    • , Mark Gerstein
    • , Gad Getz
    • , Qianyun Guo
    • , Ivo G. Gut
    • , David Haan
    • , Mark P. Hamilton
    • , Nicholas J. Haradhvala
    • , Arif O. Harmanci
    • , Mohamed Helmy
    • , Carl Herrmann
    • , Julian M. Hess
    • , Asger Hobolth
    • , Ermin Hodzic
    • , Chen Hong
    • , Henrik Hornshøj
    • , Keren Isaev
    • , Jose M. G. Izarzugaza
    • , Rory Johnson
    • , Todd A. Johnson
    • , Malene Juul
    • , Randi Istrup Juul
    • , Andre Kahles
    • , Abdullah Kahraman
    • , Manolis Kellis
    • , Ekta Khurana
    • , Jaegil Kim
    • , Jong K. Kim
    • , Youngwook Kim
    • , Jan Komorowski
    • , Jan O. Korbel
    • , Sushant Kumar
    • , Andrés Lanzós
    • , Erik Larsson
    • , Michael S. Lawrence
    • , Donghoon Lee
    • , Kjong-Van Lehmann
    • , Shantao Li
    • , Xiaotong Li
    • , Ziao Lin
    • , Eric Minwei Liu
    • , Lucas Lochovsky
    • , Shaoke Lou
    • , Tobias Madsen
    • , Kathleen Marchal
    • , Iñigo Martincorena
    • , Alexander Martinez-Fundichely
    • , Yosef E. Maruvka
    • , Patrick D. McGillivray
    • , William Meyerson
    • , Ferran Muiños
    • , Loris Mularoni
    • , Hidewaki Nakagawa
    • , Morten Muhlig Nielsen
    • , Marta Paczkowska
    • , Keunchil Park
    • , Kiejung Park
    • , Jakob Skou Pedersen
    • , Tirso Pons
    • , Sergio Pulido-Tamayo
    • , Benjamin J. Raphael
    • , Jüri Reimand
    • , Iker Reyes-Salazar
    • , Matthew A. Reyna
    • , Esther Rheinbay
    • , Mark A. Rubin
    • , Carlota Rubio-Perez
    • , S. Cenk Sahinalp
    • , Gordon Saksena
    • , Leonidas Salichos
    • , Chris Sander
    • , Steven E. Schumacher
    • , Mark Shackleton
    • , Ofer Shapira
    • , Ciyue Shen
    • , Raunak Shrestha
    • , Shimin Shuai
    • , Nikos Sidiropoulos
    • , Lina Sieverling
    • , Nasa Sinnott-Armstrong
    • , Lincoln D. Stein
    • , Joshua M. Stuart
    • , David Tamborero
    • , Grace Tiao
    • , Tatsuhiko Tsunoda
    • , Husen M. Umer
    • , Liis Uusküla-Reimand
    • , Alfonso Valencia
    • , Miguel Vazquez
    • , Lieven P. C. Verbeke
    • , Claes Wadelius
    • , Lina Wadi
    • , Jiayin Wang
    • , Jonathan Warrell
    • , Sebastian M. Waszak
    • , Joachim Weischenfeldt
    • , David A. Wheeler
    • , Guanming Wu
    • , Jun Yu
    • , Jing Zhang
    • , Xuanping Zhang
    • , Yan Zhang
    • , Zhongming Zhao
    • , Lihua Zou
    • , Christian von Mering
    • , Steven Gallinger
    •  & Lincoln Stein
  • Article
    | Open Access

    Healthspan and healthy aging are areas of research with potential socioeconomic impact. Here, the authors present the Medical Genome Reference Bank (MGRB) which consist of over 4,000 individuals aged 70 years and older without a history of the major age-related diseases and report on results from whole-genome sequencing and association analyses.

    • Mark Pinese
    • , Paul Lacaze
    • , Emma M. Rath
    • , Andrew Stone
    • , Marie-Jo Brion
    • , Adam Ameur
    • , Sini Nagpal
    • , Clare Puttick
    • , Shane Husson
    • , Dmitry Degrave
    • , Tina Navin Cristina
    • , Vivian F. S. Kahl
    • , Aaron L. Statham
    • , Robyn L. Woods
    • , John J. McNeil
    • , Moeen Riaz
    • , Margo Barr
    • , Mark R. Nelson
    • , Christopher M. Reid
    • , Anne M. Murray
    • , Raj C. Shah
    • , Rory Wolfe
    • , Joshua R. Atkins
    • , Chantel Fitzsimmons
    • , Heath M. Cairns
    • , Melissa J. Green
    • , Vaughan J. Carr
    • , Mark J. Cowley
    • , Hilda A. Pickett
    • , Paul A. James
    • , Joseph E. Powell
    • , Warren Kaplan
    • , Greg Gibson
    • , Ulf Gyllensten
    • , Murray J. Cairns
    • , Martin McNamara
    • , Marcel E. Dinger
    •  & David M. Thomas
  • Article
    | Open Access

    Four genome-wide associated loci are currently known for malaria susceptibility. Here, the authors expand on earlier work by combining data from 11 malaria-endemic countries and additional population sequencing informing an African-enriched imputation reference panel, with findings including a previously unreported association on chromosome 6.

    • Gavin Band
    • , Quang Si Le
    • , Geraldine M. Clarke
    • , Katja Kivinen
    • , Christina Hubbart
    • , Anna E. Jeffreys
    • , Kate Rowlands
    • , Ellen M. Leffler
    • , Muminatou Jallow
    • , David J. Conway
    • , Fatoumatta Sisay-Joof
    • , Giorgio Sirugo
    • , Umberto d’Alessandro
    • , Ousmane B. Toure
    • , Mahamadou A. Thera
    • , Salimata Konate
    • , Sibiri Sissoko
    • , Valentina D. Mangano
    • , Edith C. Bougouma
    • , Sodiomon B. Sirima
    • , Lucas N. Amenga-Etego
    • , Anita K. Ghansah
    • , Abraham V. O. Hodgson
    • , Michael D. Wilson
    • , Anthony Enimil
    • , Daniel Ansong
    • , Jennifer Evans
    • , Subulade A. Ademola
    • , Tobias O. Apinjoh
    • , Carolyne M. Ndila
    • , Alphaxard Manjurano
    • , Chris Drakeley
    • , Hugh Reyburn
    • , Nguyen Hoan Phu
    • , Nguyen Thi Ngoc Quyen
    • , Cao Quang Thai
    • , Tran Tinh Hien
    • , Yik Ying Teo
    • , Laurens Manning
    • , Moses Laman
    • , Pascal Michon
    • , Harin Karunajeewa
    • , Peter Siba
    • , Steve Allen
    • , Angela Allen
    • , Melanie Bahlo
    • , Timothy M. E. Davis
    • , Victoria Simpson
    • , Jennifer Shelton
    • , Chris C. A. Spencer
    • , George B. J. Busby
    • , Angeliki Kerasidou
    • , Eleanor Drury
    • , Jim Stalker
    • , Alexander Dilthey
    • , Alexander J. Mentzer
    • , Gil McVean
    • , Kalifa A. Bojang
    • , Ogobara Doumbo
    • , David Modiano
    • , Kwadwo A. Koram
    • , Tsiri Agbenyega
    • , Olukemi K. Amodu
    • , Eric Achidi
    • , Thomas N. Williams
    • , Kevin Marsh
    • , Eleanor M. Riley
    • , Malcolm Molyneux
    • , Terrie Taylor
    • , Sarah J. Dunstan
    • , Jeremy Farrar
    • , Ivo Mueller
    • , Kirk A. Rockett
    •  & Dominic P. Kwiatkowski
  • Article
    | Open Access

    Whole genome sequencing (WGS) holds promise to solve a subset of Mendelian disease cases for which exome sequencing did not provide a genetic diagnosis. Here, Wells et al. report a supervised machine learning model trained on functional, mutational and structural features for rank-scoring and interpreting variants in non-coding regions from WGS.

    • Alex Wells
    • , David Heckerman
    • , Ali Torkamani
    • , Li Yin
    • , Jonathan Sebat
    • , Bing Ren
    • , Amalio Telenti
    •  & Julia di Iulio
  • Article
    | Open Access

    Retrotransposition events have been linked to some human disorders. Here, Gardner et al. systematically search for mobile genetic elements (ME) in trio whole exome-sequencing datasets and ascertain 9 de novo MEs and further estimate genome-wide germline ME burden and constraint.

    • Eugene J. Gardner
    • , Elena Prigmore
    • , Giuseppe Gallone
    • , Petr Danecek
    • , Kaitlin E. Samocha
    • , Juliet Handsaker
    • , Sebastian S. Gerety
    • , Holly Ironfield
    • , Patrick J. Short
    • , Alejandro Sifrim
    • , Tarjinder Singh
    • , Kate E. Chandler
    • , Emma Clement
    • , Katherine L. Lachlan
    • , Katrina Prescott
    • , Elisabeth Rosser
    • , David R. FitzPatrick
    • , Helen V. Firth
    •  & Matthew E. Hurles
  • Article
    | Open Access

    Changes in body mass index (BMI) during infancy and childhood follow a well-characterized pattern. Here, Helgeland et al. perform genome-wide association studies for BMI at 12 time points between birth and 8 years of age and find transient associations at the LEP and LEPR loci.

    • Øyvind Helgeland
    • , Marc Vaudel
    • , Petur B. Juliusson
    • , Oddgeir Lingaas Holmen
    • , Julius Juodakis
    • , Jonas Bacelis
    • , Bo Jacobsson
    • , Haakon Lindekleiv
    • , Kristian Hveem
    • , Rolv Terje Lie
    • , Gun Peggy Knudsen
    • , Camilla Stoltenberg
    • , Per Magnus
    • , Jørn V. Sagen
    • , Anders Molven
    • , Stefan Johansson
    •  & Pål Rasmus Njølstad
  • Article
    | Open Access

    A number of computational methods have been developed for calling structural variants (SVs) using short read sequencing data. Here, the authors perform a comprehensive benchmarking analysis comparing 10 general-purpose callers and provide recommendations for both users and methods developers.

    • Daniel L. Cameron
    • , Leon Di Stefano
    •  & Anthony T. Papenfuss
  • Article
    | Open Access

    Systematic analysis of postzygotic mosaicism (PZM) is difficult due to challenges in detecting such events. Here, Wright et al. analyse trio exome sequencing data from blood and saliva of 4,293 probands with developmental disorders from the DDD Study and estimate that >3% of causative de novo mutations result from PZM.

    • C. F. Wright
    • , E. Prigmore
    • , D. Rajan
    • , J. Handsaker
    • , J. McRae
    • , J. Kaplanis
    • , T. W. Fitzgerald
    • , D. R. FitzPatrick
    • , H. V. Firth
    •  & M. E. Hurles
  • Article
    | Open Access

    Genetic variants in RP1 can cause hereditary retinal degeneration (HRD). Here, in a genomic screen of 331 Japanese HRD patients, the authors identify a near-polymorphic RP1 variant that causes Mendelian HRD in trans with an Alu insertion and otherwise is associated with HRD according to a complex model of inheritance.

    • Konstantinos Nikopoulos
    • , Katarina Cisarova
    • , Mathieu Quinodoz
    • , Hanna Koskiniemi-Kuendig
    • , Noriko Miyake
    • , Pietro Farinelli
    • , Atta Ur Rehman
    • , Muhammad Imran Khan
    • , Andrea Prunotto
    • , Masato Akiyama
    • , Yoichiro Kamatani
    • , Chikashi Terao
    • , Fuyuki Miya
    • , Yasuhiro Ikeda
    • , Shinji Ueno
    • , Nobuo Fuse
    • , Akira Murakami
    • , Yuko Wada
    • , Hiroko Terasaki
    • , Koh-Hei Sonoda
    • , Tatsuro Ishibashi
    • , Michiaki Kubo
    • , Frans P. M. Cremers
    • , Zoltán Kutalik
    • , Naomichi Matsumoto
    • , Koji M. Nishiguchi
    • , Toru Nakazawa
    •  & Carlo Rivolta
  • Article
    | Open Access

    Nanopore sequencing technology generates longer reads than current technologies, but with more errors. Here, the authors develop new analytical tools to improve accuracy and evaluate the potential of nanopore sequencing for clinical human genomics.

    • Rory Bowden
    • , Robert W. Davies
    • , Andreas Heger
    • , Alistair T. Pagnamenta
    • , Mariateresa de Cesare
    • , Laura E. Oikkonen
    • , Duncan Parkes
    • , Colin Freeman
    • , Fatima Dhalla
    • , Smita Y. Patel
    • , Niko Popitsch
    • , Camilla L. C. Ip
    • , Hannah E. Roberts
    • , Silvia Salatino
    • , Helen Lockstone
    • , Gerton Lunter
    • , Jenny C. Taylor
    • , David Buck
    • , Michael A. Simpson
    •  & Peter Donnelly
  • Perspective
    | Open Access

    Indigenous peoples are still underrepresented in genetic research. Here, the authors propose an ethical framework consisting of six major principles that encourages researchers and Indigenous communities to build strong and equal partnerships to increase trust, engagement and diversity in genomic studies.

    • Katrina G. Claw
    • , Matthew Z. Anderson
    • , Rene L. Begay
    • , Krystal S. Tsosie
    • , Keolu Fox
    • , Nanibaa’ A. Garrison
    • , Alyssa C. Bader
    • , Jessica Bardill
    • , Deborah A. Bolnick
    • , Jada Brooks
    • , Anna Cordova
    • , Ripan S. Malhi
    • , Nathan Nakatsuka
    • , Angela Neller
    • , Jennifer A. Raff
    • , Jamie Singson
    • , Kim TallBear
    • , Tada Vargas
    •  & Joseph M. Yracheta
  • Article
    | Open Access

    As melanoma progresses, it evolves. Here, in advanced melanoma the authors study genomic evolution, highlighting trunk mutations dominated by the ultraviolet damage signature, common late truncal whole-genome duplication events, as well as selective copy number gain of mutant BRAF.

    • E. Birkeland
    • , S. Zhang
    • , D. Poduval
    • , J. Geisler
    • , S. Nakken
    • , D. Vodak
    • , L. A. Meza-Zepeda
    • , E. Hovig
    • , O. Myklebost
    • , S. Knappskog
    •  & P. E. Lønning
  • Article
    | Open Access

    The 16p11.2 deletion leads to a range of neurodevelopmental phenotypes, but to date, sequencing studies have not been able to pinpoint individual genes that are causative for the disease on their own. Here, using Drosophila homologs of 14 16p11.2 genes, the authors take a combinatorial approach to show that gene interactions contribute to a neurological phenotype.

    • Janani Iyer
    • , Mayanglambam Dhruba Singh
    • , Matthew Jensen
    • , Payal Patel
    • , Lucilla Pizzo
    • , Emily Huber
    • , Haley Koerselman
    • , Alexis T. Weiner
    • , Paola Lepanto
    • , Komal Vadodaria
    • , Alexis Kubina
    • , Qingyu Wang
    • , Abigail Talbert
    • , Sneha Yennawar
    • , Jose Badano
    • , J. Robert Manak
    • , Melissa M. Rolls
    • , Arjun Krishnan
    •  & Santhosh Girirajan
  • Article
    | Open Access

    Adult-type granulosa cell tumors of the ovary (aGCTs) are rare and recurrence is difficult to treat. Here, the authors observe in aGCT a novel recurrent somatic truncating mutation of KMT2D, more frequent in recurrent aGCT, and also non-genetic loss of KMT2D expression.

    • R. Tyler Hillman
    • , Joseph Celestino
    • , Christopher Terranova
    • , Hannah C. Beird
    • , Curtis Gumbs
    • , Latasha Little
    • , Tri Nguyen
    • , Rebecca Thornton
    • , Samantha Tippen
    • , Jianhua Zhang
    • , Karen H. Lu
    • , David M. Gershenson
    • , Kunal Rai
    • , Russell R. Broaddus
    •  & P. Andrew Futreal
  • Article
    | Open Access

    Urinary tract infections are one of the most common infections in humans. Here, the authors use urinary cell-free DNA (cfDNA) to comprehensively monitor host and pathogen dynamics in bacterial and viral urinary tract infections, and show that it is a versatile analyte for monitoring urinary tract infections.

    • Philip Burnham
    • , Darshana Dadhania
    • , Michael Heyang
    • , Fanny Chen
    • , Lars F. Westblade
    • , Manikkam Suthanthiran
    • , John Richard Lee
    •  & Iwijn De Vlaminck
  • Article
    | Open Access

    Predicting haploinsufficient genes helps to understand the genetic risk underlying developmental disorders. Here, the authors develop a Random Forest-based method that uses epigenomic data to predict haploinsufficiency, Episcore, which is complementary to methods based on mutation intolerance scores.

    • Xinwei Han
    • , Siying Chen
    • , Elise Flynn
    • , Shuang Wu
    • , Dana Wintner
    •  & Yufeng Shen
  • Article
    | Open Access

    A proportion of neurodevelopmental disorder and congenital anomaly cases remain without a genetic diagnosis. Here, the authors study aberrations of DNA methylation in such cases and find that epivariations might provide an explanation for some of these undiagnosed patients.

    • Mafalda Barbosa
    • , Ricky S. Joshi
    • , Paras Garg
    • , Alejandro Martin-Trujillo
    • , Nihir Patel
    • , Bharati Jadhav
    • , Corey T. Watson
    • , William Gibson
    • , Kelsey Chetnik
    • , Chloe Tessereau
    • , Hui Mei
    • , Silvia De Rubeis
    • , Jennifer Reichert
    • , Fatima Lopes
    • , Lisenka E. L. M. Vissers
    • , Tjitske Kleefstra
    • , Dorothy E. Grice
    • , Lisa Edelmann
    • , Gabriela Soares
    • , Patricia Maciel
    • , Han G. Brunner
    • , Joseph D. Buxbaum
    • , Bruce D. Gelb
    •  & Andrew J. Sharp
  • Article
    | Open Access

    Examination of predicted loss-of-function (pLOF) genetic variants allows direct identification of genes with therapeutic potential. Here, Emdin et al. perform association analysis for 3759 pLOF variants with 24 traits and highlight protective variants against cardiometabolic and immune phenotypes.

    • Connor A. Emdin
    • , Amit V. Khera
    • , Mark Chaffin
    • , Derek Klarin
    • , Pradeep Natarajan
    • , Krishna Aragam
    • , Mary Haas
    • , Alexander Bick
    • , Seyedeh M. Zekavat
    • , Akihiro Nomura
    • , Diego Ardissino
    • , James G. Wilson
    • , Heribert Schunkert
    • , Ruth McPherson
    • , Hugh Watkins
    • , Roberto Elosua
    • , Matthew J. Bown
    • , Nilesh J. Samani
    • , Usman Baber
    • , Jeanette Erdmann
    • , Namrata Gupta
    • , John Danesh
    • , Daniel Chasman
    • , Paul Ridker
    • , Joshua Denny
    • , Lisa Bastarache
    • , Judith H. Lichtman
    • , Gail D’Onofrio
    • , Jennifer Mattera
    • , John A. Spertus
    • , Wayne H.-H. Sheu
    • , Kent D. Taylor
    • , Bruce M. Psaty
    • , Stephen S. Rich
    • , Wendy Post
    • , Jerome I. Rotter
    • , Yii-Der Ida Chen
    • , Harlan Krumholz
    • , Danish Saleheen
    • , Stacey Gabriel
    •  & Sekar Kathiresan
  • Article
    | Open Access

    Protein-truncating variants (PTVs) are predicted to significantly affect a gene’s function and, thus, human traits. Here, DeBoever et al. systematically analyze PTVs in more than 300,000 individuals across 135 phenotypes and identify 27 associations between PTVs and medical conditions.

    • Christopher DeBoever
    • , Yosuke Tanigawa
    • , Malene E. Lindholm
    • , Greg McInnes
    • , Adam Lavertu
    • , Erik Ingelsson
    • , Chris Chang
    • , Euan A. Ashley
    • , Carlos D. Bustamante
    • , Mark J. Daly
    •  & Manuel A. Rivas
  • Article
    | Open Access

    The detection of structural variants can be difficult with short-read sequencing technology, especially when variants are highly complex. Here, the authors use a MinION nanopore sequencer to analyse two patient genomes and develop NanoSV to map known and novel structural variants in long read data.

    • Mircea Cretu Stancu
    • , Markus J. van Roosmalen
    • , Ivo Renkens
    • , Marleen M. Nieboer
    • , Sjors Middelkamp
    • , Joep de Ligt
    • , Giulia Pregno
    • , Daniela Giachino
    • , Giorgia Mandrile
    • , Jose Espejo Valle-Inclan
    • , Jerome Korzelius
    • , Ewart de Bruijn
    • , Edwin Cuppen
    • , Michael E. Talkowski
    • , Tobias Marschall
    • , Jeroen de Ridder
    •  & Wigard P. Kloosterman
  • Article
    | Open Access

    Maturity-onset diabetes of the young (MODY) is the most common subtype of familial diabetes. Here, Patel et al. use targeted DNA sequencing of MODY patients and large-scale publically available data to show that RFX6 heterozygous protein truncating variants cause reduced penetrance MODY.

    • Kashyap A. Patel
    • , Jarno Kettunen
    • , Markku Laakso
    • , Alena Stančáková
    • , Thomas W. Laver
    • , Kevin Colclough
    • , Matthew B. Johnson
    • , Marc Abramowicz
    • , Leif Groop
    • , Päivi J. Miettinen
    • , Maggie H. Shepherd
    • , Sarah E. Flanagan
    • , Sian Ellard
    • , Nobuya Inagaki
    • , Andrew T. Hattersley
    • , Tiinamaija Tuomi
    • , Miriam Cnop
    •  & Michael N. Weedon
  • Article
    | Open Access

    Enteropathy associated T-cell lymphoma -EATL- affects the intestine and there are two different subtypes. In this study, the authors carry out exome sequencing of the type II variant and find that it is characterized by recurrent mutations in the histone methyltransferase SETD2 that are accompanied by altered H3K6 methylation.

    • Annalisa Roberti
    • , Maria Pamela Dobay
    • , Bettina Bisig
    • , David Vallois
    • , Cloé Boéchat
    • , Evripidis Lanitis
    • , Brigitte Bouchindhomme
    • , Marie- Cécile Parrens
    • , Céline Bossard
    • , Leticia Quintanilla-Martinez
    • , Edoardo Missiaglia
    • , Philippe Gaulard
    •  & Laurence de Leval