title: Autozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretation.
abstract: The purpose of this study is to describe recessive alleles in strictly dominant genes. Identifying recessive mutations in genes for which only dominant disease or risk alleles have been reported can expand our understanding of the medical relevance of these genes both phenotypically and mechanistically. The Saudi population is enriched for autozygosity, which enhances the homozygous occurrence of alleles, including pathogenic alleles in genes that have been associated only with a dominant inheritance pattern.
  
  
  
  Exome sequencing of patients from consanguineous families with likely recessive phenotypes was performed. In one family, the genotype of the deceased children was inferred from their parents due to lack of available samples.
  
  
  
  We describe the identification of 11 recessive variants (5 of which are reported here for the first time) in 11 genes for which only dominant disease or risk alleles have been reported. The observed phenotypes for these recessive variants were novel (e.g., FBN2-related myopathy and CSF1R-related brain malformation and osteopetrosis), typical (e.g., ACTG2-related visceral myopathy), or an apparently healthy state (e.g., PDE11A), consistent with the corresponding mouse knockout phenotypes.
  
  
  
  Our results show that, in the era of genomic sequencing and "reverse phenotyping," recessive variants in dominant genes should not be dismissed based on perceived "incompatibility" with the patient's phenotype before careful consideration.Genet Med advance online publication 06 April 2017.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors.forename: Dorota
authors.identifier: 0000-0001-5785-6799
authors.initials: D
authors.lastname: Monies
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Sateesh
authors.initials: S
authors.lastname: Maddirevula
authors.affiliation: Department of Obstetrics and Gynecology, King Faisal Specialist Hospital, Riyadh, Saudi Arabia.
authors.forename: Wesam
authors.identifier: 0000-0001-7958-8123
authors.initials: W
authors.lastname: Kurdi
authors.affiliation: Department of Internal Medicine, King Saud University Medical City and College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Mohammed H
authors.identifier: 0000-0001-5177-8283
authors.initials: MH
authors.lastname: Alanazy
authors.affiliation: Department of Pathology, King Saud University Medical City and College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Hisham
authors.identifier: 0000-0002-7094-5646
authors.initials: H
authors.lastname: Alkhalidi
authors.affiliation: Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Owain
authors.affiliation: Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Raashda A
authors.identifier: 0000-0002-6868-9823
authors.initials: RA
authors.lastname: Sulaiman
authors.affiliation: Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
authors.forename: Eissa
authors.initials: E
authors.lastname: Faqeih
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors.forename: Ewa
authors.initials: E
authors.lastname: Goljan
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Niema
authors.initials: N
authors.lastname: Ibrahim
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Firdous
authors.initials: F
authors.lastname: Abdulwahab
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Mais
authors.initials: M
authors.lastname: Hashem
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abouelhoda
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Ranad
authors.identifier: 0000-0002-2590-1759
authors.initials: R
authors.lastname: Shaheen
authors.affiliation: Computational Bioscience Research Center (CBRC), Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, audi Arabia.
authors.forename: Stefan T
authors.initials: ST
authors.lastname: Arold
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.|Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000483:Alleles; D001483:Base Sequence; D002648:Child; D002874:Chromosome Mapping; D003241:Consanguinity; D059472:Exome; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005799:Genes, Dominant / Q000235:genetics*; D005808:Genes, Recessive / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing / Q000379:methods; D014644:Genetic Variation / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D012529:Saudi Arabia; D017422:Sequence Analysis, DNA; D000073359:Exome Sequencing / Q000379:methods