title: Human RECQ Helicase Pathogenic Variants, Population Variation and "Missing" Diseases.
abstract: Heritable loss of function mutations in the human RECQ helicase genes BLM, WRN, and RECQL4 cause Bloom, Werner, and Rothmund-Thomson syndromes, cancer predispositions with additional developmental or progeroid features. In order to better understand RECQ pathogenic and population variation, we systematically analyzed genetic variation in all five human RECQ helicase genes. A total of 3,741 unique base pair-level variants were identified, across 17,605 potential mutation sites. Direct counting of BLM, RECQL4, and WRN pathogenic variants was used to determine aggregate and disease-specific carrier frequencies. The use of biochemical and model organism data, together with computational prediction, identified over 300 potentially pathogenic population variants in RECQL and RECQL5, the two RECQ helicases that are not yet linked to a heritable deficiency syndrome. Despite the presence of these predicted pathogenic variants in the human population, we identified no individuals homozygous for any biochemically verified or predicted pathogenic RECQL or RECQL5 variant. Nor did we find any individual heterozygous for known pathogenic variants in two or more of the disease-associated RECQ helicase genes BLM, RECQL4, or WRN. Several postulated RECQ helicase deficiency syndromes-RECQL or RECQL5 loss of function, or compound haploinsufficiency for the disease-associated RECQ helicases-may remain missing, as they likely incompatible with life.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Fu
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Alessio
authors.initials: A
authors.lastname: Ligabue
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington.|University of Iowa College of Medicine, Iowa City, Iowa.
authors.forename: Kai J
authors.initials: KJ
authors.lastname: Rogers
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Akey
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington.|Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Monnat
mesh_terms: D019295:Computational Biology / Q000379:methods; D004252:DNA Mutational Analysis; D030561:Databases, Nucleic Acid; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D009154:Mutation; D012372:ROC Curve; D053484:RecQ Helicases / Q000235:genetics*; D012984:Software; D064878:Web Browser
chemical_list: D053484:RecQ Helicases
keywords: Bloom syndrome; RECQ helicase; RECQL; RECQL5; Rothmund-Thomson syndrome; Werner syndrome; compound haploinsufficiency; heritable cancer predisposition; mutation functional prediction; pathogenic variation