title: Revisiting disease genes based on whole-exome sequencing in consanguineous populations.
abstract: Assigning a causal role for genes in disease states is one of the most significant medical applications of human genetics research. The requirement for at least two different pathogenic alleles in the same gene in individuals with a similar phenotype to assign a causal link has not always been fully adhered to, and we now know that even two alleles may not necessarily constitute sufficient evidence. Autozygosity is a rich source of natural "knockout" events by virtue of rendering ancestral loss-of-function (LOF) variants homozygous. In this study, we exploit this phenomenon by examining 523 exomes enriched for autozygosity to call into question previously published disease links for several genes based on the identification of confirmed homozygous LOF variants in the absence of the purported diseases. This study highlights an additional advantage of consanguineous populations in the quest to improve the medical annotation of the human genome.
authors.affiliation: Developmental Genetics Unit, Department of Genetics, King Faisal Specialist Hospital and Research Center, MBC-03, PO BOX 3354, Riyadh, 11211, Saudi Arabia.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Shamia
authors.forename: Ranad
authors.initials: R
authors.lastname: Shaheen
authors.forename: Nouran
authors.initials: N
authors.lastname: Sabbagh
authors.forename: Agaadir
authors.initials: A
authors.lastname: Almoisheer
authors.forename: Anason
authors.initials: A
authors.lastname: Halees
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000483:Alleles; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002648:Child; D057167:Claudins / Q000235:genetics; D017630:Connexins / Q000235:genetics; D003241:Consanguinity; D004745:Enkephalins / Q000235:genetics; D059472:Exome; D015894:Genome, Human; D055106:Genome-Wide Association Study / Q000379:methods*; D006720:Homozygote; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008074:Lipoproteins / Q000235:genetics; D008297:Male; D010641:Phenotype; D011498:Protein Precursors / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D027981:Symporters / Q000235:genetics; D050053:TRPM Cation Channels / Q000235:genetics
chemical_list: C416945:ABCG5 protein, human; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D018528:ATP-Binding Cassette Transporters; D026921:Amino Acid Transport Systems, Neutral; D018797:Cell Cycle Proteins; D057167:Claudins; D017630:Connexins; D004745:Enkephalins; C586301:FAM111B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008074:Lipoproteins; C476731:NLRP12 protein, human; D011498:Protein Precursors; D012097:Repressor Proteins; C485084:SLC36A2 protein, human; D027981:Symporters; D050053:TRPM Cation Channels; C492059:TRPM1 protein, human; C502010:claudin 16; C076275:connexin 30.3; C033660:preproenkephalin; D012697:Serine Endopeptidases; C108493:neurotrypsin