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Abstract

Objectives: Hereditary Hearing Loss (HHL) is a common genetic disorder accounting for at least 60% of prelingual deafness in children. The long tradition of consanguinity, which is widespread among populations of Arabian Peninsula, increases the prevalence of HHL. It is one of the most frequent causes for school failure in Qatar. GJB2 gene plays a worldwide major role in HHL recessive forms while in Qatar it has a minor role thus strongly suggesting the presence of additional causative genes. To overcome the remarkable genetic heterogeneity of HHL in Qatar population, an extremely powerful 2 steps "gene-identification strategy" was designed (Figure 1). STEP1 consists in a screening of 96 HHL genes by targeted re-sequencing (TS). Positive cases contribute to define an accurate molecular epidemiology picture while negative ones undergo STEP2, a combination of linkage studies and whole exome sequencing (WES) or directly to WES (depending on pedigree size). Methods: Ion Torrent (Life Technologies) (400X of mean target coverage and 581.000 Kb of targets size) was used for STEP1 and Illumina genotyping and Ion Proton (Life Technologies) (90X of mean coverage and 60Mb of target size) were used for STEP2. Sequencing variants were annotated/filtered according to standard pipelines. This strategy was applied to a first series of Qatari families. Results: STEP1 characterized 53% of Qatari families with HHL leading to the identification of 20 novel alleles in known HHL genes (i.e. GJB2, P2RX2, TECTA, TMPRSS3, LOXHD1, MYO15A, TMC1, TRIOBP, WFS1). STEP2 had already led to the discovery of 1 new gene (BDP1). The p*2625Gluext*11 mutation resulting in an elongation of 11 residues of the BDP1 protein was identified in a Qatari recessive family and its expression in the inner ear was confirmed by immunohistochemistry. Conclusion: This combined and powerful strategy proved to be very successful by explaining several HHL unsolved cases and by defining an accurate molecular epidemiology picture of Qatari genes/mutations. Moreover, this approach will be used for developing a "Qatari tailored" molecular diagnostic assay opening new important diagnostic perspectives for a such heterogeneous disorder as well as for defining targets for new possible therapeutic interventions

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/content/papers/10.5339/qfarc.2014.HBOP0092
2014-11-18
2019-12-11
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http://instance.metastore.ingenta.com/content/papers/10.5339/qfarc.2014.HBOP0092
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