title: Identification of embryonic lethal genes in humans by autozygosity mapping and exome sequencing in consanguineous families.
abstract: BACKGROUND
  Identifying genetic variants that lead to discernible phenotypes is the core of Mendelian genetics. An approach that considers embryonic lethality as a bona fide Mendelian phenotype has the potential to reveal novel genetic causes, which will further our understanding of early human development at a molecular level. Consanguineous families in which embryonic lethality segregates as a recessive Mendelian phenotype offer a unique opportunity for high throughput novel gene discovery as has been established for other recessive postnatal phenotypes.
  
  
  RESULTS
  We have studied 24 eligible families using autozygosity mapping and whole-exome sequencing. In addition to revealing mutations in genes previously linked to embryonic lethality in severe cases, our approach revealed seven novel candidate genes (THSD1, PIGC, UBN1, MYOM1, DNAH14, GALNT14, and FZD6). A founder mutation in one of these genes, THSD1, which has been linked to vascular permeability, accounted for embryonic lethality in three of the study families. Unlike the other six candidate genes, we were able to identify a second mutation in THSD1 in a family with a less severe phenotype consisting of hydrops fetalis and persistent postnatal edema, which provides further support for the proposed link between this gene and embryonic lethality.
  
  
  CONCLUSIONS
  Our study represents an important step towards the systematic analysis of "embryonic lethal genes" in humans.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. hshanseldin93@kfshrc.edu.sa.
authors.forename: Hanan E
authors.initials: HE
authors.lastname: Shamseldin
authors.affiliation: Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. mtulbah@kfshrc.edu.sa.
authors.forename: Maha
authors.initials: M
authors.lastname: Tulbah
authors.affiliation: Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. kurdi@kfshrc.edu.sa.
authors.forename: Wesam
authors.initials: W
authors.lastname: Kurdi
authors.affiliation: Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. mahanemer@kfshrc.edu.sa.
authors.forename: Maha
authors.initials: M
authors.lastname: Nemer
authors.affiliation: Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. nalsahan@kfshrc.edu.sa.
authors.forename: Nada
authors.initials: N
authors.lastname: Alsahan
authors.affiliation: Department of Obstetrics and Gynecology, Security Forces Hospital, Riyadh, Saudi Arabia. emardawi@sfh.med.sa.
authors.forename: Elham
authors.initials: E
authors.lastname: Al Mardawi
authors.affiliation: Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. olaali@kfshrc.edu.sa.|Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt. olaali@kfshrc.edu.sa.
authors.forename: Ola
authors.initials: O
authors.lastname: Khalifa
authors.affiliation: Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. amal.alhashem@gmail.com.
authors.forename: Amal
authors.initials: A
authors.lastname: Hashem
authors.affiliation: Department of Obstetrics and Gynecology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. ahmedkurdi1950@gmail.com.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kurdi
authors.affiliation: Department of Obstetrics and Gynecology, College of Medicine, King Saud University, Riyadh, Saudi Arabia. zbabay@hotmail.com.
authors.forename: Zainab
authors.initials: Z
authors.lastname: Babay
authors.affiliation: Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. dbubshait@kfshrc.edu.sa.|Department of Pediatrics, King Fahd Hospital of the University, University of Dammam, Dammam, Saudi Arabia. dbubshait@kfshrc.edu.sa.
authors.forename: Dalal K
authors.initials: DK
authors.lastname: Bubshait
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. nibrahim93@kfshrc.edu.sa.
authors.forename: Niema
authors.initials: N
authors.lastname: Ibrahim
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. fabdulwahab@kfshrc.edu.sa.
authors.forename: Firdous
authors.initials: F
authors.lastname: Abdulwahab
authors.affiliation: Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. rahbeeni@kfshrc.edu.sa.
authors.forename: Zuhair
authors.initials: Z
authors.lastname: Rahbeeni
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. mhashem@kfshrc.edu.sa.
authors.forename: Mais
authors.initials: M
authors.lastname: Hashem
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D002874:Chromosome Mapping; D003241:Consanguinity; D004622:Embryo, Mammalian; D059472:Exome; D005190:Family; D005804:Genes, Lethal; D006720:Homozygote; D006801:Humans; D009154:Mutation; D010375:Pedigree; D017422:Sequence Analysis, DNA