Development of strategies for genetic diagnosis of hereditary glomerulopathies, tubulopathies and cystic kidney diseases by the sequencing sets of genes
María Lara Besada Cerecedo1, Noa Carrera Cachaza1, María García Murias1, Ana María Barcia de la Iglesia1, Jorge Amigo Lechuga2, Beatriz Sobrino Rey2, Cándido Díaz Rodríguez3, Miguel Ángel García-González4
1 Laboratorio de Genética y Biología del Desarrollo de las Enfermedades Renales, Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago de Compostela, La Coruña, Spain
2 Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, La Coruña, Spain
3 Servicio de Nefrología, Complexo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, La Coruña, Spain
4 Grupo de Nefrología, Instituto de Investigación Sanitaria de Santiago de Compostela-Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, La Coruña, Spain
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Genetic studies have the advantage of ensuring an accurate diagnosis and anticipate the disease. The implementation of NGS technology into routine genetic diagnostic practices allows the screening of large sets of genes in a single test.</p><p id="par0010" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Methods:</span> Our group, based on the clinical classification, generated different panels for the sequence of renal disease genes in single tests: (1) panel for cystic kidney disease (up to 72 genes); (2) panel for glomerular disease (26 genes), and (3) panel for tubular disease (36 genes). Also, our group solved one of the limitations of conventional pre-designed NGS kits for target enrichment in regions with high homology pseudogenes (such as the <span class="elsevierStyleItalic">PKD1</span> gene) by developing particular primers to amplify specifically the replicated region of <span class="elsevierStyleItalic">PKD1</span> gene (exons 1-34).</p><p id="par0015" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Results:</span> Our technology proved to be more efficient compared to other technologies used in the diagnostic routine. By analyzing a cohort of 291 families with PKD clinical diagnosis, we identified the causal mutation in 88% (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>255) of the families. In 94% (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>240) of these cases the clinical and genetic diagnosis were concordant. Of the 71 patients with a clinical diagnosis of glomerular disease and 31 with tubular disease subjected to genetic analysis, we identified the causal mutation in 62% (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>44) and 52% (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>16) of the cases, respectively. The concordance between genetic and clinical diagnosis was 66% (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>29) for the glomerular cohort and 69% (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>11) for tubular cohort. Most cases of misdiagnosis were associated with syndromic diseases with very similar phenotypes, such as Gitelman and Bartter syndromes.</p><p id="par0020" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Conclusions:</span> The strategy of grouping genes by phenotype for genetic testing probed to be efficient in finding the causal mutation. 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