title: Beyond Homozygosity Mapping: Family-Control analysis based on Hamming distance for prioritizing variants in exome sequencing.
abstract: A major challenge in current exome sequencing in autosomal recessive (AR) families is the lack of an effective method to prioritize single-nucleotide variants (SNVs). AR families are generally too small for linkage analysis, and length of homozygous regions is unreliable for identification of causative variants. Various common filtering steps usually result in a list of candidate variants that cannot be narrowed down further or ranked. To prioritize shortlisted SNVs we consider each homozygous candidate variant together with a set of SNVs flanking it. We compare the resulting array of genotypes between an affected family member and a number of control individuals and argue that, in a family, differences between family member and controls should be larger for a pathogenic variant and SNVs flanking it than for a random variant. We assess differences between arrays in two individuals by the Hamming distance and develop a suitable test statistic, which is expected to be large for a causative variant and flanking SNVs. We prioritize candidate variants based on this statistic and applied our approach to six patients with known pathogenic variants and found these to be in the top 2 to 10 percentiles of ranks.
authors.affiliation: 1] Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan [2] Department of Genome Informatics, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Imai
authors.affiliation: Department of Genome Informatics, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nakaya
authors.affiliation: McGill University and Genome Québec Innovation Centre, Montréal, QC H3A 1B1, Canada.
authors.forename: Somayyeh
authors.initials: S
authors.lastname: Fahiminiya
authors.affiliation: McGill University and Genome Québec Innovation Centre, Montréal, QC H3A 1B1, Canada.
authors.forename: Martine
authors.initials: M
authors.lastname: Tétreault
authors.affiliation: McGill University and Genome Québec Innovation Centre, Montréal, QC H3A 1B1, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sakata
authors.affiliation: 1] Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan [2] Department of Medical Biochemistry, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
authors.affiliation: McGill University and Genome Québec Innovation Centre, Montréal, QC H3A 1B1, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.affiliation: Institute of Psychology, Chinese Academy of Sciences, Beijing, China 100101; and Rockefeller University, New York, NY 10065, USA.
authors.forename: Jurg
authors.initials: J
authors.lastname: Ott
mesh_terms: D004247:DNA / Q000032:analysis* / Q000737:chemistry; D059472:Exome / Q000235:genetics*; D005260:Female; D005838:Genotype; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics / Q000473:pathology; D006720:Homozygote; D006801:Humans; D007409:Intestinal Atresia / Q000235:genetics / Q000473:pathology; D008297:Male; D020125:Mutation, Missense; D010013:Osteogenesis Imperfecta / Q000235:genetics / Q000473:pathology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D004247:DNA