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PECONPI: A novel software for uncovering pathogenic copy number variations in non‐syndromic sensorineural hearing loss and other genetically heterogeneous disorders
Author(s) -
Tsai Ellen A.,
Berman Micah A.,
Conlin Laura K.,
Rehm Heidi L.,
Francey Lauren J.,
Deardorff Matthew A.,
Holst Jenelle,
Kaur Maninder,
Gallant Emily,
Clark Dinah M.,
Glessner Joseph T.,
Jensen Shane T.,
Grant Struan F.A.,
Gruber Peter J.,
Hakonarson Hakon,
Spinner Nancy B.,
Krantz Ian D.
Publication year - 2013
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.36038
Subject(s) - sensorineural hearing loss , hearing loss , copy number variation , biology , genetics , genetic heterogeneity , audiology , medicine , gene , phenotype , genome
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 heterogenous 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. © 2013 Wiley Periodicals, Inc.