Human and mouse essentiality screens as a resource for disease gene discovery
Authors: Cacheiro Pilar , Muñoz-Fuentes Violeta , Murray Stephen A. , Dickinson Mary E. , Bucan Maja , Nutter Lauryl M. J. , Peterson Kevin A. , Haselimashhadi Hamed , Flenniken Ann M. , Morgan Hugh , Westerberg Henrik , Konopka Tomasz , Hsu Chih-Wei , Christiansen Audrey , Lanza Denise G. , Beaudet Arthur L. , Heaney Jason D. , Fuchs Helmut , Gailus-Durner Valerie , Sorg Tania , Prochazka Jan , Novosadova Vendula , Lelliott Christopher J. , Wardle-Jones Hannah , Wells Sara , Teboul Lydia , Cater Heather , Stewart Michelle , Hough Tertius , Wurst Wolfgang , Sedlacek Radislav , Adams David J. , Seavitt John R. , Tocchini-Valentini Glauco , Mammano Fabio , Braun Robert E. , McKerlie Colin , Herault Yann , de Angelis Martin Hrabě , Mallon Ann-Marie , Lloyd K. C.  Kent , Brown Steve D. M. , Parkinson Helen , Meehan Terrence F. , Smedley Damian ,   The Genomics England Research Consortium, Ambrose J. C. , Arumugam P. , Baple E. L. , Bleda M. , Boardman-Pretty F. , Boissiere J. M. , Boustred C. R. , Brittain H. , Caulfield M. J. , Chan G. C. , Craig C. E. H. , Daugherty L. C. , de Burca A. , Devereau A. , Elgar G. , Foulger R. E. , Fowler T. , Furió-Tarí P. , Hackett J. M. , Halai D. , Hamblin A. , Henderson S. , Holman J. E. , Hubbard T. J. P. , Ibáñez K. , Jackson R. , Jones L. J. , Kasperaviciute D. , Kayikci M. , Lahnstein L. , Lawson K. , Leigh S. E. A. , Leong I. U. S. , Lopez F. J. , Maleady-Crowe F. , Mason J. , McDonagh E. M. , Moutsianas L. , Mueller M. , Murugaesu N. , Need A. C. , Odhams C. A. , Patch C. , Perez-Gil D. , Polychronopoulos D. , Pullinger J. , Rahim T. , Rendon A. , Riesgo-Ferreiro P. , Rogers T. , Ryten M. , Savage K. , Sawant K. , Scott R. H. , Siddiq A. , Sieghart A. , Smith K. R. , Sosinsky A. , Spooner W. , Stevens H. E. , Stuckey A. , Sultana R. , Thomas E. R. A. , Thompson S. R. , Tregidgo C. , Tucci A. , Walsh E. , Watters S. A. , Welland M. J. , Williams E. , Witkowska K. , Wood S. M. , Zarowiecki M. ,   The International Mouse Phenotyping Consortium, Marschall Susan , Lengger Christoph , Maier Holger , Seisenberger Claudia , Bürger Antje , Kühn Ralf , Schick Joel , Hörlein Andreas , Oritz Oskar , Giesert Florian , Beig Joachim , Kenyon Janet , Codner Gemma , Fray Martin , Johnson Sara J. , Cleak James , Szoke-Kovacs Zsombor , Lafont David , Vancollie Valerie E. , McLaren Robbie S. B. , Hughes-Hallett Lena , Rowley Christine , Sanderson Emma , Galli Antonella , Tuck Elizabeth , Green Angela , Tudor Catherine , Siragher Emma , Dabrowska Monika , Mazzeo Cecilia Icoresi , Griffiths Mark , Gannon David , Doe Brendan , Cockle Nicola , Kirton Andrea , Bottomley Joanna , Ingle Catherine , Ryder Edward , Gleeson Diane , Ramirez-Solis Ramiro , Birling Marie-Christine , Pavlovic Guillaume , Ayadi Abdel , Hamid Meziane , About Ghina Bou , Champy Marie-France , Jacobs Hugues , Wendling Olivia , Leblanc Sophie , Vasseur Laurent , Chesler Elissa J. , Kumar Vivek , White Jacqueline K. , Svenson Karen L. , Wiegand Jean-Paul , Anderson Laura L. , Wilcox Troy , Clark James , Ryan Jennifer , Denegre James , Stearns Tim , Philip Vivek , Witmeyer Catherine , Bates Lindsay , Seavey Zachary , Stanley Pamela , Willet Amelia , Roper Willson , Creed Julie , Moore Michayla , Dorr Alex , Fraungruber Pamelia , Presby Rose , Mckay Matthew , Nguyen-Bresinsky Dong , Goodwin Leslie , Urban Rachel , Kane Coleen 
Published: January 2020

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across theFullSpectrum ofIntolerance toLoss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery.