title: Revisiting the morbid genome of Mendelian disorders.
abstract: The pathogenicity of many Mendelian variants has been challenged by large-scale sequencing efforts. However, many rare and benign "disease mutations" are difficult to analyze due to their rarity. The Saudi Arabian variome is enriched for homozygosity due to inbreeding, a key advantage that can be exploited for the critical examination of previously published variants.
  
  
  
  We collated all "disease-related mutations" listed in the Human Gene Mutation Database (HGMD) and ClinVar, including "variants of uncertain significance" (VOUS). We find that the use of public databases including 1000 Genomes, ExAC, and Kaviar can reclassify many of these variants as likely benign. Our Saudi Human Genome Program (SHGP) can reclassify many variants that are rare in public databases. Furthermore, SGPD allows us to observe many previously reported variants in the homozygous state and our extensive phenotyping of participants makes it possible to demonstrate the lack of phenotype for these variants, thus challenging their pathogenicity despite their rarity. We also find that 18 VOUS BRCA1 and BRCA2 variants that are listed in BRCA Exchange are present at least once in the homozygous state in patients who lack features of Fanconi anemia. Reassuringly, we could reciprocally demonstrate that none of those labeled as "pathogenic" were observed in the homozygous statue in individuals who lack Fanconi phenotype in our database.
  
  
  
  Our study shows the importance of revisiting disease-related databases using public resources as well as of population-specific resources to improve the specificity of the morbid genome of Mendelian diseases in humans.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. mabouelhoda@yahoo.com.|Saudi Human Genome Program, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia. mabouelhoda@yahoo.com.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abouelhoda
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 (KACST), Riyadh, Saudi Arabia.
authors.forename: Tariq
authors.initials: T
authors.lastname: Faquih
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 (KACST), Riyadh, Saudi Arabia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Kalioby
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.|Saudi Human Genome Program, King Abdulaziz City for Science and Technology (KACST), 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: D000483:Alleles; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D003241:Consanguinity; D030541:Databases, Genetic; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D006720:Homozygote; D006801:Humans; D058977:Molecular Sequence Annotation; D009154:Mutation; D012529:Saudi Arabia
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein
keywords: Autozygosity; Disease mutations; Saudi Human Genome Program (SHGP); Variant classification