The added value of WES reanalysis in the field of genetic diagnosis: lessons learned from 200 exomes in the Lebanese population

• Published in: BMC medical genomics Vol. 12; no. 1; p. 11
• Main Authors: Jalkh, Nadine, Corbani, Sandra, Haidar, Zahraa, Hamdan, Nadine, Farah, Elias, Abou Ghoch, Joelle, Ghosn, Rouba, Salem, Nabiha, Fawaz, Ali, Djambas Khayat, Claudia, Rajab, Mariam, Mourani, Chebl, Moukarzel, Adib, Rassi, Simon, Gerbaka, Bernard, Mansour, Hicham, Baassiri, Malek, Dagher, Rawane, Breich, David, Mégarbané, André, Desvignes, Jean Pierre, Delague, Valérie, Mehawej, Cybel, Chouery, Eliane
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 21.01.2019; BioMed Central; BMC
• Subjects: Biochemistry, Molecular Biology; Bioinformatics; Computational biology; Deoxyribonucleic acid; Diagnosis; Disease; DNA; Exome; Exome - genetics; Exome sequencing; Gene mutation; Genes; Genetic aspects; Genetic counseling; Genetic diagnostics; Genetic Diseases, Inborn - diagnosis; Genetic Diseases, Inborn - genetics; Genetic disorders; Genetic diversity; Genetic heterogeneity; Genetic research; Genetic screening; Genetics; Genomes; Genomics; Health aspects; High throughput sequencing; High-Throughput Nucleotide Sequencing; High-throughput screening (Biochemical assaying); Human genetics; Human health and pathology; Humans; Laboratories; Lebanese; Lebanon; Life Sciences; Medical genetics; Medical research; Metabolic disorders; Molecular biology; Molecular Diagnostic Techniques; Mutation; Mutations; Neurodevelopmental disorders; Next-generation sequencing; NGS; Novels; Pathogenicity; Patients; Phenotypes; Phenotypic variations; Technology; Whole Exome Sequencing; Lebanon; Exome; Lebanon; Mutations; High throughput sequencing; NGS; Genetic heterogeneity; Genetic diagnostics
• ISSN: 1755-8794; 1755-8794
• DOI: 10.1186/s12920-019-0474-y

The past few decades have witnessed a tremendous development in the field of genetics. The implementation of next generation sequencing (NGS) technologies revolutionized the field of molecular biology and made the genetic information accessible at a large scale. However, connecting a rare genetic variation to a complex phenotype remains challenging. Indeed, identifying the cause of a genetic disease requires a multidisciplinary approach, starting with the establishment of a clear phenotype with a detailed family history and ending, in some cases, with functional assays that are crucial for the validation of the pathogenicity of a mutation. Two hundred Lebanese patients, presenting a wide spectrum of genetic disorders (neurodevelopmental, neuromuscular or metabolic disorders, etc.), sporadic or inherited, dominant or recessive, were referred, over the last three and a half years, to the Medical Genetics Unit (UGM) of Saint Joseph University (USJ). In order to identify the genetic basis of these diseases, Whole Exome Sequencing (WES), followed by a targeted analysis, was performed for each case. In order to improve the genetic diagnostic yield, WES data, generated during the first 2 years of this study, were reanalyzed for all patients who were left undiagnosed at the genetic level. Reanalysis was based on updated bioinformatics tools and novel gene discoveries. Our initial analysis allowed us to identify the specific genetic mutation causing the disease in 49.5% of the cases, in line with other international studies. Repeated WES analysis enabled us to increase the diagnostics yield to 56%. The present article reports the detailed results of both analysis and pinpoints the contribution of WES data reanalysis to an efficient genetic diagnosis. Lessons learned from WES reanalysis and interpretation are also shared.