title: PECONPI: a novel software for uncovering pathogenic copy number variations in non-syndromic sensorineural hearing loss and other genetically heterogeneous disorders.
abstract: This report describes an algorithm developed to predict the pathogenicity of copy number variants (CNVs) in large sample cohorts. CNVs (genomic deletions and duplications) are found in healthy individuals and in individuals with genetic diagnoses, and differentiation of these two classes of CNVs can be challenging and usually requires extensive manual curation. We have developed PECONPI, an algorithm to assess the pathogenicity of CNVs based on gene content and CNV frequency. This software was applied to a large cohort of patients with genetically heterogeneous non-syndromic hearing loss to score and rank each CNV based on its relative pathogenicity. Of 636 individuals tested, we identified the likely underlying etiology of the hearing loss in 14 (2%) of the patients (1 with a homozygous deletion, 7 with a deletion of a known hearing loss gene and a point mutation on the trans allele and 6 with a deletion larger than 1 Mb). We also identified two probands with smaller deletions encompassing genes that may be functionally related to their hearing loss. The ability of PECONPI to determine the pathogenicity of CNVs was tested on a second genetically heterogeneous cohort with congenital heart defects (CHDs). It successfully identified a likely etiology in 6 of 355 individuals (2%). We believe this tool is useful for researchers with large genetically heterogeneous cohorts to help identify known pathogenic causes and novel disease genes.
authors.affiliation: Genomics and Computational Biology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Tsai
authors.forename: Micah A
authors.initials: MA
authors.lastname: Berman
authors.forename: Laura K
authors.initials: LK
authors.lastname: Conlin
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Rehm
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Francey
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Deardorff
authors.forename: Jenelle
authors.initials: J
authors.lastname: Holst
authors.forename: Maninder
authors.initials: M
authors.lastname: Kaur
authors.forename: Emily
authors.initials: E
authors.lastname: Gallant
authors.forename: Dinah M
authors.initials: DM
authors.lastname: Clark
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Glessner
authors.forename: Shane T
authors.initials: ST
authors.lastname: Jensen
authors.forename: Struan F A
authors.initials: SF
authors.lastname: Grant
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gruber
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Spinner
authors.forename: Ian D
authors.initials: ID
authors.lastname: Krantz
mesh_terms: D056915:DNA Copy Number Variations; D016326:Extracellular Matrix Proteins / Q000235:genetics; D017353:Gene Deletion; D023281:Genomics / Q000379:methods; D005838:Genotype; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D012984:Software
chemical_list: D016326:Extracellular Matrix Proteins; C112735:USH2A protein, human
keywords: copy number variation; genetic heterogeneity
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