Mendelian gene identification through mouse embryo viability screening
Authors: Cacheiro Pilar , Westerberg Carl Henrik , Mager Jesse , Dickinson Mary E. , Nutter Lauryl M. J. , Muñoz-Fuentes Violeta , Hsu Chih-Wei , Van den Veyver Ignatia B. , Flenniken Ann M. , McKerlie Colin , Murray Stephen A. , Teboul Lydia , Heaney Jason D. , Lloyd K. C. Kent , Lanoue Louise , Braun Robert E. , White Jacqueline K. , Creighton Amie K. , Laurin Valerie , Guo Ruolin , Qu Dawei , Wells Sara , Cleak James , Bunton-Stasyshyn Rosie , Stewart Michelle , Harrisson Jackie , Mason Jeremy , Haseli Mashhadi Hamed , Parkinson Helen , Mallon Ann-Marie ,   International Mouse Phenotyping Consortium, Seavitt John R. , Gaspero Angelina , Akoma Uche , Christiansen Audrey , Kalaga Sowmya , Keith Lance C. , McElwee Melissa L. , Wong Leeyean , Rasmussen Tara , Ramamurthy Uma , Rajaya Kiran , Charoenrattanaruk Panitee , Fan-Lan Qing , Lintott Lauri G. , Danisment Ozge , Castellanos-Penton Patricia , Archer Daniel , Johnson Sara , Szoke-Kovacs Zsombor , Peterson Kevin A. , Goodwin Leslie O. , Welsh Ian C. , Palmer Kristina J. , Luzzio Alana , Carpenter Cynthia , Kane Coleen , Marcucci Jack , McKay Matthew , Burke Crystal , Seluke Audrie , Urban Rachel ,   Genomics England Research Consortium, Ambrose John C. , Arumugam Prabhu , Bevers Roel , Bleda Marta , Boardman-Pretty Freya , Boustred Christopher R. , Brittain Helen , Brown Matthew A. , Caulfield Mark J. , Chan Georgia C. , Elgar Greg , Giess Adam , Griffin John N. , Hamblin Angela , Henderson Shirley , Hubbard Tim J. P. , Jackson Rob , Jones Louise J. , Kasperaviciute Dalia , Kayikci Melis , Kousathanas Athanasios , Lahnstein Lea , Leigh Sarah E. A. , Leong Ivonne U. S. , Lopez Javier F. , Maleady-Crowe Fiona , McEntagart Meriel , Minneci Federico , Mitchell Jonathan , Moutsianas Loukas , Mueller Michael , Murugaesu Nirupa , Need Anna C. , O’Donovan Peter , Odhams Chris A. , Patch Christine , Pereira Mariana Buongermino , Perez-Gil Daniel , Pullinger John , Rahim Tahrima , Rendon Augusto , Rogers Tim , Savage Kevin , Sawant Kushmita , Scott Richard H. , Siddiq Afshan , Sieghart Alexander , Smith Samuel C. , Sosinsky Alona , Stuckey Alexander , Tanguy Mélanie , Tavares Ana Lisa Taylor , Thomas Ellen R. A. , Thompson Simon R. , Tucci Arianna , Welland Matthew J. , Williams Eleanor , Witkowska Katarzyna , Wood Suzanne M. , Zarowiecki Magdalena , Smedley Damian 
Published: October 2022

Background

The diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful. A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property.

Methods

Here we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid, or late gestation lethal. We studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes. We explored a gene similarity approach for novel gene discovery and investigated unsolved cases from the 100,000 Genomes Project.

Results

We found that genes in the early gestation lethal category have distinct characteristics and are enriched for genes linked with recessive forms of inherited metabolic disease. We identified several genes sharing multiple features with known biallelic forms of inborn errors of the metabolism and found signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes in patients recruited under this disease category. We highlight two novel gene candidates with phenotypic overlap between the patients and the mouse knockouts.

Conclusions

Information on the developmental period at which embryonic lethality occurs in the knockout mouse may be used for novel disease gene discovery that helps to prioritise variants in unsolved rare disease cases.