Abstract
At present, 51 genes are already known to be responsible for Non-Syndromic hereditary Hearing Loss (NSHL), but the knowledge of 121 NSHL-linked chromosomal regions brings to the hypothesis that a number of disease genes have still to be uncovered. To help scientists to find new NSHL genes, we built a gene-scoring system, integrating Gene Ontology, NCBI Gene and Map Viewer databases, which prioritizes the candidate genes according to their probability to cause NSHL. We defined a set of candidates and measured their functional similarity with respect to the disease gene set, computing a score () that relies on the assumption that functionally related genes might contribute to the same (disease) phenotype. A Kolmogorov-Smirnov test, comparing the pair-wise distribution on the disease gene set with the distribution on the remaining human genes, provided a statistical assessment of this assumption. We found at a p-value that the former pair-wise is greater than the latter, justifying a prioritization strategy based on the functional similarity of candidate genes respect to the disease gene set. A cross-validation test measured to what extent the ranking for NSHL is different from a random ordering: adding 15% of the disease genes to the candidate gene set, the ranking of the disease genes in the first eight positions resulted statistically different from a hypergeometric distribution with a p-value and a power . The twenty top-scored genes were finally examined to evaluate their possible involvement in NSHL. We found that half of them are known to be expressed in human inner ear or cochlea and are mainly involved in remodeling and organization of actin formation and maintenance of the cilia and the endocochlear potential. These findings strongly indicate that our metric was able to suggest excellent NSHL candidates to be screened in patients and controls for causative mutations.
Highlights
Non Syndromic hereditary Hearing Loss (NSHL) is one of the most genetically heterogeneous disorders known
All candidate genes were ranked by computing the S S M for each candidate-disease gene pair; the final score used for prioritizing each candidate was obtained as the mean of the scores estimated for that candidate against all the disease genes and was defined Semantic Similarity Measure Average (S S Mavg)
To test these two aspects is equivalent to answer the following question: are the disease genes more functionally related than two generic human genes according to S S M? A positive answer would yield a positive result for both aspects at the same time, implying that the more a candidate gene obtains a high S S M score respect to the disease gene set, the higher is its probability to cause NSHL when mutated
Summary
Non Syndromic hereditary Hearing Loss (NSHL) is one of the most genetically heterogeneous disorders known It can present an autosomal recessive, autosomal dominant, X-linked or mitochondrial pattern of inheritance; mutations in the same gene may cause syndromic or non syndromic hearing loss, and recessive forms may be caused by a combination of two mutations in different genes from the same functional group [1]. About 50% of cases of NSHL are due to mutations of GJB2, a gene coding for a gap-junction protein called connexin 26, involved in the cell-cell communication process Another important gene responsible for NSHL is GJB6, belonging to the same family of GJB2 and adjacent to it. The identification of these two genes highlighted the role of connexins, and of the cochlear gap-junction ion channels, in the auditory function [2,3]
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