title: VAR-MD: a tool to analyze whole exome-genome variants in small human pedigrees with mendelian inheritance.
abstract: The analysis of variants generated by exome sequencing (ES) of families with rare Mendelian diseases is a time-consuming, manual process that represents one barrier to applying the technology routinely. To address this issue, we have developed a software tool, VAR-MD (http://research.nhgri.nih.gov/software/var-md/), for analyzing the DNA sequence variants produced by human ES. VAR-MD generates a ranked list of variants using predicted pathogenicity, Mendelian inheritance models, genotype quality, and population variant frequency data. VAR-MD was tested using two previously solved data sets and one unsolved data set. In the solved cases, the correct variant was listed at the top of VAR-MD's variant ranking. In the unsolved case, the correct variant was highly ranked, allowing for subsequent identification and validation. We conclude that VAR-MD has the potential to enhance mutation identification using family based, annotated next generation sequencing data. Moreover, we predict an incremental advancement in software performance as the reference databases, such as Single Nucleotide Polymorphism Database and Human Gene Mutation Database, continue to improve.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-1851, USA. sincanm@mail.nih.gov
authors.forename: Murat
authors.initials: M
authors.lastname: Sincan
authors.forename: Dimitre R
authors.initials: DR
authors.lastname: Simeonov
authors.forename: David
authors.initials: D
authors.lastname: Adams
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Markello
authors.forename: Tyler M
authors.initials: TM
authors.lastname: Pierson
authors.forename: Camilo
authors.initials: C
authors.lastname: Toro
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.forename: Cornelius F
authors.initials: CF
authors.lastname: Boerkoel
mesh_terms: D059472:Exome; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D012984:Software; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: D006899:Mixed Function Oxygenases; C019081:fatty acid alpha-hydroxylase; C061901:GLB1 protein, human; D001616:beta-Galactosidase